Author: "Carol Forsblom" - Searchworks@Jio Institute Digital Library Search Results

334 results on '"Carol Forsblom"'

251. Arterial stiffness and vascular complications in patients with type 1 diabetes: the Finnish Diabetic Nephropathy (FinnDiane) Study

Author: Lena M. Thorn, Tomi Peltola, Outi Heikkilä, Luciano Bernardi, Aino Soro-Paavonen, Johan Wadén, Per-Henrik Groop, Daniel Gordin, Ville-Petteri Mäkinen, Carol Forsblom, Markku Saraheimo, Kustaa Hietala, Nina Tolonen, Milla Rosengård-Bärlund, and Laura Salovaara
Subjects: Adult, Male, medicine.medical_specialty, Manometry, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Statistics, Nonparametric, Nephropathy, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Vascular Stiffness, Diabetes mellitus, Internal medicine, medicine, Albuminuria, Humans, Diabetic Nephropathies, Pulse wave velocity, Finland, Type 1 diabetes, business.industry, General Medicine, Diabetic retinopathy, Middle Aged, medicine.disease, 3. Good health, Surgery, Diabetes Mellitus, Type 1, Case-Control Studies, Arterial stiffness, Cardiology, Regression Analysis, Female, business, Diabetic Angiopathies, Retinopathy
Abstract: While patients with type 1 diabetes (T1D) are known to suffer from early cardiovascular disease (CVD), we examined associations between arterial stiffness and diabetic complications in a large patient group with T1D.This study included 807 subjects (622 T1D and 185 healthy volunteers (age 40.6 ± 0.7 versus 41.6 ± 1.2 years; P = NS)). Arterial stiffness was measured by pulse wave analysis from each participant. Furthermore, information on diabetic retinopathy, nephropathy, and CVD was collected. The renal status was verified from at least two out of three urine collections.Patients with T1D without signs of diabetic nephropathy had stiffer arteries measured as the augmentation index (AIx) than age-matched control subjects (17.3% ± 0.6% versus 10.0% ± 1.2%; P0.001). Moreover, AIx (OR 1.08; 95% CI 1.03-1.13; P = 0.002) was associated with diabetic laser-treated retinopathy in patients with normoalbuminuria in a multivariate logistic regression analysis. The same was true for AIx and diabetic nephropathy (1.04 (1.01-1.08); P = 0.004) as well as AIx and CVD (1.06 (1.00-1.12); P = 0.01) in patients with T1D.Arterial stiffness was associated with microvascular and macrovascular complications in patients with T1D.
Published: 2010

252. Many patients with Type 1 diabetes estimate their prandial insulin need inappropriately

Author: Aila J, Ahola, Sari, Mäkimattila, Markku, Saraheimo, Vera, Mikkilä, Carol, Forsblom, Riitta, Freese, and Per-Henrik, Groop
Subjects: Adult, Blood Glucose, Male, Sex Characteristics, Dose-Response Relationship, Drug, Reproducibility of Results, Middle Aged, Postprandial Period, Drug Administration Schedule, Hypoglycemia, Diabetes Mellitus, Type 1, Insulin Infusion Systems, Hyperglycemia, Humans, Hypoglycemic Agents, Insulin, Female, Energy Intake, Finland
Abstract: Many factors contribute to the need for prandial insulin in Type 1 diabetes. However, patients' success in achieving normal postprandial glucose concentration is understudied. The aim of the present study was to determine how often patients with Type 1 diabetes achieve normal postprandial glucose concentrations and to evaluate factors associated with postprandial hypo- and hyperglycemia.Data on food intake, physical activity, insulin administration, and blood glucose concentration were collected using a self-administered questionnaire from 331 patients with Type 1 diabetes (43% men; mean age 49 ± 12 years; mean diabetes duration 32 ± 13 years). Of these, 179 provided data on blood glucose concentrations measured 110-150 min postprandially. One such meal per patient was randomized for analyses.Hypoglycemia (4.0 mmol/L), normoglycemia (4.0-7.9 mmol/L), and hyperglycemia (≥ 8.0 mmol/L) were observed after 23%, 36%, and 41% of meals, respectively. The three postprandial glycemia groups did not differ with respect to the meal composition or the timing of the postprandial blood glucose measurement. In women, postprandial hyperglycemia was associated with shorter diabetes duration and higher preprandial blood glucose concentration, whereas postprandial hypoglycemia was associated with higher physical activity. No single factor explained the postprandial glycemic state in men.A total of 64% of patients estimated their prandial insulin need inappropriately, suggesting that estimation of the optimal prandial insulin dose is not easy, even after a long duration of diabetes.
Published: 2010

253. Genetic polymorphisms in nitric oxide synthase 3 gene and implications for kidney disease: a meta-analysis

Author: Alexander P. Maxwell, Jill Kilner, M. Parkkonen, Theresa A Buckham, Carol Forsblom, Niina Sandholm, Denise M. Sadlier, P. H. Groop, Amy Jayne McKnight, and Christopher Patterson
Subjects: Nos3 gene, medicine.medical_specialty, Nitric Oxide Synthase Type III, Bioinformatics, Polymorphism, Single Nucleotide, Nitric oxide, Diabetic nephropathy, chemistry.chemical_compound, Risk Factors, Internal medicine, mental disorders, medicine, Humans, Diabetic Nephropathies, cardiovascular diseases, Gene, Alleles, Proteinuria, biology, business.industry, medicine.disease, body regions, Nitric oxide synthase, Endocrinology, Diabetes Mellitus, Type 1, chemistry, Nephrology, Meta-analysis, Case-Control Studies, cardiovascular system, biology.protein, medicine.symptom, business, Kidney disease
Abstract: Background/Aims: The NOS3 gene is a biological and positional candidate for diabetic nephropathy. However, the relationship between NOS3 polymorphisms and renal disease is inconclusive. This study aimed to clarify the association of NOS3 variants with nephropathy in individuals with type 1 diabetes. Methods:We conducted a case-control study examining all common SNPs in the NOS3 gene by a tag SNP approach. Individuals with type 1 diabetes and persistent proteinuria (cases, n = 718) were compared with individuals with type 1 diabetes but no evidence of renal disease (controls, n = 749). Our replication collection comprised 1,105 individuals with type 1 diabetes recruited to a nephropathy case group and 862 control individuals with normal urinary albumin excretion rates. Meta-analysis was conducted for SNPs where more than three genotype datasets were available. Results: A novel association was identified in the discovery collection (rs1800783, pgenotype = 0.006, pallele = 0.002, OR = 1.26, 95% CI: 1.08–1.47) and supported by independent replication using a tag SNP (rs4496877, pairwise r2 = 0.96 with rs1800783) in the replication collection (pgenotype = 0.002, pallele = 0.0006, OR = 1.27, 95% CI: 1.10–1.45). Conclusion: The A allele of rs1800783 is a significant risk factor for nephropathy in individuals with type 1 diabetes, and further comprehensive studies are warranted to confirm the definitive functional variant in the NOS3 gene.
Published: 2010

254. Cumulative cost of prescription medication in outpatients with type 1 diabetes in Finland

Author: Carol Forsblom, Raija Lithovius, Valma Harjutsalo, and P.-H. Groop
Subjects: Adult, Male, medicine.medical_specialty, Pediatrics, Endocrinology, Diabetes and Metabolism, Drug Prescriptions, End stage renal disease, Diabetes mellitus, Internal Medicine, Medicine, Humans, In patient, Longitudinal Studies, Vascular Diseases, Medical prescription, Intensive care medicine, Finland, Macrovascular disease, Type 1 diabetes, business.industry, Middle Aged, medicine.disease, Comorbidity, Diabetes Mellitus, Type 1, Cumulative cost, Kidney Failure, Chronic, Female, business
Abstract: We examined the 11-year cumulative outpatient cost of prescription medication in patients with type 1 diabetes by subgroups according to the presence of complications and duration of diabetes.This longitudinal study included a nationally representative cohort of patients with type 1 diabetes (N = 3,717) from the Finnish Diabetic Nephropathy Study (FinnDiane). The data were linked to the Drug Prescription Register. The cumulative cost was calculated between 1998 and 2008. Information on complications was updated until 2008. Patients were divided into 10-year groups according to the duration of diabetes in 1998. Generalised linear mixed models under gamma distribution were used to evaluate the costs.Approximately 25% of the patients had macrovascular disease (MVD) and/or end-stage renal disease (ESRD). The adjusted cumulative cost of medications increased 56% when MVD was present compared with those without complications. In patients with ESRD or with both complications present the cost increased fourfold or 15-fold, respectively, when diabetes medications were excluded. The proportion of renal failure related medications (immunosuppressants, peritoneal dialytics and erythropoietin) accounted for more than 70% of these costs. The cost of diabetes medication was rather stable, irrespective of complication status or duration of diabetes. However, when complications were present these costs were markedly lower in all 10-year duration groups.This study shows that ESRD has a great impact on outpatient prescription medication costs. Since no considerable differences were observed in the cost of diabetes medication, the increase was completely due to the cost of medications related to comorbidity.
Published: 2010

255. Association of the SLC22A1, SLC22A2, and SLC22A3 genes encoding organic cation transporters with diabetic nephropathy and hypertension

Author: R Sallinen, Mari A. Kaunisto, J. Fagerudd, Carol Forsblom, Per-Henrik Groop, Merlin C. Thomas, K. Pettersson-Fernholm, and Maija Wessman
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Organic Cation Transport Proteins, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, SLC22A3, Diabetic nephropathy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Diabetes mellitus, medicine, SNP, Humans, Diabetic Nephropathies, Finland, 030304 developmental biology, 0303 health sciences, Type 1 diabetes, Organic cation transport proteins, biology, Organic Cation Transporter 1, Organic Cation Transporter 2, General Medicine, Middle Aged, medicine.disease, 3. Good health, Endocrinology, Diabetes Mellitus, Type 1, Case-Control Studies, Hypertension, biology.protein, Albuminuria, Female, medicine.symptom
Abstract: Diabetic nephropathy (DN) is a severe long-term complication of diabetes characterized by continuous albuminuria, a relentless decline in renal function, and an increased arterial blood pressure.Our aim was to find out if single nucleotide polymorphisms (SNPs) within the SLC22A1, SLC22A2, and SLC22A3 genes encoding organic cation transporters (OCTs) associate with DN or hypertension.We selected 90 SNPs ( approximately 1 SNP/4 kb) in and surrounding SLC22A1, SLC22A2, and SLC22A3 using the HapMap data. The SNPs were tested for association with DN and hypertension in 1,086 unrelated Finnish patients with type 1 diabetes mellitus (T1DM). Eight of the SNPs were genotyped in 1,252 additional Finnish patients to verify the findings.We detected nominal evidence of association (P0.05) between the SLC22A2 (SNPs rs653753, rs596881, and rs316019) and SLC22A3 (SNPs rs376563, rs2048327, rs2457576, and rs1567438) genes and DN and hypertension in Finnish men with T1DM. We were not, however, able to replicate the associations, and none of them reached the significance limit adjusted for multiple testing (P0.00009).There was no clear association between the SLC22A1, SLC22A2, and SLC22A3 genes and DN or hypertension. Although several SLC22A2 and SLC22A3 SNPs indicated association, lack of association was evident after the replication study.
Published: 2010

256. Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes

Author: Carol Forsblom, Lena M. Thorn, Torben Hansen, P. Høyem, Allan Flyvbjerg, Jakob Appel Østergaard, Johan Wadén, Per-Henrik Groop, and Markku Saraheimo
Subjects: Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, urologic and male genital diseases, Mannose-Binding Lectin, Gastroenterology, Nephropathy, Diabetic nephropathy, Young Adult, Diabetes mellitus, Internal medicine, Internal Medicine, Humans, Medicine, Diabetic Nephropathies, Prospective Studies, Type 1 diabetes, biology, business.industry, Hazard ratio, C-reactive protein, Middle Aged, medicine.disease, C-Reactive Protein, Diabetes Mellitus, Type 1, Endocrinology, biology.protein, Albuminuria, Female, Microalbuminuria, medicine.symptom, business
Abstract: Udgivelsesdato: 2010-Apr-16 AIMS/HYPOTHESIS: Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. METHODS: Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. RESULTS: Both baseline MBL (p = 0.038) and hsCRP (p < 0.001) increased with increasing level of albuminuria. During 5.8 +/- 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06-3.32, p = 0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97-2.51, p = 0.068). CONCLUSIONS/INTERPRETATION: This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes.
Published: 2010
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257. DDOST, PRKCSH and LGALS3, which encode AGE-receptors 1, 2 and 3, respectively, are not associated with diabetic nephropathy in type 1 diabetes

Author: M. Parkkonen, A. Hoverfelt, R Sallinen, Per-Henrik Groop, Jenny Söderlund, Carol Forsblom, K. Pettersson-Fernholm, and Maija Wessman
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, Galectin 3, Receptor for Advanced Glycation End Products, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Diabetic nephropathy, Polymorphism (computer science), Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Diabetic Nephropathies, Genetic Predisposition to Disease, Receptors, Immunologic, Genetic association, Type 1 diabetes, PRKCSH, Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Middle Aged, medicine.disease, Endocrinology, Diabetes Mellitus, Type 1, Hexosyltransferases, Female, Glucosidases, Kidney disease
Abstract: The AGE receptors 1, 2 and 3, which are encoded by DDOST, PRKCSH and LGALS3, respectively, may be involved in the pathogenesis of diabetic complications. We sought to find out whether these genes are associated with diabetic nephropathy, cardiovascular disease and type 1 diabetes or related quantitative traits. Using the Tagger program, we selected 28 single nucleotide polymorphisms (SNPs) based on the HapMap Centre d’Etude du Polymorphisme (Utah residents with northern and western European ancestry) data. The SNPs were genotyped in 2,719 Finnish patients with type 1 diabetes and tested for association with diabetic nephropathy (821 cases, 1,060 controls), cardiovascular disease and related quantitative traits. For association analysis with type 1 diabetes, 703 non-diabetic control participants were genotyped. We found evidence of genotype association between diabetic nephropathy and the SNPs rs2170336 in DDOST (p = 0.03), rs311788 in PRKCSH (p = 0.04) and rs311778 in PRKCSH (p = 0.02). However, these associations did not reach the significance limit of 0.0008 adjusted for multiple testing. None of the DDOST, PRKCSH or LGALS3 SNPs were associated with quantitative traits related to diabetic nephropathy, including AER and estimated GFR. No associations were found between the SNPs and cardiovascular disease, blood pressure, serum lipid levels or type 1 diabetes. The common SNPs tested in DDOST, PRKCSH and LGALS3 do not seem to be associated with diabetic micro- or macrovascular complications or with type 1 diabetes in Finnish patients.
Published: 2009

258. Effects of long-term fenofibrate treatment on markers of renal function in type 2 diabetes: the FIELD Helsinki substudy

Author: Carol, Forsblom, Anne, Hiukka, Eeva S, Leinonen, Jouko, Sundvall, Per-Henrik, Groop, and Marja-Riitta, Taskinen
Subjects: Blood Glucose, Male, Clinical Care/Education/Nutrition/Psychosocial Research, Blood Pressure, Middle Aged, urologic and male genital diseases, Kidney, Kidney Function Tests, Prognosis, Placebos, Diabetes Mellitus, Type 2, Fenofibrate, Creatinine, Albuminuria, Humans, Female, Triglycerides, Aged, Glomerular Filtration Rate, Hypolipidemic Agents, Original Research
Abstract: OBJECTIVE Although fenofibrate was associated with less progression of albuminuria in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, it is unknown if it has any effect on renal function. We explored if there were changes in commonly available markers of renal function during fenofibrate treatment in the FIELD Helsinki cohort excluding statin users. RESEARCH DESIGN AND METHODS One hundred and seventy subjects with type 2 diabetes were randomly assigned to micronized fenofibrate (200 mg/day) or placebo for 5 years. In this substudy, we measured several markers of albumin excretion and renal function. RESULTS After intensified treatment, blood pressure and fasting glucose decreased in both groups while A1C remained at 7.2%. Plasma creatinine increased with fenofibrate while urine creatinine remained comparable between the groups, resulting in significant decreases in both creatinine clearance and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD)-4 and Cockroft-Gault equations in the fenofibrate group. Cystatin C increased during fenofibrate treatment. Urinary albumin-to-creatinine ratio and diurnal urine protein remained unchanged, whereas overnight urinary albumin excretion rate showed minor decreases in both groups. CONCLUSIONS We report concomitant decreases in creatinine clearance and eGFR by fenofibrate. These changes complicate the clinical surveillance during fenofibrate treatment. We could not demonstrate the beneficial effects of fenofibrate on albumin excretion. A novel finding is the increase of cystatin C in type 2 diabetic patients during fenofibrate treatment. The clinical relevance of the changes needs to be assessed in a long-term outcome study of renal function.
Published: 2009

259. Network of vascular diseases, death and biochemical characteristics in a set of 4,197 patients with type 1 diabetes (The FinnDiane Study)

Author: Kimmo Kaski, Lena M. Thorn, Mika Ala-Korpela, Per-Henrik Groop, Johan Wadén, Ville-Petteri Mäkinen, and Carol Forsblom
Subjects: Male, medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, Biochemical Phenomena, Endocrinology, Diabetes and Metabolism, Disease, chemistry.chemical_compound, Internal medicine, Diabetes mellitus, medicine, Humans, Diabetic Nephropathies, Vascular Diseases, Mortality, Finland, Original Investigation, Macrovascular disease, Creatinine, Type 1 diabetes, business.industry, medicine.disease, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Blood pressure, chemistry, lcsh:RC666-701, Female, business, Cardiology and Cardiovascular Medicine, Metabolic Networks and Pathways, Retinopathy, Kidney disease
Abstract: Background Cardiovascular disease is the main cause of premature death in patients with type 1 diabetes. Patients with diabetic kidney disease have an increased risk of heart attack or stroke. Accurate knowledge of the complex inter-dependencies between the risk factors is critical for pinpointing the best targets for research and treatment. Therefore, the aim of this study was to describe the association patterns between clinical and biochemical features of diabetic complications. Methods Medical records and serum and urine samples of 4,197 patients with type 1 diabetes were collected from health care centers in Finland. At baseline, the mean diabetes duration was 22 years, 52% were male, 23% had kidney disease (urine albumin excretion over 300 mg/24 h or end-stage renal disease) and 8% had a history of macrovascular events. All-cause mortality was evaluated after an average of 6.5 years of follow-up (25,714 patient years). The dataset comprised 28 clinical and 25 biochemical variables that were regarded as the nodes of a network to assess their mutual relationships. Results The networks contained cliques that were densely inter-connected (r > 0.6), including cliques for high-density lipoprotein (HDL) markers, for triglycerides and cholesterol, for urinary excretion and for indices of body mass. The links between the cliques showed biologically relevant interactions: an inverse relationship between HDL cholesterol and the triglyceride clique (r < -0.3, P < 10-16), a connection between triglycerides and body mass via C-reactive protein (r > 0.3, P < 10-16) and intermediate-density cholesterol as the connector between lipoprotein metabolism and albuminuria (r > 0.3, P < 10-16). Aging and macrovascular disease were linked to death via working ability and retinopathy. Diabetic kidney disease, serum creatinine and potassium, retinopathy and blood pressure were inter-connected. Blood pressure correlations indicated accelerated vascular aging in individuals with kidney disease (P < 0.001). Conclusion The complex pattern of links between diverse characteristics and the lack of a single dominant factor suggests a need for multifactorial and multidisciplinary paradigms for the research, treatment and prevention of diabetic complications.
Published: 2009

260. A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes

Author: Lena M. Thorn, Johan Wadén, Markku Saraheimo, Carol Forsblom, Per-Henrik Groop, and Daniel Gordin
Subjects: Adult, Male, medicine.medical_specialty, Complications, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Blood Pressure, Diabetic angiopathy, Diabetic nephropathy, Predictive Value of Tests, Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, Medicine, Albuminuria, Humans, Diabetic Nephropathies, Finland, Glycated Hemoglobin, Type 1 diabetes, Autoanalysis, business.industry, Patient Selection, Hazard ratio, Middle Aged, medicine.disease, Lipids, Surgery, Survival Rate, Diabetes Mellitus, Type 1, Glucose, Cardiovascular Diseases, Cardiology, Kidney Failure, Chronic, Microalbuminuria, Female, Original Article, medicine.symptom, business, Biomarkers, Diabetic Angiopathies, Kidney disease, Follow-Up Studies
Abstract: OBJECTIVE Recent data from the Diabetes Control and Complications Trial (DCCT) indicated that A1C variability is associated with the risk of diabetes microvascular complications. However, these results might have been influenced by the interventional study design. Therefore, we investigated the longitudinal associations between A1C variability and diabetes complications in patients with type 1 diabetes in the observational Finnish Diabetic Nephropathy (FinnDiane) Study. RESEARCH DESIGN AND METHODS A total of 2,107 patients in the FinnDiane Study had complete data on renal status and serial measurements of A1C from baseline to follow-up (median 5.7 years), and 1,845 patients had similar data on cardiovascular disease (CVD) events. Intrapersonal SD of serially measured A1C was considered a measure of variability. RESULTS During follow-up, 10.2% progressed to a higher albuminuria level or to end-stage renal disease, whereas 8.6% had a CVD event. The SD of serial A1C was 1.01 versus 0.75 (P < 0.001) for renal status and 0.87 versus 0.79 (P = 0.023) for CVD in progressors versus nonprogressors, respectively. In a Cox regression model, SD of serial A1C was independently associated with progression of renal disease (hazard ratio 1.92 [95% CI 1.49–2.47]) and of a CVD event (1.98 [1.39–2.82]) even when adjusting for mean A1C and traditional risk factors. Interestingly for CVD, mean serial A1C itself was not predictive even though SD of A1C was. CONCLUSIONS In patients with type 1 diabetes, A1C variability was not only predictive of incident microalbuminuria and progression of renal disease but also of incident CVD events.
Published: 2009

261. Telomere length and progression of diabetic nephropathy in patients with type 1 diabetes

Author: Frej Fyhrquist, Per-Henrik Groop, A. Tiitu, Outi Saijonmaa, and Carol Forsblom
Subjects: Adult, Male, medicine.medical_specialty, Gastroenterology, Diabetic nephropathy, Predictive Value of Tests, Diabetes mellitus, Internal medicine, Internal Medicine, Leukocytes, Medicine, Albuminuria, Humans, Diabetic Nephropathies, Finland, Type 1 diabetes, Proteinuria, business.industry, Middle Aged, Telomere, medicine.disease, Endocrinology, Diabetes Mellitus, Type 1, Predictive value of tests, Disease Progression, Microalbuminuria, Female, medicine.symptom, business, Kidney disease
Abstract: Fyhrquist F, Tiitu A, Saijonmaa O, Forsblom C, Groop P-H, on behalf of the FinnDiane Study Group (Minerva Institute for Medical Research; Helsinki University Central Hospital; and Folkhalsan Institute of Genetics; Helsinki, Finland). Telomere length and progression of diabetic nephropathy in patients with type 1 diabetes. J Intern Med 2010; 267: 278–286. Objectives. To determine whether short telomere length of blood leucocytes from patients with type 1 diabetes is associated with or predictive of progression of diabetic nephropathy. Design and methods. Two consecutive DNA samples were obtained from 132 patients from the nationwide Finnish Diabetic Nephropathy Study with type 1 diabetes. Control DNA samples were taken from 44 healthy blood donors. Telomere length was measured by Southern blot. Patients were divided into three groups according to their urinary albumin excretion rate (AER): 48 patients with normoalbuminuria (AER
Published: 2009

262. Serum lipopolysaccharide activity is associated with the progression of kidney disease in finnish patients with type 1 diabetes

Author: Markku Lehto, Per-Henrik Groop, Anita M. Tuomainen, Carol Forsblom, Pirkko J. Pussinen, and Mariann Nymark
Subjects: Adult, Lipopolysaccharides, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Gastroenterology, Nephropathy, Diabetic nephropathy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Insulin resistance, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Diabetic Nephropathies, Prospective Studies, Age of Onset, Pathophysiology/Complications, Finland, 030304 developmental biology, Original Research, Advanced and Specialized Nursing, 0303 health sciences, Type 1 diabetes, business.industry, Middle Aged, medicine.disease, Endocrinology, Diabetes Mellitus, Type 1, Microalbuminuria, Female, Kidney Diseases, Metabolic syndrome, business, Kidney disease
Abstract: OBJECTIVE The aim of the study was to investigate whether serum lipopolysaccharide (LPS) activities are associated with the progression of kidney disease in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS For this prospective study, we chose 477 Finnish patients with type 1 diabetes, who were followed for 6 years. At the baseline visit, 239 patients had a normal albumin excretion rate (normoalbuminuria) and 238 patients had macroalbuminuria. Patients were further divided into nonprogressors and progressors based on their albumin excretion rate at follow-up. Eighty normoalbuminuric patients had developed microalbuminuria, and 79 macroalbuminuric patients had progressed to end-stage renal disease. Serum LPS activity was determined with the Limulus amoebocyte lysate chromogenic end point assay. RESULTS Serum LPS activity was significantly higher in the macroalbuminuric group than in the normoalbuminuric group (P < 0.001). Notably, normoalbuminuric progressor patients had a significantly higher LPS activity at baseline than normoalbuminuric nonprogressor patients (median 49 [interquartile range 34–87] vs. 39 [29–54] EU/ml; P = 0.001). The normoalbuminuric progressor patients exhibited features of the metabolic syndrome with higher triglyceride concentrations and lower estimated glucose disposal rate. A high LPS-to-HDL ratio was associated with the progression of kidney disease in both groups. Insulin resistance (P < 0.001) and serum LPS activity (P = 0.026) were independent risk factors of disease development, when A1C was removed from the regression analysis. CONCLUSIONS High serum LPS activity is associated with the development of diabetic nephropathy in Finnish patients with type 1 diabetes.
Published: 2009

263. Adult stature and diabetes complications in patients with type 1 diabetes: the FinnDiane Study and the diabetes control and complications trial

Author: Johan, Wadén, Carol, Forsblom, Lena M, Thorn, Markku, Saraheimo, Milla, Rosengård-Bärlund, Outi, Heikkilä, Kustaa, Hietala, Ken, Ong, Nicholas, Wareham, and Per-Henrik, Groop
Subjects: Adult, Glycated Hemoglobin, Male, Diabetic Retinopathy, Complications, Middle Aged, Body Height, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Cardiovascular Diseases, Albuminuria, Humans, Diabetic Nephropathies, Female, Original Article, Age of Onset, Diabetic Angiopathies, Finland
Abstract: OBJECTIVE Short adult stature has previously been associated with cardiovascular disease, but its relationship with the microvascular complications of diabetes is uncertain. Therefore, we evaluated the association between adult stature and prevalence and incidence of diabetic microvascular complications. RESEARCH DESIGN AND METHODS This cross-sectional and longitudinal study comprises 3,968 adult patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and 1,246 adult patients from the Diabetes Control and Complications Trial (DCCT). In FinnDiane, diabetic nephropathy was defined as urinary albumin excretion ≥300 mg/24 h, dialysis, or renal transplantation. Retinopathy was divided into background and proliferative (laser-treated) retinopathy. In the DCCT, original nephropathy (class 1–6) and retinopathy (Early Treatment of Diabetic Retinopathy Study) classifications were used. RESULTS In the FinnDiane study, patients in the lowest quartile of adult height had increased risks of prevalent diabetic nephropathy (odds ratio [OR] 1.71, 95% CI 1.44–2.02) and prevalent laser-treated retinopathy (1.66, 1.43–1.93) compared with other patients. Similarly, in the DCCT, patients in the lowest quartile of adult height had increased risks of incident diabetic nephropathy class 4–6 (hazard ratio 2.70, 95% CI 1.59–4.59) and incident proliferative retinopathy (2.06, 1.15–3.71). In the FinnDiane study, the associations were largely explained by childhood exposure to diabetes. However, in the DCCT, where a greater proportion of patients had diabetes onset >18 years, the association with nephropathy was independent of childhood diabetes exposure. CONCLUSIONS Short adult stature is associated with microvascular complications in patients with type 1 diabetes. These findings are compatible with either childhood diabetes exposure or “common soil” or both as potential explanations.
Published: 2009

264. Estimation of VLDL, IDL, LDL, HDL2, apoA-I, and apoB from the Friedewald inputs--apoB and IDL, but not LDL, are associated with mortality in type 1 diabetes

Author: Markku J. Savolainen, Minna L. Hannuksela, Yrjö Hiltunen, Jaakko Niemi, Marja-Riitta Taskinen, Petri T. Kovanen, Ville-Petteri Mäkinen, M. Ala-Korpela, Y. Antero Kesäniemi, Kimmo Kaski, Per-Henrik Groop, Leena Tenkanen, Carol Forsblom, Jukka Heikkonen, and Matti Jauhiainen
Subjects: medicine.medical_specialty, Very low-density lipoprotein, Apolipoprotein B, Lipoproteins, 030204 cardiovascular system & hematology, Risk Assessment, Unmet needs, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Triglycerides, 030304 developmental biology, Lipoprotein cholesterol, Dyslipidemias, 0303 health sciences, Type 1 diabetes, Models, Statistical, Plasma samples, biology, Cholesterol, business.industry, General Medicine, medicine.disease, 3. Good health, Endocrinology, Diabetes Mellitus, Type 1, chemistry, Cardiovascular Diseases, biology.protein, Regression Analysis, lipids (amino acids, peptides, and proteins), business, Algorithms, Lipoprotein
Abstract: There is an unmet need for a straightforward and cost-effective assessment of multiple lipoprotein risk factors for vascular diseases.1) To study the relation of various lipoprotein lipid and apolipoprotein (apo) measures on the Friedewald inputs, i.e. plasma triglycerides (TG), cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). 2) To build up regression models for the appropriate measures based solely on the Friedewald inputs.Data were available for 1,775 plasma samples, from which very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL were also isolated by ultracentrifugation. For HDL(2)-C and apolipoproteins, 343 and 247 samples were available, respectively.Accurate models were obtained for VLDL-TG (cross-validation r=0.98), LDL-C (r=0.91), HDL(2)-C (r=0.92), apoA-I (r=0.92), and apoB (r=0.95). A semi-quantitative model was obtained for IDL-C (r=0.78). Due to the anticipated role of IDL-C in atherosclerosis, it was still kept within the accepted models and pursued further. The associations of the estimates with premature deaths were studied in 4,084 patients with type 1 diabetes. The associations of IDL-C and LDL-C were markedly different, the best predictors of mortality being apoB, apoB to apoA-I ratio, and IDL-C.The new models allow identification of clinically relevant lipoprotein profiles with no added cost to the conventional Friedewald formula.
Published: 2009

265. Early autonomic dysfunction in type 1 diabetes: a reversible disorder?

Author: C G af Björkesten, M. Mäntysaari, Johan Wadén, Per-Henrik Groop, Carol Forsblom, Luciano Bernardi, Milla Rosengård-Bärlund, H. Lindholm, and J. Fagerudd
Subjects: Adult, Male, medicine.medical_specialty, Diabetic neuropathy, Endocrinology, Diabetes and Metabolism, Blood Pressure, Baroreflex, Organic disease, Autonomic Nervous System, Young Adult, Diabetic Neuropathies, Heart Rate, Internal medicine, Diabetes mellitus, Heart rate, Internal Medicine, medicine, Heart rate variability, Humans, Type 1 diabetes, business.industry, medicine.disease, Blood pressure, Endocrinology, Diabetes Mellitus, Type 1, Cardiology, Female, business
Abstract: Cardiac autonomic neuropathy is associated with increased morbidity and mortality rates in patients with type 1 diabetes. The prevalence of early autonomic abnormalities is relatively high compared with the frequency of manifest clinical abnormalities. Thus, early autonomic dysfunction could to some extent be functional and might lead to an organic disease in a subgroup of patients only. If this is true, manoeuvres such as slow deep-breathing, which can improve baroreflex sensitivity (BRS) in normal but not in denervated hearts, could also modify autonomic modulation in patients with type 1 diabetes, despite autonomic dysfunction. We compared 116 type 1 diabetic patients with 36 matched healthy control participants and 12 heart-transplanted participants with surgically denervated hearts. Autonomic function tests and spectral analysis of heart rate and blood pressure variability were performed. BRS was estimated by four methods during controlled (15 breaths per minute) and slow deep-breathing (six breaths per minute), and in supine and standing positions. Conventional autonomic function tests were normal, but resting spectral variables and BRS were reduced during normal controlled breathing in patients with type 1 diabetes. However, slow deep-breathing improved BRS in patients with type 1 diabetes, but not in patients with surgically denervated hearts. Standing induced similar reductions in BRS in diabetic and control participants. Although we found signs of increased sympathetic activity in patients with type 1 diabetes, we also observed a near normalisation of BRS with a simple functional test, indicating that early autonomic derangements are to a large extent functional and potentially correctable by appropriate interventions.
Published: 2009

266. Mutation in the HNF-4alpha gene affects insulin secretion and triglyceride metabolism

Author: Ylva Wessman, Carol Forsblom, P O Bitzén, B Isomaa, Leif Groop, Tiinamaija Tuomi, Marja-Riitta Taskinen, M Lehto, and C Wipemo
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Biology, medicine.disease_cause, chemistry.chemical_compound, Internal medicine, Insulin Secretion, Internal Medicine, medicine, Humans, Insulin, Triglyceride metabolism, Gene, Transcription factor, Triglycerides, Pancreatic hormone, Aged, Mutation, Triglyceride, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Metabolism, Middle Aged, Phosphoproteins, DNA-Binding Proteins, Endocrinology, Diabetes Mellitus, Type 2, Hepatocyte Nuclear Factor 4, chemistry, Female, Transcription Factors
Published: 1999
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267. Effect of parental type 2 diabetes on offspring with type 1 diabetes

Author: Johan Wadén, Per-Henrik Groop, Jenny Söderlund, Jorma Ilonen, Milla Rosengård-Bärlund, Lena M. Thorn, Outi Heikkilä, K. Pettersson-Fernholm, Carol Forsblom, Kustaa Hietala, and Markku Saraheimo
Subjects: Adult, Male, Parents, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Nephropathy, Body Mass Index, Nuclear Family, Diabetic nephropathy, Insulin resistance, Internal medicine, Diabetes mellitus, Surveys and Questionnaires, Internal Medicine, medicine, Humans, Family history, Age of Onset, Epidemiology/Health Services Research, Child, Advanced and Specialized Nursing, Metabolic Syndrome, Type 1 diabetes, business.industry, Middle Aged, medicine.disease, Endocrinology, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Metabolic syndrome, Insulin Resistance, Waist Circumference, business
Abstract: OBJECTIVE—The purpose of this study was to study the association between a parental history of type 2 diabetes and the metabolic profile as well as the presence of the metabolic syndrome and diabetes complications in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—This was a cross-sectional study design in 1,860 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study (620 patients with and 1,240 age-matched patients without a parental history of type 2 diabetes). Information on parental history was received from the type 1 diabetic offspring by a standardized questionnaire. RESULTS—Patients with type 1 diabetes and a positive parental history of type 2 diabetes had a higher prevalence of the metabolic syndrome (44 vs. 38%; P = 0.013) and a metabolic profile related to insulin resistance (higher BMI, larger waist circumference, and higher triglycerides, A1C, and insulin dose per kilogram) and also had a later onset of type 1 diabetes (17.2 ± 9.2 vs. 16.1 ± 8.9 years; P = 0.008), which was also confirmed in the publicly available Diabetes Control and Complications Trial data set. In contrast, no association was observed with blood pressure, diabetes complications, or HLA genotype distribution. Parental history of type 2 diabetes was independently associated with age at onset of type 1 diabetes (odds ratio 1.02 [95% CI 1.01–1.03]), BMI (1.07 [1.02–1.12]), triglycerides (1.18 [1.03–1.35]), and insulin dose per kilogram (1.63 [1.04–2.54]). CONCLUSIONS—Parental history of type 2 diabetes is associated with a later onset of type 1 diabetes, the metabolic syndrome, and a metabolic profile related to insulin resistance.
Published: 2008

268. G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes

Author: François Cambien, Simon Heath, M. Parkkonen, Martin Farrall, Viviane Nicaud, Carol Forsblom, Steven McGinn, Lise Tarnow, David-Alexandre Trégouët, Dominique Gauguier, Fumihiko Matsuda, Roger D. Cox, Michel Marre, Tiphaine Godefroy, Ivo Gut, Stefan Martin Brand-Herrmann, Per-Henrik Groop, Gbenga Kazeem, Nathalie Vionnet, Rachel Rousseau, Hans-Henrik Parving, Mark Lathrop, Anna Hoverfält, Ralph Telgmann, and Samy Hadjadj
Subjects: Candidate gene, Genotype, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Nephropathy, Cell Line, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Risk Factors, Cell Line, Tumor, Internal Medicine, medicine, Genetics, Odds Ratio, Animals, Humans, Diabetic Nephropathies, Genetic Predisposition to Disease, education, Allele frequency, 030304 developmental biology, 0303 health sciences, education.field_of_study, Haplotype, medicine.disease, Introns, 3. Good health, Rats, Diabetes Mellitus, Type 1, Haplotypes, HeLa Cells
Abstract: OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy. RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations. RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29–2.19) (P = 1.0 × 10−4). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30–2.05], P = 2.3 × 10−5). CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.
Published: 2008

269. Acute hyperglycaemia induces an inflammatory response in young patients with type 1 diabetes

Author: Johan Wadén, Per-Henrik Groop, Daniel Gordin, Carol Forsblom, Kustaa Hietala, Mats Rönnback, and Maija Parkkonen
Subjects: Adult, Blood Glucose, Male, endocrine system, medicine.medical_specialty, endocrine system diseases, Inflammation, medicine.disease_cause, Young Adult, Internal medicine, medicine, Humans, Myocardial infarction, Interleukin 6, Macrovascular disease, Type 1 diabetes, biology, business.industry, Interleukin-6, Superoxide Dismutase, Tumor Necrosis Factor-alpha, Case-control study, nutritional and metabolic diseases, Interleukin, General Medicine, medicine.disease, Oxidative Stress, Endocrinology, Diabetes Mellitus, Type 1, Case-Control Studies, Hyperglycemia, Acute Disease, biology.protein, medicine.symptom, business, Oxidative stress
Abstract: Patients with type 1 diabetes (T1D) are at a substantially increased risk of cardiovascular disease. Stress-induced hyperglycaemia in turn is shown to worsen the prognosis of patients suffering from an acute myocardial infarction. However, the mechanisms behind these findings are incompletely known.To investigate whether markers of chronic inflammation, and oxidative stress respond to acute hyperglycaemia in patients with T1D.The plasma glucose concentration was rapidly raised from 5 to 15 mmol/L in 35 males (22 men with T1D and 13 age-matched non-diabetic volunteers) and maintained for 2 h. All participants were young non-smokers without any signs of diabetic or other complications. Markers of chronic inflammation, and oxidative stress were analysed in serum/plasma samples drawn at base-line and after 120 min of hyperglycaemia.Compared to normoglycaemia, acute hyperglycaemia increased the interleukin (IL)-6 concentrations by 39% in patients with T1D (P0.01) and 26% in healthy volunteers (P0.05). During hyperglycaemia the superoxide dismutase concentration was increased by 17% in the healthy volunteers (P0.01) and 5% in the patients with type 1 diabetes (P=NS). The increase in tumour necrosis factor (TNF)-alpha was larger in patients with type 1 diabetes than in non-diabetic volunteers (35% versus -10%, P0.05).This study shows that acute hyperglycaemia induces an inflammatory response in patients with type 1 diabetes.
Published: 2008

270. Metabolic phenotypes, vascular complications, and premature deaths in a population of 4,197 patients with type 1 diabetes

Author: Lena M. Thorn, Carol Forsblom, Daniel Gordin, Kimmo Kaski, Maija Parkkonen, Milla Rosengård-Bärlund, Per-Henrik Groop, Laura Kyllönen, Outi Heikkilä, Johan Wadén, Ville-Petteri Mäkinen, Markku Saraheimo, Mika Ala-Korpela, Nina Tolonen, Janne P. Kytö, and Kustaa Hietala
Subjects: Adult, Male, medicine.medical_specialty, Complications, Endocrinology, Diabetes and Metabolism, Abdominal Fat, 030209 endocrinology & metabolism, High cholesterol, Medical Records, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Obesity, Abdominal obesity, Finland, 030304 developmental biology, Metabolic Syndrome, 0303 health sciences, Type 1 diabetes, Adiponectin, business.industry, Middle Aged, medicine.disease, 3. Good health, Endocrinology, Diabetes Mellitus, Type 1, Phenotype, Multivariate Analysis, Albuminuria, Female, Kidney Diseases, medicine.symptom, Insulin Resistance, business, Energy Metabolism, Diabetic Angiopathies, Kidney disease
Abstract: OBJECTIVE—Poor glycemic control, elevated triglycerides, and albuminuria are associated with vascular complications in diabetes. However, few studies have investigated combined associations between metabolic markers, diabetic kidney disease, retinopathy, hypertension, obesity, and mortality. Here, the goal was to reveal previously undetected association patterns between clinical diagnoses and biochemistry in the FinnDiane dataset. RESEARCH DESIGN AND METHODS—At baseline, clinical records, serum, and 24-h urine samples of 2,173 men and 2,024 women with type 1 diabetes were collected. The data were analyzed by the self-organizing map, which is an unsupervised pattern recognition algorithm that produces a two-dimensional layout of the patients based on their multivariate biochemical profiles. At follow-up, the results were compared against all-cause mortality during 6.5 years (295 deaths). RESULTS—The highest mortality was associated with advanced kidney disease. Other risk factors included 1) a profile of insulin resistance, abdominal obesity, high cholesterol, triglycerides, and low HDL2 cholesterol, and 2) high adiponectin and high LDL cholesterol for older patients. The highest population-adjusted risk of death was 10.1-fold (95% CI 7.3–13.1) for men and 10.7-fold (7.9–13.7) for women. Nonsignificant risk was observed for a profile with good glycemic control and high HDL2 cholesterol and for a low cholesterol profile with a short diabetes duration. CONCLUSIONS—The self-organizing map analysis enabled detailed risk estimates, described the associations between known risk factors and complications, and uncovered statistical patterns difficult to detect by classical methods. The results also suggest that diabetes per se, without an adverse metabolic phenotype, does not contribute to increased mortality.
Published: 2008

271. Serum adiponectin and progression of diabetic nephropathy in patients with type 1 diabetes

Author: Markku, Saraheimo, Carol, Forsblom, Lena, Thorn, Johan, Wadén, Milla, Rosengård-Bärlund, Outi, Heikkilä, Kustaa, Hietala, Daniel, Gordin, Jan, Frystyk, Allan, Flyvbjerg, Per-Henrik, Groop, and I, Rusk
Subjects: Adult, Male, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Urology, Renal function, urologic and male genital diseases, Body Mass Index, Diabetic nephropathy, Predictive Value of Tests, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Albuminuria, Humans, Diabetic Nephropathies, Finland, Advanced and Specialized Nursing, Type 1 diabetes, Adiponectin, business.industry, nutritional and metabolic diseases, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, Endocrinology, Diabetes Mellitus, Type 1, Disease Progression, Kidney Failure, Chronic, Microalbuminuria, Female, medicine.symptom, business, Kidney disease, Follow-Up Studies
Abstract: OBJECTIVE—The purpose of this study was to elucidate whether serum adiponectin is associated with progression of diabetic nephropathy in type 1 diabetic patients. RESEARCH DESIGN AND METHODS—This was a prospective follow-up study as a part of the nationwide Finnish Diabetic Nephropathy Study; 1,330 type 1 diabetic patients were followed for 5.0 ± 2.2 years. Patients were divided at baseline into three groups according to their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: 818 patients with normoalbuminuria (AER RESULTS—Progression either to the next albuminuria level or to end-stage renal disease (ESRD) occurred in 193 patients. No difference in adiponectin concentrations was observed between progressors and nonprogressors in patients with normoalbuminuria or microalbuminuria. In the patients with macroalbuminuria, progression to ESRD was associated with higher adiponectin in the entire group (23.4 ± 17.1 vs. 16.0 ± 8.5 mg/l, P < 0.001) and in men (P < 0.001) and women (P < 0.001) separately. Progression to ESRD was also associated with systolic blood pressure, insulin dose, A1C, serum cholesterol, serum triglycerides, AER, and estimated glomerular filtration rate (eGFR). When these covariates were inserted in a Cox regression analysis, A1C, triglycerides, eGFR, and adiponectin were significantly associated with progression from macroalbuminuria. CONCLUSIONS—Increased serum adiponectin levels predict the progression from macroalbuminuria to ESRD in type 1 diabetic patients.
Published: 2008
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272. Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy

Author: Carol Forsblom, K. Pettersson-Fernholm, Markku Saraheimo, Jan Frystyk, Allan Flyvbjerg, and Per-Henrik Groop
Subjects: Adult, Male, medicine.medical_specialty, alpha-Defensins, Renal function, 030209 endocrinology & metabolism, Type 2 diabetes, Kidney, Nephropathy, Diabetic nephropathy, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Medicine, Albuminuria, Humans, Diabetic Nephropathies, Finland, 030304 developmental biology, 0303 health sciences, Transplantation, Type 1 diabetes, business.industry, medicine.disease, Lipids, Endocrinology, Diabetes Mellitus, Type 1, Nephrology, Linear Models, Microalbuminuria, Female, medicine.symptom, business, Biomarkers, Glomerular Filtration Rate
Abstract: Diabetic nephropathy is associated with low-grade inflammation and activation of the complement system. Defensins, as part of the innate immune system, may play a regulatory role in the complement cascade and may also augment the production of proinflammatory cytokines. The aim of this study was therefore to elucidate whether alpha-defensin is associated with diabetic nephropathy, low-grade inflammation and lipid profiles.Data were obtained from 189 patients with type 1 diabetes selected from the FinnDiane Study. Patients were divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: normoalbuminuria (AER20 microg/min or30 mg/24 h), microalbuminuria (20AER200 microg/min or 30AER300 mg/24 h) and macroalbuminuria (200 microg/min or300 mg/24 h). Alpha-defensin was determined by a novel, solid-phase radioimmunoassay (RIA) based on a monoclonal antibody, which recognizes alpha-defensin isoforms 1-3.Total serum alpha-defensin (-1, -2 and -3) concentrations were higher (P0.001) in patients with macroalbuminuria compared to micro- and normoalbuminuria, but no difference was observed between normoalbuminuria and microalbuminuria. In multiple linear regression analysis alpha-defensin was associated with systolic blood pressure (P = 0.032), HDL-cholesterol (P = 0.013), total cholesterol (P = 0.008), age (P = 0.001) and estimated glomerular filtration rate (P = 0.001), but not with low-grade inflammatory markers. CONCLUSIONS; Serum alpha-defensin (-1, -2 and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy.
Published: 2007

273. Physical activity and diabetes complications in patients with type 1 diabetes: the Finnish Diabetic Nephropathy (FinnDiane) Study

Author: Johan, Wadén, Carol, Forsblom, Lena M, Thorn, Markku, Saraheimo, Milla, Rosengård-Bärlund, Outi, Heikkilä, Timo A, Lakka, Heikki, Tikkanen, and Per-Henrik, Groop
Subjects: Adult, Aged, 80 and over, Adolescent, Middle Aged, Renal Replacement Therapy, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Surveys and Questionnaires, Albuminuria, Humans, Diabetic Nephropathies, Child, Exercise, Diabetic Angiopathies, Finland, Aged
Published: 2007

274. HDL composition predicts new-onset cardiovascular disease in patients with type 1 diabetes

Author: Per-Henrik Groop, Milla Rosengård-Bärlund, Carol Forsblom, Vashti Mills, Maria Rita Taskinen, Stephen Thomas, Merlin C. Thomas, Giancarlo Viberti, and Mats Rönnback
Subjects: medicine.medical_specialty, Time Factors, Medication history, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Outpatient clinic, Humans, Diabetic Nephropathies, Myocardial infarction, Stroke, Finland, Dyslipidemias, Advanced and Specialized Nursing, Type 1 diabetes, business.industry, Vascular disease, Incidence, medicine.disease, Survival Analysis, United Kingdom, 3. Good health, Surgery, Diabetes Mellitus, Type 1, Cardiovascular Diseases, business, Lipoproteins, HDL, Dyslipidemia, Diabetic Angiopathies, Follow-Up Studies
Abstract: Dyslipidemia is independently associated with cardiovascular disease (CVD) in type 1 diabetes (1,2). In this article, we report the specific lipid abnormalities associated with new-onset CVD in an enriched cohort of patients with type 1 diabetes. The study design and selection criteria have been previously described (3,4). Briefly, 153 patients with type 1 diabetes were recruited in the U.K. from the Diabetes outpatient clinics at Guy's and King's College Hospitals ( n = 75) and in Finland from the Helsinki University Central Hospital ( n = 78). Patients were recruited to represent differing degrees of urinary albumin excretion and matched for duration of diabetes and glycemic control. Participants were then followed for a median of 8.8 years, during which time they received standard medical care, including lipid-lowering agents where indicated. Full methods of baseline examination have been published elsewhere (3–6). Briefly, clinical data were obtained from patient records including age, sex, diabetes onset, duration of diabetes, medication history, and the presence of microvascular complications. Lipids and lipid fractions were estimated in fasting samples and processed as previously described (3–6). The study outcome was defined post hoc by the occurrence of a fatal or nonfatal cardiovascular event, including coronary heart disease (myocardial infarction, coronary revascularization, or angioplasty), cerebrovascular disease (stroke), or peripheral vascular disease (amputation associated with large vessel disease) based on clinical records. A total of 148 …
Published: 2007

275. Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy

Author: Maija Wessman, Riika Kilpikari, Per-Henrik Groop, Harry Holthöfer, M. Parkkonen, Mari A. Kaunisto, Pekka Ihalmo, and Carol Forsblom
Subjects: Adult, Male, medicine.medical_specialty, Pathology, genetic structures, Endocrinology, Diabetes and Metabolism, Sialoglycoproteins, Podocyte foot, Biology, Polymorphism, Single Nucleotide, Podocyte, Diabetic nephropathy, Internal medicine, Internal Medicine, medicine, Humans, Actinin, Diabetic Nephropathies, Genetic Predisposition to Disease, Finland, Proteinuria, urogenital system, Podocytes, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Kidney Glomerulus, musculoskeletal system, medicine.disease, Slit, eye diseases, Diaphragm (structural system), Endocrinology, medicine.anatomical_structure, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Slit diaphragm, Female, sense organs, medicine.symptom
Abstract: The slit diaphragm is an adhesion and signalling protein complex linking the interdigitating podocyte foot processes in the kidney glomerulus, and mutations in slit diaphragm-associated genes result in severe proteinuria. Here we report a genetic association analysis of four slit diaphragm genes, LRRC7, KIRREL, NPHS2 and ACTN4, in a Finnish diabetic nephropathy cohort.A total of 40 single nucleotide polymorphisms (SNPs) were genotyped in 1103 patients with type 1 diabetes. The patients were classified according to their renal status, and the genotype data were analysed in a cross-sectional case-control setting. To confirm positive associations, four SNPs were genotyped in 1,025 additional patients with type 1 diabetes.No associations with diabetic nephropathy were observed for any of the analysed SNPs. The SNPs were not associated with the time from the onset of diabetes to the diagnosis of nephropathy or with glomerular filtration rate or AER as quantitative variables. In a sex-specific sub-analysis, the variants rs979972 and rs749701 in the first intron of ACTN4 were nominally associated with diabetic nephropathy in females, with odds ratios of 1.81 (95% CI 1.18-2.79, p = 0.007) and 1.93 (95% CI 1.26-2.96, p = 0.003) respectively.Our study has not found any evidence that common variants in LRRC7, KIRREL, NPHS2 and ACTN4 contribute to susceptibility to diabetic nephropathy in Finnish patients with type 1 diabetes.
Published: 2007

276. Relationship between lipid profiles and kidney function in patients with type 1 diabetes

Author: Milla Rosengård-Bärlund, Carol Forsblom, Marja-Riitta Taskinen, Per-Henrik Groop, K. Pettersson-Fernholm, Outi Heikkilä, Lena M. Thorn, Nina Tolonen, Markku Saraheimo, and Johan Wadén
Subjects: Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Renal function, urologic and male genital diseases, Kidney, Gastroenterology, Nephropathy, Diabetic nephropathy, Cohort Studies, Diabetes mellitus, Internal medicine, Albumins, Internal Medicine, Medicine, Humans, Diabetic Nephropathies, Obesity, Type 1 diabetes, medicine.diagnostic_test, business.industry, Kidney metabolism, Cholesterol, LDL, Middle Aged, medicine.disease, Lipids, Endocrinology, Diabetes Mellitus, Type 1, Hypertension, Female, business, Lipid profile, Kidney disease, Glomerular Filtration Rate
Abstract: We studied the relationship between the lipid profile, estimated GFR (eGFR) and AER in patients with type 1 diabetes. We also assessed the association between the lipid profile and glycaemic control, obesity and hypertension in an environment free of manifest renal disease, as well as exploring how well the patients would have achieved the targets set in international guidelines.A total of 2,927 adult patients who had type 1 diabetes and for whom lipid profiles were available were included from people participating in the nationwide, multicentre Finnish Diabetic Nephropathy Study (FinnDiane). eGFR was determined using the Cockcroft-Gault formula adjusted for body surface area.Patients with impaired renal function (eGFR60 ml min(-1) 1.73 m(-2)) had higher total cholesterol, triacylglycerol and apolipoprotein B, and lower HDL-cholesterol concentrations than patients with normal renal function (eGFR90 ml min(-1) 1.73 m(-2)) or mildly impaired renal function (eGFR 60-90 ml min(-1) 1.73 m(-2)) (p0.001 for all associations). In type 1 diabetic patients without manifest renal disease, similar adverse lipid profiles could be observed in those who were overweight or obese and in those who had intermediate or poor glycaemic control or hypertension. In all the different patient groups 14 to 43% would have achieved the recommended target of2.6 mmol/l for LDL-cholesterol.Multiple lipid abnormalities are not only present in type 1 diabetic patients with an abnormal AER, but also in those with impaired renal function. In patients without manifest renal disease, obesity, glycaemic control or hypertension were associated with an adverse lipid profile. A substantial number of patients studied would have exceeded the targets set by international guidelines, particularly the targets for LDL-cholesterol.
Published: 2007

277. Acute hyperglycaemia rapidly increases arterial stiffness in young patients with type 1 diabetes

Author: Daniel Gordin, Carol Forsblom, Mats Rönnback, Per-Henrik Groop, Outi Heikkilä, and Markku Saraheimo
Subjects: Adult, Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Blood Pressure, Heart Rate, Reference Values, Internal medicine, Diabetes mellitus, Heart rate, Internal Medicine, medicine, Humans, Pulse, Pulse wave velocity, Type 1 diabetes, business.industry, Arteries, Glucose clamp technique, medicine.disease, Pulse pressure, Endocrinology, Blood pressure, Diabetes Mellitus, Type 1, Cardiovascular Diseases, Hyperglycemia, Arterial stiffness, Cardiology, Glucose Clamp Technique, business, Diabetic Angiopathies
Abstract: Augmentation index (AIx) and pulse wave velocity (PWV), both measures of arterial stiffness, constitute risk factors for cardiovascular disease. Notably, hyperglycaemia during an acute cardiovascular event is associated with poor prognosis. The objective of this study was to investigate whether acute hyperglycaemia increases arterial stiffness in patients with type 1 diabetes and in healthy subjects.Twenty-two male patients with type 1 diabetes and thirteen healthy men, who were age-matched non-smokers and without any diabetic complications, underwent a 120 min hyperglycaemic clamp (15 mmol/l). AIx was calculated to assess arterial stiffness. Before and during the clamp, carotid-radial (brachial) and carotid-femoral (aortic) PWV was measured.At baseline there was a difference in the AIx between patients with type 1 diabetes and healthy volunteers (-5 +/- 2.7 vs -20 +/- 2.8%, p0.05). Acute hyperglycaemia rapidly increased AIx in patients with type 1 diabetes (-5 +/- 2.7 vs 8 +/- 2.5%, p0.001) and healthy volunteers (-20 +/- 2.8 vs 6 +/- 8.8%, p0.001). Brachial PWV increased during acute hyperglycaemia in patients with type 1 diabetes (7.1 +/- 1.2 vs 8.0 +/- 1.0 m/s, p0.001), but not in healthy men (7.4 +/- 1.7 vs 7.3 +/- 1.4 m/s, NS).Acute hyperglycaemia increases the stiffness of intermediate-sized arteries and resistance arteries in young patients with type 1 diabetes and consequently emphasises the importance of strict daily glycaemic control. No change was observed in aortic PWV during the clamp, indicating that acute hyperglycaemia does not affect the large vessels.
Published: 2007

278. Leisure-time physical activity is associated with the metabolic syndrome in type 1 diabetes: effect of the PPARgamma Pro12Ala polymorphism: the FinnDiane Study

Author: Johan, Wadén, Lena M, Thorn, Carol, Forsblom, Timo, Lakka, Markku, Saraheimo, Milla, Rosengård-Bärlund, Outi, Heikkilä, Maija, Wessman, Joni A, Turunen, Maija, Parkkonen, Heikki, Tikkanen, and Per-Henrik, Groop
Subjects: Adult, Metabolic Syndrome, PPAR gamma, Alanine, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Leisure Activities, Polymorphism, Genetic, Amino Acid Substitution, Proline, Physical Fitness, Prevalence, Humans
Published: 2007

279. Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway

Author: Sanna Lehtonen, Mariann I. Lassenius, Markku Lehto, Christopher L. Fogarty, Pauliina Saurus, P-H Groop, Harry Holthöfer, Mervi E. Hyvönen, Sara Kuusela, Jukka-Pekka Tienari, Mervi Ristola, Moin A. Saleem, Carol Forsblom, and Eero Lehtonen
Subjects: Lipopolysaccharides, Male, Cancer Research, medicine.medical_specialty, animal structures, Toll-Like Receptor Pathway, p38 mitogen-activated protein kinases, Immunology, 030232 urology & nephrology, Apoptosis, Acetates, Protein Serine-Threonine Kinases, Biology, Podocyte, Diabetic nephropathy, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, Oxazoles, Protein kinase B, PI3K/AKT/mTOR pathway, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, Podocytes, Toll-Like Receptors, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Cell Biology, medicine.disease, Rats, 3. Good health, Diabetes Mellitus, Type 1, medicine.anatomical_structure, Endocrinology, Cancer research, Original Article, Signal transduction, Signal Transduction
Abstract: High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.
Published: 2015
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280. Bacterial infections in patients with type 1 diabetes: a 14-year follow-up study

Author: Johan R Simonsen, Asko Järvinen, Per-Henrik Groop, Carol Forsblom, Juha Kirveskari, Valma Harjutsalo, Markku Lehto, Clinicum, Nefrologian yksikkö, Diabetes and Obesity Research Program, Research Programs Unit, Department of Medicine, Infektiosairauksien yksikkö, Medicum, Department of Bacteriology and Immunology, Department of Diagnostics and Therapeutics, and Per Henrik Groop / Principal Investigator
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, education, Infectious Disease, 030209 endocrinology & metabolism, Glycemic Control, Rate ratio, Nephropathy, Diabetic nephropathy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Diabetes mellitus, medicine, 030212 general & internal medicine, Epidemiology/Health Services Research, Intensive care medicine, Dialysis, Type 1 diabetes, business.industry, medicine.disease, 3. Good health, chemistry, 3121 General medicine, internal medicine and other clinical medicine, Microalbuminuria, Glycated hemoglobin, business
Abstract: Objective This study explored the annual occurrence/incidence of bacterial infections, and their association with chronic hyperglycemia and diabetic nephropathy, in patients with type 1 diabetes. Design In a register-based follow-up study, we investigated the frequency of bacterial infections in patients with type 1 diabetes (n=4748) and age-matched and sex-matched non-diabetic control (NDC) subjects (n=12 954) using nationwide register data on antibiotic drug prescription purchases and hospital discharge diagnoses, collected between 1996 and 2009. Diabetic nephropathy was classified based on the urinary albumin excretion rate (AER). Results The hospitalization rate due to bacterial infections was higher in patients with diabetes compared with NDCs (rate ratio (RR) 2.30 (95% CI 2.11 to 2.51)). The rate correlated with the severity of diabetic nephropathy: RR for microalbuminuria was 1.23 (0.94 to 1.60), 1.97 (1.49 to 2.61) for macroalbuminuria, 11.2 (8.1 to 15.5) for dialysis, and 6.72 (4.92 to 9.18) for kidney transplant as compared to patients with diabetes and normal AER. The annual number of antibiotic purchases was higher in patients with diabetes (1.00 (1.00 to 1.01)) as compared with NDCs (0.47 (0.46 to 0.47)), RR=1.71 (1.65 to 1.77). Annual antibiotic purchases were 1.18-fold more frequent in patients with microalbuminuria, 1.29-fold with macroalbuminuria, 2.43-fold with dialysis, and 2.74-fold with kidney transplant as compared to patients with normal AER. Each unit of increase in glycated hemoglobin was associated with a 6–10% increase in the number of annual antibiotic purchases. Conclusions The incidence of bacterial infections was significantly higher in patients with type 1 diabetes compared with age-matched and sex-matched NDC subjects, and correlated with the severity of diabetic nephropathy in inpatient and outpatient settings.
Published: 2015
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281. Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy

Author: Maria Svensson, Gisela Dahlquist, M. Parkkonen, Per-Henrik Groop, Anna Möllsten, Carol Forsblom, Kerstin Brismar, and Maija Wessman
Subjects: Adult, Genetic Markers, Male, medicine.medical_specialty, Time Factors, Nitric Oxide Synthase Type III, Statistics as Topic, Nitric oxide, Diabetic nephropathy, chemistry.chemical_compound, Risk Factors, Internal medicine, Diabetes mellitus, Surveys and Questionnaires, medicine, Albuminuria, Humans, Diabetic Nephropathies, Finland, Autoimmune disease, Sweden, Type 1 diabetes, Polymorphism, Genetic, biology, business.industry, Smoking, Case-control study, food and beverages, General Medicine, Middle Aged, medicine.disease, Nitric oxide synthase, Endocrinology, Cross-Sectional Studies, Diabetes Mellitus, Type 1, chemistry, Case-Control Studies, biology.protein, Female, business, Kidney disease
Abstract: The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO-production can be affected by polymorphisms in the endothelial NO-synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients.A total of 1510 Finnish and Swedish T1D patients were included in a cross-sectional case-control study. Incipient DN was defined as an albumin excretion rate (AER) of 20-200 microg/min (n = 336). Overt DN = AER200 microg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration 20 years, AER20 microg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27 bp repeat (NOS4ab) and Glu298Asp (rs1799983).Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu-allele of the Glu298Asp-polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12-1.91). The variables smoking (OR = 2.13; 95% CI = 1.63-2.78), male sex (OR = 1.61; 95% CI = 1.23-2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02-1.03), systolic (OR = 1.05; 95% CI = 1.04-1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02-1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a-allele was not associated with DN.The Glu/Glu-genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.
Published: 2006

282. Analysis of 14 candidate genes for diabetic nephropathy on chromosome 3q in European populations: strongest evidence for association with a variant in the promoter region of the adiponectin gene

Author: Nathalie, Vionnet, David, Tregouët, Gbenga, Kazeem, Ivo, Gut, Per-Henrik, Groop, Lise, Tarnow, Hans-Henrik, Parving, Samy, Hadjadj, Carol, Forsblom, Martin, Farrall, Dominique, Gauguier, Roger, Cox, Fumihiko, Matsuda, Simon, Heath, Alexandre, Thévard, Rachel, Rousseau, François, Cambien, Michel, Marre, and Mark, Lathrop
Subjects: Male, Genotype, Chromosome Mapping, Coronary Disease, Polymorphism, Single Nucleotide, White People, Pedigree, Europe, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Gene Frequency, Reference Values, Risk Factors, Humans, Diabetic Nephropathies, Female, Chromosomes, Human, Pair 3, Obesity
Abstract: Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66-0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03-1.32], P = 0.016; 1.46 [1.11-1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86-2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27-0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.
Published: 2006

283. Diagnosing diabetic nephropathy by 1H NMR metabonomics of serum

Author: Maija Parkkonen, Pasi Soininen, Kimmo Kaski, Per-Henrik Groop, Ville-Petteri Mäkinen, Carol Forsblom, Petri Ingman, and Mika Ala-Korpela
Subjects: Male, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Proteome, Biophysics, Early detection, Urine, Gastroenterology, Sensitivity and Specificity, Diabetic nephropathy, Blood serum, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Diabetic Nephropathies, Severe complication, Type 1 diabetes, Radiological and Ultrasound Technology, business.industry, Reproducibility of Results, Nuclear magnetic resonance spectroscopy, Blood Proteins, medicine.disease, Endocrinology, Proton NMR, Female, business, Biomarkers, Blood Chemical Analysis
Abstract: Object: The most severe complication of type 1 diabetes (T1DM) is diabetic nephropathy. It is associated with a high risk of cardiovascular complications and premature death and requires early detection to be efficiently treated. The clinical practice to diagnose diabetic nephropathy is also a non-optimal and tedious set up based on albumin excretion rate in multiple overnight or 24h urine samples. Conversely, in this study, these independent diagnostic data are used to provide a realistic testing case for applying 1H NMR metabonomics of serum in a diagnostic fashion. Materials and Methods: 182 T1DM and 21 non-diabetic (non-T1DM) individuals were studied. The 1H NMR of serum at 500 MHz was targeted at two molecular windows: lipoprotein lipids and low-molecular-weight metabolites. Results: T1DM and non-T1DM individuals were exclusively separated by 1H NMR. For diabetic nephropathy diagnosis in the T1DM patients, 1H NMR data (and clinical biochemistry data) gave a sensitivity of 87.1% (83.9%) and a specificity of 87.7% (95.9%). The predictive values of positive and negative tests were 89.0% (95.5%) and 83.6% (79.2%), respectively. Conclusions: 1H NMR metabonomics clearly distinguishes metabolic characteristics of T1DM and appears approximately as good a means to diagnose diabetic nephropathy from serum as an advanced set of biochemical variables.
Published: 2006

284. Low birth weight does not increase the risk of nephropathy in Finnish type 1 diabetic patients

Author: Clas-Göran af Björkesten, Per-Henrik Groop, Lena M. Thorn, Milla Rosengård-Bärlund, K. Pettersson-Fernholm, Maija Wessman, Johan Wadén, Mats Rönnback, J. Fagerudd, Markku Saraheimo, and Carol Forsblom
Subjects: Male, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Gastroenterology, Fetal Macrosomia, Diabetic nephropathy, 0302 clinical medicine, Pregnancy, Risk Factors, Odds Ratio, Prevalence, Birth Weight, Diabetic Nephropathies, Prospective Studies, Age of Onset, Social Change, Finland, Macrovascular disease, Fetal Growth Retardation, Prenatal Care, 3. Good health, Nephrology, Female, medicine.symptom, Adult, medicine.medical_specialty, Birth weight, Diabetic angiopathy, Risk Assessment, White People, Nephropathy, 03 medical and health sciences, Diabetes mellitus, Internal medicine, medicine, Albuminuria, Humans, Transplantation, Type 1 diabetes, Diabetic Retinopathy, business.industry, Malnutrition, Infant, Newborn, Infant, Low Birth Weight, medicine.disease, Pregnancy Complications, Low birth weight, Endocrinology, Cross-Sectional Studies, Diabetes Mellitus, Type 1, business, Diabetic Angiopathies, Forecasting
Abstract: Background. Low birth weight (LBW) has been linked to renal disease both in animal models and human studies. However, the role of birth weight in the development of diabetic nephropathy is unclear. We, therefore, studied the impact of birth weight on the development of diabetic nephropathy and other related traits, such as diabetic retinopathy and macrovascular disease, in Caucasian type 1 diabetic patients. Methods. Data on size at birth were obtained from original birth certificates in 1543 Finnish patients with type 1 diabetes. The patients were divided into those with low (LBW; below the 10th percentile), normal (NBW; 11–90th percentile) and high birth weight (HBW; above the 90th percentile). Results. Diabetic nephropathy was equally common in the groups with various birth weight (LBW vs NBW vs HBW: 21 vs 20 vs 17%, P ¼ NS). End-stage renal disease (3 vs 5 vs 4%, P ¼ NS), laser-treated retinopathy (31 vs 31 vs 31%, P ¼ NS) and macrovascular disease (5 vs 5 vs 8%, P ¼ NS) were equally prevalent in the various birth weight groups. The time from the onset of diabetes to the onset of diabetic nephropathy was similar irrespective of birth weight (log-rank test; P ¼ NS). Conclusions. Based on our cross-sectional data, LBW does not have an impact on the development of diabetic nephropathy, laser-treated retinopathy or macrovascular disease later in life in Caucasians with type 1 diabetes.
Published: 2006

285. Complex relationship between blood pressure and mortality in type 2 diabetic patients: a follow-up of the Botnia Study

Author: Per-Henrik Groop, Leif Groop, J. Fagerudd, Tiinamaija Tuomi, Bo Isomaa, Mats Rönnback, and Carol Forsblom
Subjects: Male, medicine.medical_specialty, Systole, 030209 endocrinology & metabolism, Blood Pressure, Type 2 diabetes, 030204 cardiovascular system & hematology, Prehypertension, Medical Records, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Diastole, Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Risk factor, Aged, Aged, 80 and over, business.industry, Age Factors, Middle Aged, medicine.disease, 3. Good health, Pulse pressure, Surgery, Blood pressure, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Heart failure, Arterial stiffness, Cardiology, Female, business, Follow-Up Studies
Abstract: The presence of hypertension aggravates the high cardiovascular risk in type 2 diabetic patients. Pulse pressure is a marker of arterial stiffness and constitutes a risk factor for cardiovascular mortality. This study examines the relationship between different blood pressure indices and mortality in a cohort of type 2 diabetic patients. A total of 1294 type 2 diabetic patients with a median age of 69.1 years participated in the Botnia Study from 1990 to 1997. In 2004, after a median follow-up of 9.5 years, data on mortality was collected from the national population registry and hospital records. Systolic and diastolic blood pressure correlated negatively with mortality after adjustment for other risk factors. The association between low systolic and diastolic blood pressure and mortality was pronounced in patients with previous cardiovascular disease. A U-shaped association between pulse pressure and mortality was observed in elderly patients. These observations could be linked to arterial stiffness and heart failure. Low blood pressure in high-risk patients is likely to be a marker of poor health rather than the cause of mortality. The results suggest that the role of blood pressure as a risk marker in elderly type 2 diabetic patients with cardiovascular disease needs to be reevaluated.
Published: 2005

286. Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study)

Author: Lena M, Thorn, Carol, Forsblom, Johan, Fagerudd, Merlin C, Thomas, Kim, Pettersson-Fernholm, Markku, Saraheimo, Johan, Wadén, Mats, Rönnback, Milla, Rosengård-Bärlund, Clas-Göran Af, Björkesten, Marja-Riitta, Taskinen, and Per-Henrik, Groop
Subjects: Adult, Blood Glucose, Male, Metabolic Syndrome, Diabetes Mellitus, Type 1, Prevalence, Albuminuria, Humans, Diabetic Nephropathies, Female, Age of Onset, Kidney Function Tests, Finland
Abstract: The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 diabetic patients and to assess whether it is associated with diabetic nephropathy or poor glycemic control.In all, 2,415 type 1 diabetic patients (51% men, mean age 37 years, duration of diabetes 22 years) participating in the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) study were included. Metabolic syndrome was defined according to the National Cholesterol Education Program diagnostic criteria. Patients were classified as having normal albumin excretion rate (AER) (n = 1,261), microalbuminuria (n = 326), macroalbuminuria (n = 383), or end-stage renal disease (ESRD) (n = 164). Glycemic control was classified as good (HbA1c7.5%), intermediate (7.5-9.0%), or poor (9.0%). Creatinine clearance was estimated with the Cockcroft-Gault formula.The overall prevalence of metabolic syndrome was 38% in men and 40% in women. The prevalence was 28% in those with normal AER, 44% in microalbuminuric patients, 62% in macroalbuminuric patients, and 68% in patients with ESRD (P0.001). Patients with metabolic syndrome had a 3.75-fold odds ratio for diabetic nephropathy (95% CI 2.89-4.85), and all of the separate components of the syndrome were independently associated with diabetic nephropathy. The prevalence of metabolic syndrome was 31% in patients with good glycemic control, 36% in patients with intermediate glycemic control, and 51% in patients with poor glycemic control (P0.001). Similarly, metabolic syndrome increased with worsening creatinine clearance.The metabolic syndrome is a frequent finding in type 1 diabetes and increases with advanced diabetic nephropathy and worse glycemic control.
Published: 2005

287. The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population

Author: Simó Schwartz, Heli Rasinperä, Nabil Enattah, K. Salo, Gabrielle S. Sellick, Heikki Järvinen, Per-Henrik Groop, Hafid Alazzouzi, Richard S. Houlston, Lauri A. Aaltonen, Mecklin Jp, M. Victorzon, James P. Robinson, P. Halonen, Susa Enholm, Irma Järvelä, Carol Forsblom, and Ian Tomlinson
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Colorectal cancer, medicine.medical_treatment, Single-nucleotide polymorphism, Gastroenterology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Lactase activity, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Nutritional Physiological Phenomena, Genotyping, Finland, Aged, Lactase, Neoplasm Staging, 2. Zero hunger, Aged, 80 and over, Colorectal Cancer, business.industry, Odds ratio, Middle Aged, medicine.disease, United Kingdom, 3. Good health, Lactase persistence, Endocrinology, Spain, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, business, Colorectal Neoplasms
Abstract: Background and aims: The role of nutrition in the pathogenesis of colorectal cancer is not fully understood. Milk products are an essential part of human nutrition in Western countries. Absorption of lactose, the main sugar of milk, is regulated by the activity of the lactase enzyme in the gut wall. The activity of lactase is genetically determined and is associated with a C/T single nucleotide polymorphism residing 13910 bp upstream of the lactase coding sequence. Here we have studied the relationship between the C/T −13910 polymorphism and colorectal cancer in Finnish, British, and Spanish populations. Patients and methods: A total of 2766 subjects, including 963 Finnish, 283 British, and 163 Spanish subjects with colorectal cancer, and 773 Finnish, 363 British, and 221 Spanish control subjects, were genotyped for the C/T −13910 variant by polymerase chain reaction minisequencing. Results: The C/C −13910 genotype, which is a robust molecular marker of low lactase activity (lactase non-persistence), was found to significantly associate with the risk of colorectal cancer (p = 0.015) in the Finnish subjects, with an odds ratio of 1.40 (95% confidence interval 1.07–1.85). No association was found with site, histology, or stage of the tumour. No significant risk was detected in the British or Spanish populations. Conclusion: Low lactase enzyme activity, defined by genotyping of the C/T −13910 variant, may increase the risk of colorectal cancer. Further studies are warranted to investigate the role of milk and other dairy products in the pathogenesis of colon cancer in different populations.
Published: 2005

288. Leisure time physical activity is associated with poor glycemic control in type 1 diabetic women: the FinnDiane study

Author: Johan, Wadén, Heikki, Tikkanen, Carol, Forsblom, Johan, Fagerudd, Kim, Pettersson-Fernholm, Timo, Lakka, Mikael, Riska, and Per-Henrik, Groop
Subjects: Adult, Blood Glucose, Glycated Hemoglobin, Male, Sex Characteristics, Diabetic Retinopathy, Reproducibility of Results, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Leisure Activities, Surveys and Questionnaires, Humans, Diabetic Nephropathies, Female, Exercise, Life Style, Diabetic Angiopathies, Finland
Abstract: We studied the association between leisure time physical activity (LTPA) and glycemic control, insulin dose, and estimated glucose disposal rate (eGDR) in type 1 diabetes.This is a cross-sectional study of 1,030 type 1 diabetic patients participating in the Finnish Diabetic Nephropathy Study, a nationwide multicenter study. LTPA was assessed by a validated 12-month questionnaire and expressed in metabolic equivalent (MET) units. Patients were grouped as sedentary (LTPA10 MET h/week, n = 247), moderately active (LTPA 10-40 MET h/week, n = 568), and active (LTPA40 MET h/week, n = 215). Outcome measures were HbA(1c), insulin dose, and eGDR (estimate of insulin sensitivity based on waist-to-hip ratio, hypertension, and HbA(1c)).LTPA correlated with HbA(1c) in women (r = -0.12, P = 0.007) but not in men (r = -0.03, P = 0.592). Sedentary women had higher HbA(1c) than moderately active and active women: 8.8 +/- 1.4% vs. 8.3 +/- 1.4% vs. 8.3 +/- 1.4% (P = 0.004), whereas HbA(1c) in men was 8.4 +/- 1.3% vs. 8.2 +/- 1.4% vs. 8.2 +/- 1.3% (P = 0.774), respectively. In men, insulin doses were 0.74 +/- 0.21 vs. 0.71 +/- 0.20 vs. 0.68 +/- 0.23 IU . kg(-1) . 24 h(-1) (P = 0.003). In both sexes, sedentary patients had lower eGDRs than active patients [median (interquartile range) 5.5 (4.0-8.2) vs. 6.8 (4.7-8.8) vs. 6.7 (4.6-8.6) mg . kg(-1) . min(-1); P0.01 for sedentary vs. others]. Age, obesity, smoking, insulin dose, social class, diabetic nephropathy, or cardiovascular disease did not explain the results.Low levels of LTPA were associated with poor glycemic control in type 1 diabetic women. Men seem to use less insulin when physically active. Increased LTPA levels were associated with increased estimated insulin sensitivity. Longitudinal studies are needed to further clarify the effects of LTPA on type 1 diabetes.
Published: 2005

289. Birth weight is inversely correlated to adult systolic blood pressure and pulse pressure in type 1 diabetes

Author: Johan, Fagerudd, Carol, Forsblom, Kim, Pettersson-Fernholm, Markku, Saraheimo, Johan, Wadén, Mats, Rönnback, Milla, Rosengård-Bärlund, Clas-Göran, Af Björkesten, Lena, Thorn, Maija, Wessman, and Per-Henrik, Groop
Subjects: Adult, Male, medicine.medical_specialty, Systole, Birth weight, Population, Blood Pressure, Prehypertension, Risk Factors, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Birth Weight, Humans, Age of Onset, education, Pulse, Type 1 diabetes, education.field_of_study, Fetal Growth Retardation, business.industry, medicine.disease, Pulse pressure, Endocrinology, Blood pressure, Diabetes Mellitus, Type 1, Hypertension, Albuminuria, Regression Analysis, Female, medicine.symptom, business
Abstract: In the general population, there is an inverse relationship between birth weight and adult systolic blood pressure. Because blood pressure in diabetic patients at least in part seems to be regulated by different mechanisms than in nondiabetic subjects, it is not known whether a similar correlation exists in diabetic individuals. Therefore, we obtained data on birth weight from original birth certificates in 1543 type 1 diabetic patients. Blood pressure was measured auscultatorily on a single occasion. In the 1225 patients born at term (after 37 weeks of gestation), the age- and sex-adjusted regression coefficients between systolic blood pressure and birth weight was −1.90 mm Hg/kg (95% confidence interval [CI], −3.71 to −0.09). The finding remained unchanged after adjustment for body mass index, current smoking, duration of diabetes, social class, antihypertensive therapy, glomerular filtration rate, glycemic control, and elevated albuminuria. The regression coefficient between birth weight and pulse pressure was of a similar magnitude. The age-adjusted regression coefficient between systolic blood pressure and birth weight seemed stronger in females (−3.34 mm Hg/kg; 95% CI, −6.06 to −0.62) than in males (−0.42 mm Hg/kg; 95% CI, −2.80 to 1.95), although this difference was not statistically significant. As a new finding, we report an inverse relationship between weight at birth and systolic blood pressure and pulse pressure in adult type 1 diabetic patients. Given the deleterious effects of elevated arterial blood pressure in diabetes, the impact of intrauterine growth retardation on the development of end-organ damage needs to be clarified.
Published: 2004

290. Altered age-related blood pressure pattern in type 1 diabetes

Author: Mats Rönnback, K. Pettersson-Fernholm, J. Fagerudd, Per-Henrik Groop, Carol Forsblom, and Antti Reunanen
Subjects: Adult, Male, medicine.medical_specialty, Aging, Adolescent, Systole, Population, Hemodynamics, Blood Pressure, Body Mass Index, Diastole, Physiology (medical), Internal medicine, Diabetes mellitus, medicine, Albuminuria, Humans, Diabetic Nephropathies, Age of Onset, education, Antihypertensive Agents, education.field_of_study, Type 1 diabetes, business.industry, Middle Aged, medicine.disease, Pulse pressure, medicine.anatomical_structure, Endocrinology, Blood pressure, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Case-Control Studies, Hypertension, Arterial stiffness, Vascular resistance, Cardiology, Female, Vascular Resistance, Disease Susceptibility, Cardiology and Cardiovascular Medicine, business
Abstract: Background— Pulse pressure (PP) increases with age as a result of arterial stiffening and is a powerful predictor of cardiovascular disease. Type 1 diabetes is associated with excessive cardiovascular mortality and increased arterial stiffness. We examined whether the age-related blood pressure changes in type 1 diabetic patients differ from those of the nondiabetic background population. Methods and Results— We performed a cross-sectional, case-control study of 2988 consecutively selected diabetic subjects and 5486 randomly selected nondiabetic control subjects. Blood pressure was measured twice by mercury sphygmomanometry on a single occasion. Compared with controls, diabetic subjects had a higher systolic blood pressure in all age groups, whereas diastolic blood pressure was higher in those 45 years of age. Consequently, diabetic subjects had a higher PP and a higher prevalence of isolated systolic hypertension. The early age-related rise in PP was more pronounced in subjects with diabetic nephropathy but was also evident in diabetic subjects with normal albumin excretion rate. In a multiple regression analysis, PP in diabetic patients was associated with age, male sex, duration of diabetes, and albuminuria. Conclusions— A higher systolic pressure and an earlier decrease in diastolic pressure result in a higher and more rapidly increasing PP in type 1 diabetic patients. Our findings indicate accelerated arterial aging, which may contribute to the higher cardiovascular morbidity and mortality in these patients.
Published: 2004

291. The genetic variant of lactase persistence C (-13910) T as a risk factor for type I and II diabetes in the Finnish population

Author: Nabil Enattah, Irma Järvelä, Carol Forsblom, Heli Rasinperä, Tiinamaija Tuomi, and Per-Henrik Groop
Subjects: Adult, Male, medicine.medical_specialty, Genotype, medicine.medical_treatment, Medicine (miscellaneous), Single-nucleotide polymorphism, Type 2 diabetes, Biology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Lactase activity, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, Internal medicine, medicine, Diabetes Mellitus, Humans, Finland, 030304 developmental biology, Aged, Lactase, 0303 health sciences, Type 1 diabetes, Nutrition and Dietetics, Genetic Variation, Middle Aged, medicine.disease, Genotype frequency, Lactase persistence, Endocrinology, Genetics, Population, 030211 gastroenterology & hepatology, Female
Abstract: Objective: Lactase persistence (LP), the ability to maintain a high lactase activity throughout life, has been suggested to be a possible risk factor for diabetes. Recently, a single nucleotide polymorphism C (−13910) T, residing 14 kb from the 5′ end of the lactase (LCT) gene was shown to be associated with LP. Here we have studied the relationship between C (13910) T polymorphism and diabetes in the Finnish population. Patients and design: In all, 1455 patients with type I and 615 with type II diabetes and 446 nondiabetic controls in the Finnish population were genotyped for the C (-13910) T polymorphism by PCR minisequencing. Results: No differences were detected in the LP genotype frequencies (CT&TT) between diabetic and nondiabetic subjects. Conclusions: We conclude that the C (−13910) T polymorphism associated with lifelong LP is not a risk factor for type I or type II diabetes in the Finnish population.
Published: 2004

292. Dopamine D3 receptor gene polymorphisms, blood pressure and nephropathy in type 1 diabetic patients

Author: Per-Henrik Groop, K. Pettersson-Fernholm, Markus Perola, J. Fagerudd, and Carol Forsblom
Subjects: Adult, Male, medicine.medical_specialty, Blood Pressure, Nephropathy, Diabetic nephropathy, Diabetic Neuropathies, Internal medicine, Diabetes mellitus, Medicine, Humans, Finland, Transplantation, Type 1 diabetes, Kidney, Proteinuria, Polymorphism, Genetic, business.industry, Receptors, Dopamine D2, Receptors, Dopamine D3, medicine.disease, medicine.anatomical_structure, Endocrinology, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Nephrology, Microalbuminuria, Female, medicine.symptom, business, Kidney disease
Abstract: Background. Dopamine modulates blood pressure in the kidney. The aim of this study was to investigate whether two previously known (� 707 G/C, Ser9Gly) and one novel (Ala17Ala) polymorphism in the dopamine D3 receptor gene and/or their haplotypes are associated with blood pressure, diabetic nephropathy or renal variables in the study subjects. Methods. A cross-sectional, case-control study with a total of 996 type 1 diabetic patients from the multicentre, nationwide FinnDiane Study. Patients were recruited consecutively and classified into four groups according to their renal status. Results. The frequencies of the genotypes harbouring the minor allele were 33, 51 and 19% for the � 707 G/C, Ser9Gly and Ala17Ala polymorphisms, respectively. Frequencies of the � 707 G/C minor genotypes were 35 (normoalbuminuria), 32 (microalbuminuria), 28 (proteinuria) and 39% (end-stage renal disease) (w 2 ¼ 6.3, df ¼ 3, P ¼ 0.1), of the Ser9Gly 52, 51, 46 and 57% (w 2 ¼ 6.3, df ¼ 3, P ¼ 0.1) and of the Ala17Ala polymorphism 18, 19, 19 and 21% (w 2 ¼ 0.7, df ¼ 3, P ¼ 0.9), respectively. Five haplotypes were identified, but no differences were seen between those with and without diabetic nephropathy. Furthermore, there were no differences in blood pressure levels nor in any renal variables between genotypes or haplotypes. Conclusions. These results do not provide evidence for an involvement of the dopamine D3 receptor gene in blood pressure levels or in the pathogenesis of diabetic nephropathy in type 1 diabetic patients.
Published: 2004

293. Implementation of guidelines for the prevention of diabetic nephropathy

Author: Per-Henrik Groop, Carol Forsblom, K. Pettersson-Fernholm, and J. Fagerudd
Subjects: Blood Glucose, medicine.medical_specialty, Quality Assurance, Health Care, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Disease, 030204 cardiovascular system & hematology, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, Medicine, Humans, Diabetic Nephropathies, Finland, Glycemic, Advanced and Specialized Nursing, Type 1 diabetes, business.industry, medicine.disease, 3. Good health, Surgery, Blood pressure, Diabetes Mellitus, Type 1, Albuminuria, medicine.symptom, business, Kidney disease
Abstract: Effective treatment of hyperglycemia, cessation of smoking, and treatment of elevated blood pressure are important means to prevent and retard the progression of diabetic kidney disease in type 1 diabetes (1–4). Guidelines regarding management of these risk factors have become increasingly common, but little is known about how efficiently they are implemented in clinical practice. The national guidelines for the prevention of diabetic nephropathy published in 1991 by the Finnish Diabetes Association state the following: 1 ) aim for strict glycemic control (HbA1c 7.0–7.5%); 2 ) encourage the patient to stop smoking; 3 ) in patients with elevated albuminuria, initiate antihypertensive therapy with ACE inhibitors as first-line agents if blood pressure exceeds 140/90 mmHg, with the target for treatment
Published: 2004

294. Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated with proteinuria, coronary heart disease, and glycemic control in type 1 diabetic patients

Author: Carol Forsblom, Per-Henrik Groop, Markku Koulu, K. Pettersson-Fernholm, Ullamari Pesonen, Jaana Kallio, J. Fagerudd, and Matti K. Karvonen
Subjects: Adult, Blood Glucose, Male, medicine.medical_specialty, Genotype, Proline, Endocrinology, Diabetes and Metabolism, Mutation, Missense, Coronary Disease, Body Mass Index, Diabetic nephropathy, chemistry.chemical_compound, Leucine, Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, Medicine, Humans, Neuropeptide Y, Protein Precursors, Triglycerides, Glycemic, Advanced and Specialized Nursing, Glycated Hemoglobin, Type 1 diabetes, Proteinuria, business.industry, Cholesterol, Diabetic retinopathy, medicine.disease, Neuropeptide Y receptor, Endocrinology, Diabetes Mellitus, Type 1, chemistry, Amino Acid Substitution, Female, medicine.symptom, business
Abstract: OBJECTIVE—Neuropeptide Y is a potent vasoconstrictor thought to enhance the development of atherosclerosis. The leucine 7 to proline 7 (Leu7Pro) polymorphism, located in the signal peptide part of the human preproneuropeptide Y, has been associated with serum lipid levels, intima-media thickness of the common carotid arteries, and diabetic retinopathy in type 2 diabetic patients. Therefore, we investigated the impact of the Leu7Pro polymorphism on diabetic nephropathy, cardiovascular risk factors, and cardiovascular disease in type 1 diabetic patients. RESEARCH DESIGN AND METHODS—A total of 996 patients from the Finnish Diabetic Nephropathy study were studied in a case-control, cross-sectional study. The carrier frequency of the Pro7 substitution was 13% in the entire study population. RESULTS—The Pro7 substitution was more common in patients with proteinuria than in those with a normal albumin excretion rate (16 vs. 11%, P < 0.05). Patients with the Pro7 allele had worse glycemic control (HbA1c 8.8 vs. 8.5%, P < 0.005), more coronary heart disease (CHD) (14 vs. 8%, P < 0.05), and higher serum triglycerides (1.65 vs. 1.35 mmol/l, P < 0.005) than patients with the wild-type genotype. There were no differences in the plasma neuropeptide Y levels between the patients with Pro7 compared with those with the wild-type genotype. The Leu7Pro polymorphism was independently associated with HbA1c (P < 0.001), proteinuria (P < 0.01), and CHD (P < 0.01) in multiple regression analyses. CONCLUSIONS—We conclude that the Leu7Pro polymorphism may contribute to the genetic susceptibility to diabetic nephropathy and CHD in type 1 diabetic patients, possibly by influencing glycemic control and triglycerides.
Published: 2004

295. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Author: S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. Lindsay, M Christoforidou, A Abicht, E Harno, K Cyganek, A Fitchet, S Neelotpol, P Nikishin, P Serradas, J Hinrichsen, M Halvorson, M Chovatia, B Voet, Jinny Willis, E Parretti, M Haslbeck, M Wellard, L Teng, Julio Wainstein, J S Fischer, K. Lalic, D Roggenland, I Gich, R Anwar, Maurizio Cassader, D Serota, X J Li, R J Schotzinger, Vilmundur Gudnason, Björn Zethelius, S A Wootton, W Andrzejewski, R Rezsohazy, R Gao, T Klimentova, T Mazurek, I Bruckner, C Dohrmann, R E James, G daSilva Xavier, Kim S-Y., A Dorca, Stuart J. Pocock, Terri J. Allen, I Giovos, P B Parab, N H Andersen, P Fotinakis, Miriam Cnop, H Lee, Norbert Tennagels, Omorodola I. Abatan, F Ailett, I. Lager, D Manzella, H Hut, Larry A. Distiller, G Lip, Lim S-K., Rong Zhang, T Tsuno, Steen Knudsen, M. Bajardi, Manuel Benito, Dai Sugimoto, Melvin J. Prince, D W Dunstan, D Rankins, K A Majali, G Ozansoy, Isabella Russo, S Uçak, G Annuzzi, R Talar-Wojnarowska, K Lange, S Neugebauer-Baba, Campbell H. Thompson, Eric Renard, P. D. Mountjoy, Z Morrison, Elizabeth A. Davis, Franco Cavallo, C Corvaja, R Antuña, Craig John Currie, H Linnebjerg, He Y-L., A J Palmer, Mariola R. Chacón, H Malinska, M. Jones, R Lichnovská, K Mandes, Paolo Tessari, T Mokhort, A Laina, H. L. Y. Chan, I Schmidt, R Banks, Richard G. IJzerman, L Ksinantova, G Setti, H Vaudry, A Gallo, V Spallone, Chen J-W., Thomas Danne, A Chong, M Hallschmid, S Aczel, S Hulme, N Islam, M Hosoi, P M Ternan, P Di Bartolo, N Bishara, T Shibasaki, Martin A. Osterhoff, Im S-S., M Jecht, T Hamaguchi, S Mattera, K Ways, Elizabeth Northam, U Rajala, Reinhard W. Holl, L Yang, S Panaiotopoulos, K Horvath, R Kluge, Thora B. Bodvarsdottir, Y Dong, Irene Alemanno, C McDougall, Reimar W. Thomsen, M Campbell, W Rabl, John Öhrvik, Yuichiro Yamada, Paola Ungaro, W Benzer, Mike Sampson, Roberto Trevisan, R G Radu, Aas A-M., P E Lobo, Ricardo Scott, S M Son, Josephine M. Forbes, T A Hillier, K L Wyne, Louis L. Nguyen, J Farmer, M H Tan, Kwon H-S., J Yang, L Sandvik, Franco Folli, A K Jenum, M Nguyen, W Pratipanawatr, A L Frederiksen, Rebecca Smith, Lee H-J., A Schäfer, C Manuelli, G S Denver, T Vukovich, B Maceira, K Matsumoto, K. Chokkalingam, Nurcan Üçeyler, P Modi, Timothy M. Morgan, S Mertens, B M Singh, Michaela Riedl, K Iso, C Cucurullo, G. F. Bottazzo, M Calvani, K Hur, J Wetzels, Kazuhiro Takahashi, Y Aso, H Stammer, M G Masding, Fitsum Guebre-Egziabher, J L González-Sánchez, L Armstrong, Alberto Maran, Peter G.F. Swift, S S Popovic, J Starczynski, E Vitacolonna, Luigi Laviola, R W Gelling, Marina Cardellini, D Barilla, Rosa de Diego Martínez, W H Landschulz, Anne Mette Rosenfalck, R K Wong, Kevin E. Schneider, K Peros, Giuseppe Nanni, F Zhang, I Rákóczi, T Iburi, M Nakhjavani, X Q Zhang, S Tournis, Per Lav Madsen, Graham A. Hitman, A. Tura, K Laubner, N D Kostic, Lawrence M. Dolan, R. Sinha Roy, J A Wagner, J. Tuomilehto, J Hauptman, M Abdel-Ghany, D Lacombe, Toralph Ruge, Johannes A Maassen, Triantafyllos Didangelos, K Sasaki, I Argüelles, Klaus Levin, C Popow, Emanuel Christ, R Chetty, L Baillet-Blanco, Jo-Ann Salmon, T Mine, James L. Trevaskis, I Franke, J Gorski, E A Andrianova, A Dayan, A Caballero, Aleksandra Gilis-Januszewska, M Yasujima, Z Kasalová, C.D.A. Stehouwer, F. K. Gorus, G A Nichols, A Glowania, David P. Strachan, P Fredlund, N. F. da Silva, P Reboldi, M Sausbier, K H Groenier, G Stuccio, N Guttman, K R Ahmed, A D Ristic, T Kapellen, J Coutcher, Aldo V. Greco, Oswald Wagner, A Zagayko, Maria Alevizaki, B B Zhang, W F Ferris, Jenny Fredriksson, Lois Jovanovic, J Hänninen, R De Giglio, Kazuo Yagui, O Potterat, P Hamliton, R E Scranton, B Mankovsky, A Stylianou, B Fellström, Abdel-Wahab Yha., M Kitagawa, Katherine L. Baldock, F R Johnson, F Baigts, S D'Addato, F J Sanz, A Mistry, S D Wise, T Pratipanawatr, U R Fölsch, James R.C. Parkinson, Claudia Sommer, C Park, F E Griffiths, M L Martí, R Demirtunc, S Taniguchi, J Lundkvist, T Siegmund, Juan Sztajzel, C Dienesch, F Baumgartner, L Scalone, T M Mckolanis, K Otake, Ullrik Pedersen-Bjergaard, T M Vriesendorp, Michael B. Wheeler, Henry Schmitt, Peter Hovind, S Lange, Stephane Roze, L. Van Gaal, B Klaproth, Anthony E. Civitarese, D Eckland, A Dagar, D F Hopkins, Kari Stefansson, C Gonzalez-Yanes, B Meyboom-de Jong, D. J. Betteridge, K Buhling, M Crepaldi, Ana M. Wägner, L Renna, L Volpe, R McBride, V Corbo, E O Brennesvik, R P Hayes, R Abdollahnia, G Viviani, C F Liew, Francisco Pérez-Bravo, Jeffrey Baron, Brian M. Frier, H H Samira, D Szentendrei, K. J. Schjoedt, W K Waldhäusl, D Gniuli, D Zou, G Tschank, V Urbančič, A L Nolan, Albertini J-P., J Malcomson, M Larbig, C Cheyssac, K Aurich, C M Kesson, S Heller, Maija E. Miettinen, R F Luco, Adrian J. Cameron, Luigi Mattiello, Z. Metelko, X E Zhang, M Parramón, I. G. Obrosova, J Fruchart, M Ilic, Björn Eliasson, Gilles Chatellier, M A Martín, D M Kendall, Holger Luthman, V F Varillas, D Maccubbin, Jang S-A., Amalia Gastaldelli, E Salzsieder, P. de Mol, A Yoshida, H D Lindner, D Gostiljac, M Just, Pan C-Y., J M Fujitaki, G Eiermann, K Bergenheim, A D Frick, A Agacdiken, K Varytimiadis, K Cseh, D A Jackson, S Calderari, Dena G. Hernandez, H M Liebich, K Min, F. de Zegher, Bernd Kulzer, K Han, Ulrich A. Müller, D Marrero, H Hatakeyama, René Koopman, Doo H-K., Petr Wohl, P. Sharp, P Forder, Thor Aspelund, N Meneveau, R M Schmülling, R Aubert, Thom Sam., H Youshikawa, M Ankelo, D Bowden, I Kelly, Frédéric Fumeron, M Sartini, Robert S. Sherwin, L Varadhan, A Criscimanna, John Betteridge, V Jelic, M Bartnik, N Lemke, B Ursø, A Bertoldo, A M Owona, H Okochi, L Pérez-Tamajó, S L Monfre, Daniel Brandhorst, K T Legg, Andries J. Smit, Veronica Sancho, Masashi Hirai, C Klein, Paul J. Thornalley, A Chaidaroglou, K Miura, B Zinman, O M Dvoynishnikova, J Plank, Jan Bolinder, C Lush, B Rubi, R Pozzilli, M Bashir, S A Shtandel, F Mosca, A Naskalska, Josef Vcelak, U Sausbier, P Cavaiani, T U Baehring, Michele Solimena, P Formisano, M Rastaldi, Bernard Thorens, J Ruzzin, E Arbit, M. Hori, Torkel B. Brismar, E Soltes Rak, A Filo, P Heinke, Matthew P. Coghlan, M Masotti, I Perevozskaya, K Ahn, I Moules, K Van Dyck, I Goldstein, Z Mathe, G Z Zhao, S Fajardo, J Taylor, S Chrul, J C Pareja, D Hadjidakis, A J Scheen, N Siddiqua, D C Cavan, R Grella, Krabbe S, H J Rochlitz, A E Hinkkanen, W Wilpshaar, Richard Stevens, M Dreyer, S Hara, X Wang, Melania Manco, D Gillen, Magalie A. Ravier, Olli Simell, John C. Lawrence, Kohnert K-D., Agardh C-D., A Berghold, L Kristensen, Grant Sfa., N Gursoy, Leif Groop, N Freemantle, Anja Schweizer, L Pala, Legros J-J., C. Di Pietro, N. Yamamoto, J Magyar, B Nikolovski, H Ikeda, D Lee, Bruce A. Buckingham, A O Wollitzer, I Kennedy, C Ernest, Neville H. McClenaghan, S Tanaka, Asimina Mitrakou, T Heinze, W Kerner, Moeenaldeen Al-Sayed, Charles Thivolet, L Klaff, A Miconi, Cristina Valeri, J. O. Christensen, K. Ekberg, A Jardine, T Endo, X Zhang, D F Child, A Kienitz, D K Seidel, H. Tada, Sylvie Abouna, Cyrus Cooper, Catherine R Chittleborough, Roberta Assaloni, S Corbi, A K Bose, K Ozawa, C Ahn, K A Deans, G Jackowski, Martin Gibson, Patrick McElduff, O A Mojiminiyi, Manuel Serrano-Ríos, O Dupuy, A L Davydov, Iwar Klimes, Sten-Anders Ivarsson, N Ichino, R Matsutomo, E R Smith, A Stefanovska, B Dehmel, K Koniavitou, E Agascioglu, M Hatazaki, J. M. Gibson, T Yada, P Ribaux, M Rupnik, K Fridell, G Scutaru, L Chugunova, Henrietta Mulnier, A Kendereski, H Lehnert, C Billi, M Sobczak, Francisco M-Mj., L K Archibald, S Sukumvanich, David B. Dunger, I. Benke, G Yillar, N Stingemore, J. M. Boavida, Y Shi, Jimmy D. Bell, L Bozzetto, Andrew J. Ahmann, E Jebens, J Keiding, Elena Henkel, Mark Fineman, J F McRae, Carol Forsblom, S Martemucci, Lourdes Ibáñez, P G Prieto, L Ringholm Nielsen, S Pratas, B von Stritzky, Julio Rosenstock, Lee K-W., J Stocks, L J Strow, I Samarguliani, L Wennekes, R Cheung, Abhishek Nag, Roberto Gambino, Y Suleymanoglu, E Murphy, T T Durck, M F Peyrot, Y Unno, Alexander Mayorov, Eleuterio Ferrannini, D. C. Rao, D Neely, H Karunajeewa, J Palmisano, Julia B. Lewis, M Ravid, G Pons, E Junca, P Vexiau, S Sailesh, D K Miloslavskiy, O N Bondarenko, U Smith, S Torri, Constantine Tsigos, Cesario Bianchi, Mattia Locatelli, D Jaquet, Virpi Lindi, M Moroi, M E Tushuizen, P Pelicci, R Scognamiglio, Pal Pacher, S M Thyssen, A Péterfalvi, Y Ho, S Guntram, L Romics, T Nakagami, Clive S. Cockram, Irina Kowalska, K Brodbeck, Gojka Roglic, J. Dörig, Lise Tarnow, Therese Tillin, A López-Alba, Martin Krššák, Moses Elisaf, S Hata, D P Snoeck, D Schmoll, O V Udovichenko, A Scaramuzza, J Paul, John H. Fuller, Nicholas Katsilambros, Michele Muggeo, Pia Ekbom, Piero Marchetti, V Melki, C Bailleau, H Stavrianos, A D'Errico, Geremia B. Bolli, Amabile Maier, Kelter A-R., Anders Green, Q J Morélis, Steffen Thiel, C Watkins, R C Cheung, A Clark, Elvira Fioriti, N Ari, Nam J-Y., Y Cottin, L G Krinelke, H Al Mohammedi, Simon C. Fleming, C Jones, Z Kerényi, Ahn Y-H., Meile M-J., P Nánási, M Graner, V Canonico, Gangnerau M-N., Hugh R. Taylor, Giovanni Sartore, A. Dejgaard, Carol Kelley, S. Ali, Stéphane Dalle, Jeffrey S. Gonzalez, Elena Šeböková, Alexander Beck, Ingo B. Leibiger, M Rosu, C Pencea, Werner Waldhäusl, Kaltenbacher M-C., R Butzer, S Thore, Adam G. Tabak, Angelo Avogaro, E Standi, Boris Kovatchev, O Bradescu, Patrizia Dentelli, A Fujita, C Verri, R Chlup, Prasad Ydm., S V Hörsten, van der Merwe M-T., D Hilliard, W Klein, D Worthley, M Udvardy, Berit R. Jensen, A D'Avanzo, J Monaghan, K P Yeo, Guivarch P-H., B Bauduceau, D Weghuber, P Tatti, J Ybarra, S Gwozdziewiczová, E Gasparini, B Saltin, Charlotte Granhall, Howard Leventhal, R Marin, M Tumiati, Cicero Afg., L Csémy, B Berger, S Mikros, D Dall'Asta, M Shahmanesh, Y G Vasiljev, F Potthoff, H S Randeva, G De Berardis, J O Logan, K Warncke, P Uitterlinden, E Rehring, K Gilmore, K Shankhdhar, V V Bojko, M Vahatalo, E A Korolyova, D Wiemann, P G Lankisch, D Hendrie, F Galtier, M Rybarczyk, Gisela Dahlquist, N N Rudovich, G Stein, A Liebl, F Tan, A Westerlund, S Gronemann, I Franklin, Jonathan A. Prince, Peter Arner, E Skliros, T. Sparre, M Vigas, Maddalena Trombetta, L. Bjerre Knudsen, A C Sima, I Dubroca, Alastair Gray, I Weets, R Ferraresi, Schauer Ujw., E. Leinonen, S Corazza, Jonathan Levy, P K Prakash, R Guzder, S. Barnhill, John Blangero, J Herreros, G. de Vries, Cheng Ptw., A Macías-Batista, K. Capito, R Thomas, G Thomas, G Boemi, Lotte Pietraszek, Pierre Fontaine, I Holme, J Smedegaard, C A Harrop, U Helwig, B Levy, A P Gribben, Hiroto Furuta, P Beckett, S Giannini, Ruth L. Coleman, Eva Fernqvist-Forbes, N Cugnardey, A Dumas, Jane Pinaire, S E Hofer, D Shimono, Erik H. Serné, Alain D. Baron, C Battista, M Tanen, M Klementova, V Adams, J Komorowski, Antonio Nicolucci, E. C. Burns, H Sydall, M G Fanara, M G Giovannitti, N Okabayashi, Magdalena Szurkowska, I A Eroshkin, M. I. J. Uusitupa, D Ma, C C Dieguez, J Sutcliffe-Goulden, A V Gaddi, Michał Arabski, Serge Halimi, Wendy C. Burns, S Seclén, H Sugano, A Vinterby, K Backx, L F Diaconu, Fernando Gomez-Peralta, O'Harte Fpm., G Lepeniotis, D Laune, H Kvasničková, N H Wallén, G Boner, G Cieślik, Robert Hermann, Paul Q. Thomas, Y Kumon, Maria Maiello, M Atkins, Kenneth A. Earle, Guowang Xu, H Y Bae, I Reynisdottir, D Perez, D E Cannon, P Fabietti, I Geronooz, J Østergaard, K J Jeitler, S Skourtis, A Zambanini, A Saemann, K Kuboki, Helen L. Lutgers, A C Thai, Arne Melander, D Pinkowski, S G Straub, S A Wolfe-Coote, A Totora, Hayley Dickinson, A Lindenmair, A Ginis, I Faturos, F Van Eylen, C Huard, F Fu, N Wang, B M Rasmussen, Angela Napoli, L Granato, Markus M. Lerch, M. Frandsen, A Lyras, Lawrence S. Phillips, J Mabley, R Goldschmeding, B K Kilhovd, W Liu, Greg Poffenberger, P Cipriano, Anna Maria Charlotte K Lindqvist, A Matsuzawa, J Wang, T Yu, M S Pepper, Lena M. Thorn, Y Sakamoto, Blanche Schwappach, Anna L. Gloyn, P Dupraz, A. M. Schmidt, M Psallas, V Tsirimbis, Carl D. Langefeld, D Sass, H E Scholtz, M. Cailleau, Lauren Julia Brown, K Phillips, M. Iezzi, C Jayawarna, Eleni Anastasiou, R Lobmann, R Lundershausen, H Fujiwara, H R Nan, I C Smith, I A Karpova, A Navazio, S Kang, T. Hansen, T Watanabe, Gang Hu, Malik Rja., T Kennedy-Martin, Ulla M Smidt, J.M. Dekker, A A Fisher, H Liu, R E Pratley, B Sun, C Fledelius, J F Raposo, R Langham, Ahn S-Y., B R Waterhouse, Shaoping Deng, W Ricart, S V Melnichenko, Henrike Sell, M. Tomalino, N Takeda, Paola Massucco, A Harlan, W Henrich, C D Byrne, R Junik, Khalid Hussain, D Pop Gorceva, Torben Hansen, C Ritterath, K Ogawa, D V Phan, Bradley S Metcalf, Robb E. Moses, Juan P. Frias, Hitoshi Ishii, C Brisard, P Wolkow, H H Maurer, Ingo Rustenbeck, Juris J. Meier, Octavian Savu, S D Lin, V B Bregovski, A Fox, S Cicala, M. Koenen, L Vignati, O de Divitiis, Constantin Ionescu-Tirgoviste, Kilian Rittig, J Song, Riccardo Candido, F Cohen-Boulakia, U Shankhdhar, P Jahan, Antonio Tiengo, E Liepinsh, C Álvarez, Sigurd Lenzen, James E. Foley, A. del Arco, M A Maitan, U Mollenhauer, M A Na, A Beha, B Aicher, Gabriele Meyer, E Sommariva, J Åman, B Gmeinhart, Theede A-M., Bjorn Bolinder, Giulio Ceolotto, S Sbrana, F Biarnes, Damini Dey, Barbara Thorand, H H Klein, Juliana C.N. Chan, L Piconi, S Gudbjornsdottir, E Bobbioni-Harsch, Joanna Polanska, Cristian Serafinceanu, S Gambardella, Olivier Huber, J D Brunzell, T Nagasawa, Loretta Vileikyte, A Szocs, H Löwel, Z Lin, Anders Juul, H Tsuneki, L Sauriol, G Siebert, Marit E. Jørgensen, K Matthies, Brian D. Green, P Jurowski, Z Gao, M Furuya, Silvia Manfrini, Efthymios Motakis, E Souvatzoglou, Qian Y-Z., Byun S-H., T Nguyen, M R Anwar, Geltrude Mingrone, B. Idzior-Walus, Mamas A. Mamas, G Scholl-Schilling, C Bittner, A E Raptis, L Laghi, Murray Stewart, M Orel, Janet M. Bryson, Chris P Gale, Åke Lernmark, A B Escorza-Domínguez, C Fuentes, A S Einarsdottir, M O Akinsola, P Maisonneuve, K S Leong, B Missler, Simona Frontoni, Con Tsalamandris, Flavio Francini, D Rouiller, B.E. de Galan, Girolama Alessandra Marfia, M Fioravanti, A E Weber, M Nargis, P Nowacki, Y Chen, B Larsen, Ruth E. Gimeno, A Wojciechowska Luźniak, R Meisterfeld, Limei Liu, A Ohashi, T Pieber, Bin Yao, G A Herman, M Pallini, R E Honkanen, H Nyblom, R Humbrecht, Takashi Tsuboi, Pinar Topsever, Monika Kellerer, J Woods, Steen Stender, C Kapitza, Sherwyn Schwartz, M Taskiran, N Hashimoto, A Jabin Gustafsson, K C Silva, I Nitz, S Dzienis-Straczkowska, H Elouil, L Sommese, Patricia A. McKinney, S Ogawa, E Carr, I Porchay, Robyn G Langham, Bruno Vergès, K H Usadel, S Sivakumaran, H M Hearnshaw, José Luis Santos, R Ishibashi, F Huq, Lebrethon M-C., Z Leshchenko, Elisabetta Torlone, A Saltiki, A Plaschke, Wolfgang Koenig, D. D'Avola, C L McTernan, Haruhiko Osawa, G Cazzetta, S J Lee, S Al Jebely, Hoogma Rpl., A Shimizu, Tack Cjj., Itamar Raz, Adrian Vella, P. B. M. de Andrade, Aguiar Lgk., Wolfgang E. Schmidt, T Wolthers, W. Gatling, T S Purewal, Philipp E. Scherer, E Heller, Stephan Gielen, Jo S-R., Monica Vedovato, L Nosek, R Ryder, G Giassakis, A Cretti, A Wajngot, T Waldhör, S Zoric, H C Lee, L Pulkkinen, L Lacey, I Tomescu, R S Patarrao, X C Liu, Lauge Schäffer, Jarkko Ustinov, Anders Thorell, K Kangawa, P J Wood, T Yeoh, Jo Satoh, G Psaras, Volker Burkart, Karin Schindler, Dario Pitocco, M Kolopp, Gabriela Roman, E Renström, M Goldberg, M Beregszaszi, S Senkel, M F Meyer, María Luisa Villanueva-Peñacarrillo, Elena Beltramo, J E Snaar, A Hayward, C Abreu-Padí, S E Vielwerth, R Krones, C C Stanciu, M Izquierdo, I Elbing, R Astorga, V I Bouloukos, P Zabielski, S Precerutti, Kang S-Y., K L Pratt, Joost H-G., Matthew L. Iorio, Naomi S. Levitt, Yutaka Seino, Peter A. Gottlieb, I Ehrén, Y Matsuyama, Jean Claude Mbanya, S Parveen, R Purvis, A Cappadona, V V Afanasyeva, K Löbner, S Del Guerra, V Valle, Victor A. Gault, M Tan, M M Budge, I Ioannidis, M Ishizawa, Castelli, D Nowak, János Rigó, Claudia Bleck, E Degli Esposti, C Tortul, M Klebach, E Schvarcz, L Pauline, D Krusova, J Csillag, Park K-G., Kaichi Kida, P Bialasiewicz, S Seeliger, B A Williams, P Mistry, T Nicer, N Ahmed, H Ohashi, Peter Achenbach, van Hessen Paw., Jesús Cancelas, E Cizmarova, D Takahashi, K Tanaka, A M Rojo Llobet, Q Chen, A J Garber, P Halban, B Brunmair, A Barthel, M R Katdare, Dominique Laude, M E Pavkov, C Leach, C M Breschi, S Okada, B Balent, Ornella Massa, Ravi K. Garg, van Loon Ljc., K Obuobie, W Moll, L Varanese, V Smejkalova, B Royer, M Roth, M Belfiglio, Chae M-K., I Kimura, Casper G. Schalkwijk, Hans-Jürgen Hedrich, Heinsbroek Acm., Jared Rutter, Ken Williams, K O Lee, A N Symeonidis, J B Brown, M Pfeuffer, W. C. Knowler, A N Barsukov, A Woods, T W Kim, Khalid Bak., Andrea Mari, David J. Pettitt, Y Tomioka, J Hochman, Mireia Mora Porta, K Pagava, Krzysztof C. Lewandowski, J Taton, T Yasaka, M Tyrberg, M Sargin, P Szenthe, R Sicree, C Abreu-Padín, Magdalena Lundgren, J Radziuk, Eili Tranheim Kase, W L Goudzwaard, Yanbing Li, E Ramos, H Monastiriotis, J Cur, S Pu, Lakka H-M., Park J-S., Fabrizio Barbetti, S. Ciani, Pavel Flachs, N C Correia, Angela A. Rivellese, F Ebara, Nicolas Musi, H van Ahlen, Helen M. Colhoun, Anna Czech, Steen B. Pedersen, N Jost, N Da Silva, J Nóvoa, Y Onuma, Anna Körner, D Michael, M Straczkowski, I. Truyen, R. Schmid, Søren Paaske Johnsen, H Koenig, B. Miranda-Palma, E Wasén, F Pervin, P Cavallo-Perin, M Niessen, E P Shavrikova, P Tarkun, M Vavlukis, H Gang, O Sánchez-Vilar, C Dalla Man, S. M. Haffner, R Eggertsen, L Pucci, F T Fiedorek, E I Mainas, H Holdass, Peter R. Shepherd, A Banu, R Lichiardopol, Lee M-K., N Zaytseva, B Gumbiner, Strotmann H-J., L Y Baranova, A Kissebah, A Pezzatini, I Kharroubi, N A Thornberry, A J Buckley, B Pontiggia, T Chen, M Ikebukuro, J Leach, C Frost, J Han, H Hashizume, G Poulsen, H Eckert, Paul Zimmet, Lee J-H., Peter E. Heding, S A Ross, Nils J. Færgeman, Giuseppe Penno, T Varbanova, H S Shon, Z Canturk, S Akahane, Noel G. Morgan, A Sener, Seronde M-E., P K Thaware, W Insull, S Forst, K E White, Christoffer Hedetoft, M R Holland, K Okamoto, F Yamagata, Markus Lassila, N Tanaka, Kristian Midthjell, R Isoaho, D A Legemate, M Motzkau, Y H Kang, A P Nescheret, J Boiko, Hemmo A. Drexhage, Gagik R Galstyan, Naim Shehadeh, Henning Beck-Nielsen, T I Justesen, O Kalter-Leibovici, T Vahlberg, M Mozdzan, G Siegert, V Dumenil, Katsumi Eguchi, J A Vazquez, Sally Hollis, H Haberland, A Souvatzoglou, M L Gavete, K. S. Nair, Katharine R. Owen, C Garcia-Rodenas, Gerald I. Shulman, Peters, H A Parkes, Y S Kim, Mats Rönnback, Isabelle Leclerc, Marie-Hélène Giroix, I D Caterson, S G Rønn, L Scionti, Silvia Pinach, Hans Christian Reinecker, Kathryn Noyes, P McTernan, C Y Tan, N. Lalic, Richard D. Carr, M. Toman, D Papazoglou, Domenico Bosco, G Lübben, F. Costanza, Tania Maffucci, Jonas Nygren, Ole Lander Svendsen, Kristin Taylor, Ugo Boggi, A Kayserilioglu, Gudmar Thorleifsson, G J Dunseath, B. Balkau, T Zieher, M Schwarts, A. R. Cobitz, P de Pablos, I Recas, Carlos Lorenzo, Pamela J. Shaw, Y Cho, C Münscher, Anna Maestroni, Milan Zdravkovic, Gerstl E-M., L L Xiu, Yoshitaka Kajimoto, A Deb, F Osaki, G Kirilov, B Staffler, Běla Bendlová, M Rebelatto, Frank Reimann, B Ø Christoffersen, S Durant, Fruchart J-C., Ravinder J. Singh, V Connolly, Q Zhang, Alexandra Kautzky-Willer, Francesco Andreozzi, N Talai Rad, V Loyková, Trampisch H-J., Stefano Menini, F. Rodríguez de Fonseca, W Hanif, H J Böhles, S Fotiadis, Philippe André, T Kubiak, T Friede, J Murin, Erwin Schleicher, Adam Garrow, M Takahashi, P Valensi, S Pappas, E Lim, D N Staroverova, C Tadgell, C Dessapt, Brittany A. Rasmussen, L Cheung, L E Porter, R Ishihara, J Ravisy, T Inukai, Christine Winzer, E M Özer, Nish Chaturvedi, Ana Chico, Ville-Petteri Mäkinen, N Bellili, Howlader, Jansson P-A., A Martella, Jan Frystyk, T Kakko, K Hershon, S Hoashi, B Nag, C Chabrolle, B Leatherdale, J. Lu, Stephen Colagiuri, C Brendel, Michael Roden, Peter Clausen, A L Macdonald, R A DeFronzo, F A VanNieuwenhoven, Sirkka Keinänen-Kiukaanniemi, Jonas J-C., Hobbs Fdr., H Uchino, S Del Prato, E Polakowska, L Shankhdhar, Hedrich H-J., S Rodriguez-Cuenca, A Schwarzmaier-D'Assie, K Fukuda, Robert H. Eckel, A. Hilding, A Rutscher, D Kerr, Junhua Li, C. Köhler, A Banaszak, Peter Lönnroth, P Wulff, M A Gruzov, Fariba Shojaee-Moradie, S Matsumoto, J P New, N Barthes, M G Leyck Dieken, Mian Li, O Ivanova, G Papalia, K A Nilsson, Parving H-H., P Merz, M. A. Schweitzer, A Morris, P. Andersen, O Tschritter, M Fitch, V Fejfarova, Elisabeth Bernroider, E C Kiawi, M de Kerdanet, Claus B. Juhl, C Taxvig, Kerstin Berntorp, Birgitte Andersen, C Coscelli, C Ktori, Norio Abiru, R Mössner, Hiroko Hirooka, Jens J. Holst, Q Dan, H F Gu, C Gimpelewicz, A Oeckinghaus, B DelBuono, J Kuroda, P Kastner, Clemens Fürnsinn, H Usui, R Mosqueda-Garcia, P De Meyts, K Yamagami, M Tóth, V Leite, H Alberti, M Meneses, Gregory Collier, E G Starostina, C Delaporte, Agostino Consoli, François Alhenc-Gelas, S Tonstad, G Schuler, J Juszczyk, G Hoefle, M Wilken, Mark A. Yorek, Volker Lodwig, G Edwards, E Catellani, Ewa Wender-Ozegowska, Kurt Hoffmann, I Markova, Steven J. Hunter, A Venkataraman, Bente Klarlund Pedersen, A Kengne, Ken K. Ong, L A Calo, M Huckova, Y Morikawa, Pierina Richiusa, D Giuffrida, Sonia Brichard, Giuseppe Paolisso, Andrew T. Hattersley, M Vankova, Jon G. Mabley, G Salvidio, M Montolio, X Yang, Barbara N. Campaigne, Ralph R. Turner, Andrew J.M. Boulton, P Johnston, S Berchtold, Roger Corder, D Ledwig, M. Di Mauro, Houweling, J H Bowker, J Hilsted, Shin D-W., B Kiran, E Esteve, A J Cameron, S Spera, Kathrin Maedler, S Tsujii, J. H. DeVries, S Cailleaux, M Walter, A Florén, R Lehtonen, Davis Tme., N Patsourakos, J. Marco, G Lepore, L Morcillo, J Burén, Paul Smits, Juraj Koska, Chung J-H., Katherine S. Elliott, Bong Soo Cha, Christian Weyer, F Montorsi, L G Søndergaard, H Horie, M Herten, N Aghamohamadzadeh, L A Scrocchi, A Oyarzún, Rutten Geh., K Yamada, M Zivkovic, R S Beifort, Lee I-K., S D Bouman, H Böhles, Dwight E. Matthews, Orville G. Kolterman, Bidda Rolin, I Shymanskyy, P Thomakos, John Strand, A Virkamäki, C M Clark, Y Tokumasa, Odusanya Pot., Joel F. Habener, Abel López-Bermejo, Anders Tengholm, D Argon, Lajoix A-D., N Aki, L Kessler, N Takahashi, A Zmysłowska, Kåre I. Birkeland, D Soon, Lars Køber, M Vaňková, Lee W-C., F Payeras-Más, C Lau, E Ramos Lopez, L Lukic, A Suehiro, Stephan J-A., I Estalella, Jørgen Jensen, Liaqat Ali, V S Dimitrijevic Sreckovic, V P Maximova, G Salietti, M Ding, Yuksel Altuntas, Chung K-D., F Kaufman, Ludwig Wagner, C Calvi, D X Gram, David G. Bruce, K Sprenger, M Schweers, D Kush, D B Panagiotakos, J. M. Currie, Luis Castaño, Dag E. Undlien, D. Haspel, A Suzuki, J Cederholm, S Garcia, L Cynober, P O'Hare, A Tsur, Christine Zimmermann, M Faimalie, V V Poltorak, S Alba, Axel Haupt, J Varga, Tetsuya Yamada, M Shoji, R H Lloyd-Mostyn, Péter Pusztai, Doney Asf., M N Gangnerau, I Shimizu, Henrik Ortsäter, F Liska, Mandeep Bajaj, H Sarui, Michal Andel, S Chiheb, Diane Barker, A. van Tol, Brigitte Reusens, I Anafaroglu, Giel Nijpels, F Bongardt, K Taxildaris, M. 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Ward, René Gross, S K Althouse, S Woodhead, Emmanuel Cosson, T Rönnemaa, T M Filiz, Jerzy Loba, S Sha, Klas Malmberg, Carlo Pesce, Jung D-S., I Majdrakova, Thomas Forst, M Schütt, Hierl F-X., A M Efanov, I Verschraegen, H B Jensen-Holm, D Deckhut, Frida Leonetti, N Selzle, G Cassetti, Jose L Mesa, G Morrison, Christian-Heinz Anderwald, C Kliebe-Frisch, J H Moffitt, P Lahm, Hiroshi Ishiguro, E. Borgo, A Keech, L Quagliaro, Thomas O. Ola, Henquin J-C., W J Sluiter, F Leprêtre, Kalliopi Kotsa, Peter Karl Jacobsen, E Sanchez-Largo, E Gaia, Daniel R. Witte, Sidsel Graff-Iversen, G Seebohm, E Cacès, R G Khalifah, W Wilson, Avan Aihie Sayer, C Raffaitin, J Gumprecht, T Lehmann, E Migliaccio, R Urrutia, E Shelestova, A V Chervonsky, Stefan Mustafa, Y Hisano, Erik A. Richter, J Miettinen, K M Gottesdiener, Gangyi Yang, D Chevenne, A Girach, P Samuelsson, Taskinen M-R., D Ciociaro, D Aydemir, Yang S-B., P De, Dongliang Zhuang, Nathan R. 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Jensen, G, Fisher, A, Petrovsky, N, Srikusalanukul, W, Budge, M, Trifunovic zamaklar, D, Zivkovic, M, Jelic, V, Vukomanovic, G, Ristic, A, Seferovic, P, Costa, J, Duarte, S, Manley, S, Sailesh, S, Venkataraman, A, Haider, Y, Groza, I, Oprean, M, Ardelean, A, Morosanu, A, Darkow, T, Vanderplas, A, Mamas, M, Mcelduff, P, Burns, J, Edwards, R, Fitchet, A, Young, R, Gibson, J, Lichiardopol, R, Niculescu, N, Totora, A, Pencea, C, Tomescu, I, Cinteza, M, Manicardi, V, Coscelli, C, Navazio, A, Catellani, E, Michelini, M, Dall'Asta, D, Guberti, A, Piazza, A, Gasparini, E, Pantaleoni, M, Guiducci, U, Manari, A, Sejil, S, Janand delenne, B, Avierinos, J, Habib, G, Labastie, N, Vague, P, Lassmann vague, V, Luźniak, P, Tatoń, J, Wojciechowska Luźniak, A, Zairis, M, Lyras, A, Patsourakos, N, Tsirimbis, V, Foussas, S, Lupón, J, Urrutia, A, Herreros, J, González, B, Coll, R, Altimir, S, Prats, M, Valle, V, Abreu padí, C, Rábago, G, Ivanova, L, Brasacchio, D, Harno, E, Keenan, A, Li, H, Lu, Z, Ke, L, Liu, H, Jeong, I, Chae, M, Choi, M, Yoo, H, Kim, C, Yun, M, Na, M, Kang, Y, Kong, O, Son, S, Kim, I, Tanaka, N, Hosoi, M, Matsuyama, Y, Fukumoto, M, Yamakita, T, Yoshioka, K, Ishii, T, Sato, T, Fujii, S, Aoki, T, Shibata, T, Mizutani, N, Suzuki, J, Fowelin, J, Samuelsson, P, Brandrup wogsen, G, Okumura, K, Tokmakova, A, Staroverova, D, Antcieferov, M, Shutichina, I, Kuntchevich, G, Vriesendorp, T, Morélis, Q, Legemate, D, Schaper, F, Mainas, E, Gkioulmpasanis, I, Panagiotou, I, Vassilikos, G, Skorda, L, Sidira, M, Christoforidou, M, Alaveras, A, Artikis, V, Evdemon, E, Lechleitner, M, Koch, T, Ebenbichler, C, Sturm, W, Moretti, L, Moruzzo, D, Boldrini, E, Pandolfo, C, Kameyama, M, Iwasa, R, Cho, M, Nam, J, Huh, K, Kaplar, M, Paragh, G, Erdei, A, Csongradi, E, Garai, I, Varga, J, Galuska, L, Udvardy, M, Higa, M, Kaneko, Y, Hiroi, N, Koziarska, D, Nowacki, P, Majkowska, L, Luzniak, P, Wojciechowska luźniak, A, Tushuizen, M, Nieuwland, R, Snoeck, D, Sturk, A, Diamant, M, Aguiar, L, Bahia, L, Villela, N, Laflor, C, Conde, C, Bottino, D, Dorigo, D, Bouskela, E, Pu, S, Luo, Z, Lam, K, Dan, Q, Xu, A, Shen, J, Cheng, K, Xu, J, Thamer, C, Stefan, N, Haap, M, Heller, E, Tschritter, O, De Prado, A, Ortiz, A, Ybarra, J, Gich, I, Pou, J, Ehren, M, Roggenland, D, Reinsen, B, Klein, H, Rittig, K, Stock, J, Kocher, B, Balletshofer, B, Shon, H, Chung, D, Nakatani, Y, Matsuhisa, M, Kaneto, H, Hatazaki, M, Yoshiuchi, K, Katakami, N, Kawamori, D, Ohtoshi, K, Sakamoto, K, Matsuoka, T, Ozawa, K, Ogawa, S, Hori, M, Yamasaki, Y, Zitouni, K, Harry, D, Nourooz zadeh, J, Earle, K, Olesen, P, Franco, L, Corvaja, C, Semplicini, A, Ceylan işık, A, Arı, N, Rösen, P, Lee, I, Park, K, Jung, E, Shin, D, Jo, S, Obuobie, K, Prakash, P, Hanna, F, Lazarus, J, Varadhan, L, Gurushankar, J, James, D, Sheikh, S, Gaede, P, Zou, D, Vilarrasa, N, Perez maraver, M, Mena, E, Perez, D, Setti, G, Buckingham, R, Urbančič, V, Stefanovska, A, Bernjak, A, Ažman juvan, K, Kocijančič, A, Glowania, A, Filters, T, Fosmark, D, Torjesen, P, Kilhovd, B, Berg, T, Sandvik, L, Hanssen, K, Mentink, C, Donchenko, G, Stepanenko, S, Maingrette, F, Deng, H, Lindenmair, A, Freudenthaler, A, Baumgartner parzer, S, Nizheradze, K, Khoruzhenko, A, Tronko, N, Sheu, W, Ou, H, Shen, H, Lin, T, Wu, H, Yang, C, Mogylnytska, L, Schmoelzer, I, Davies, J, Band, M, Struthers, A, Prázný, M, Škrha, J, Kasalová, Z, Neelotpol, S, Jahan, P, Kauschke, S, Harrop, C, Schäfer, A, Widder, J, Eigenthaler, M, Walter, U, Uchimura, I, Ikebukuro, M, Kaibara, M, Hirata, M, Helal, R, Pervin, F, Yang, X, Jansson, P, Nagaev, I, Jack, M, Carvalho, E, Sunnerhagen, K, Cam, M, Cushman, S, Smith, U, Creely, S, Farmer, J, Gustafson, B, Kusminski, C, Krusinova, E, Wohl, P, Klementova, M, Lanska, V, Mcdougall, C, Kelly, I, Abbas, Z, Lutale, J, Archibald, L, Karunajeewa, H, Stingemore, N, Stuccio, G, Mcgechie, D, Muller, L, Hak, E, Goudzwaard, W, Montorsi, F, Homering, M, Sprenger, K, Goldstein, I, Asnaghi, V, Ferrari, G, Rastaldi, M, Gabellini, D, Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, EASD, Endocrinology, Diabetes and Metabolism, Human physiology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Family medicine, Internal Medicine, Medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published: 2004

296. Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

Author: Markku Saraheimo, Carol Forsblom, J. Fagerudd, Per-Henrik Groop, and A.-M. Teppo
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, Gastroenterology, Severity of Illness Index, Nephropathy, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Albuminuria, Humans, Diabetic Nephropathies, 030304 developmental biology, Inflammation, 0303 health sciences, Type 1 diabetes, biology, business.industry, Interleukin-6, C-reactive protein, Cholesterol, HDL, medicine.disease, 3. Good health, Endocrinology, C-Reactive Protein, Diabetes Mellitus, Type 1, biology.protein, Microalbuminuria, Female, business, Biomarkers, Kidney disease
Abstract: Increased concentrations of C-reactive protein and interleukin-6, a finding suggestive of the presence of inflammation, have been observed in Type 2 diabetes. In such patients, C-reactive protein was predictive of diabetic nephropathy. Studies on low-grade inflammatory markers and nephropathy in Type 1 diabetic patients have shown conflicting results. Therefore we studied whether low-grade inflammation is associated with diabetic nephropathy in Type 1 diabetic patients.We divided 194 Type 1 diabetic patients into three groups from the Finnish Diabetic Nephropathy Study based upon their albumin excretion rate. Patients with normoalbuminuria (n=67) had no antihypertensive medication or signs of cardiovascular disease, while patients with microalbuminuria (n=64) or macroalbuminuria (n=63) were all treated with an angiotensin-converting enzyme inhibitor, a drug that could attenuate low-grade inflammation. As a measure of insulin sensitivity we used estimated glucose disposal rate. C-reactive protein was measured by radioimmunoassay and interleukin-6 by high sensitivity enzyme immunoassay.C-reactive protein was higher in micro- and macroalbuminuric patients compared to normoalbuminuric patients (normoalbuminuria 2.0+/-1.7, microalbuminuria 2.6+/-1.7, macroalbuminuria 2.9+/-2.5 mg/l; p=0.016), while interleukin-6 increased in parallel with the severity of the renal disease (1.9+/-1.5, 2.9+/-3.3, 3.6+/-3.1 ng/l; p0.0001). In multiple regression analysis albumin excretion rate was the only variable independently associated with C-reactive protein (p=0.03), whereas albumin excretion rate (p=0.0003), HDL-cholesterol (p=0.0135) and duration of diabetes (p=0.0176) were independently associated with interleukin-6.Low-grade inflammatory markers are associated with diabetic nephropathy in Type 1 diabetic patients. The predictive value needs to be assessed.
Published: 2003

297. Polymorphisms in the nephrin gene and diabetic nephropathy in type 1 diabetic patients

Author: K. Pettersson-Fernholm, Markus Perola, Carol Forsblom, and Per-Henrik Groop
Subjects: Adult, Male, medicine.medical_specialty, Genotype, type 1 diabetes, 030204 cardiovascular system & hematology, urologic and male genital diseases, Nephropathy, End stage renal disease, polymorphism, Diabetic nephropathy, Nephrin, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Diabetes mellitus, Internal medicine, Medicine, Humans, Diabetic Nephropathies, end stage renal disease, 030304 developmental biology, 0303 health sciences, Proteinuria, Polymorphism, Genetic, biology, business.industry, urogenital system, diabetic nephropathy, Membrane Proteins, Proteins, nephrin, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, slit diaphragm, Endocrinology, Diabetes Mellitus, Type 1, Nephrology, biology.protein, Slit diaphragm, Microalbuminuria, Female, medicine.symptom, proteinuria, business
Abstract: Polymorphisms in the nephrin gene and diabetic nephropathy in type 1 diabetic patients. Background Several mutations in the nephrin gene are responsible for the lack of slit membrane of the glomeruli leading to massive proteinuria present already in utero. Variations in the nephrin gene may also affect the degree of proteinuria in acquired kidney diseases. We tested the hypothesis of whether any of the polymorphisms identified in the coding region of the nephrin gene were associated with diabetic nephropathy. Methods In a case-control, cross-sectional study, 996 Finnish type 1 diabetic patients from the FinnDiane Study were genotyped by standard polymerase chain reaction protocol. Results The frequencies of the rare alleles in the E117K, R408Q, and N1077S polymorphisms in the entire cohort were 34%, 8%, and 12%, respectively. When comparing patients with a mutant allele with the wild genotype there was no difference between the patients with end-stage renal disease, proteinuria, microalbuminuria, and those with a normal albumin excretion rate (df =3, χ 2 =1.62, 1.31 and 0.77). Neither were the polymorphisms associated with the progression of kidney disease, nor with creatinine clearance and albumin excretion rate. Conclusion This study does not support an involvement of the coding region of the nephrin gene in the pathogenesis of diabetic nephropathy in type 1 diabetic patients.
Published: 2003

298. The functional -374 T/A RAGE gene polymorphism is associated with proteinuria and cardiovascular disease in type 1 diabetic patients

Author: K. Pettersson-Fernholm, Per-Henrik Groop, Barry I. Hudson, Carol Forsblom, Peter J. Grant, and Markus Perola
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, Receptor for Advanced Glycation End Products, 030204 cardiovascular system & hematology, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Glycation, Diabetes mellitus, Internal medicine, Internal Medicine, Medicine, Albuminuria, Humans, Diabetic Nephropathies, Receptors, Immunologic, Receptor, Promoter Regions, Genetic, Finland, 030304 developmental biology, 0303 health sciences, Proteinuria, Polymorphism, Genetic, business.industry, Vascular disease, Homozygote, medicine.disease, Endocrinology, Diabetes Mellitus, Type 1, Cardiovascular Diseases, Metabolic control analysis, Female, Gene polymorphism, medicine.symptom, business
Abstract: The hyperglycemic milieu in diabetes results in the formation of advanced glycation end products (AGEs) that predominantly act through specific receptors, particularly the receptor for AGEs (RAGE). Two functional polymorphisms in the promoter of the RAGE gene (−429 T/C and −374 T/A) and one in the AGE binding domain in exon 3 (G82S) were studied in 996 Finnish type 1 diabetic patients. In patients with poor metabolic control (HbA1c >9.5%), the AA genotype of the −374 T/A polymorphism was more common in those with a normal albumin excretion rate than in those with proteinuria (30 vs. 10%, P = 0.01). We observed less coronary heart disease (6 vs. 14%, P < 0.05), acute myocardial infarction (2 vs. 14%, P = 0.01), and peripheral vascular disease (2 vs. 14%, P < 0.05) in patients with the AA genotype of the −374 T/A polymorphism than in those with the TT + TA genotype. Thus, the association between the RAGE −374 T/A homozygous AA genotype and cardiovascular disease as well as albumin excretion in type 1 diabetic patients with poor metabolic control suggests a gene-environment interaction in the development of diabetic nephropathy and cardiovascular complications.
Published: 2003

299. Erratum to: Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

Author: Mark E. Cooper, Karly C. Sourris, Jorma Ilonen, Carol Forsblom, Sof Andrikopoulos, Josephine M. Forbes, Per-Henrik Groop, Robyn Maree Slattery, Hiroshi Yamamoto, Angelika Bierhaus, Olli Simell, Riitta Veijola, Shane T. Grey, Felicia Y. T. Yap, Melinda T. Coughlan, Maija Wessman, Mikael Knip, and Jenny Söderlund
Subjects: medicine.medical_specialty, Type 1 diabetes, business.industry, Endocrinology, Diabetes and Metabolism, medicine.disease, RAGE (receptor), Endocrinology, Glycation, Internal medicine, Internal Medicine, Genetic predisposition, medicine, Receptor, business
Published: 2011
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300. A gene conferring susceptibility to type 2 diabetes in conjunction with obesity is located on chromosome 18p11

Author: Gayun Chan, Carol Forsblom, Steve Lewitzky, Jeffrey Thomas, Jean S. Rennich, Joanne M. Meyer, Martin Carlsson, Marju Orho-Melander, Leif Groop, Mikko Lehtovirta, Auli Hyrkkö, Alex Parker, and Cecilia M. Lindgren
Subjects: Adult, Genetic Linkage, Endocrinology, Diabetes and Metabolism, Marker chromosome, Biology, Body Mass Index, Chromosome 18, Genetic linkage, Internal Medicine, Humans, Genetic Predisposition to Disease, Obesity, Aged, Genetics, Aged, 80 and over, Gene map, Chromosome Mapping, Genetic Variation, Middle Aged, Chromosome 17 (human), Chromosome 4, Diabetes Mellitus, Type 2, Y linkage, Lod Score, Chromosomes, Human, Pair 18, Sex linkage, Chromosomes, Human, Pair 17, Microsatellite Repeats
Abstract: Genome-wide nonparametric linkage analysis of 480 sib-pairs affected with type 2 diabetes revealed linkage to a previously unreported susceptibility locus on chromosome 18p11. This result improved with stringent subphenotyping using age- and sex-adjusted BMI, ultimately reaching a logarithm of odds of 3.82 (allele sharing 0.6654) at a point between markers D18S976 and D18S391 when the most obese 20% of the sample was analyzed. Several genes on chromosome 18 have been suggested as metabolic disease candidates, but none of these colocalize with our linkage result. We conclude that our results provide support for the presence of a currently uncharacterized gene on chromosome 18p, certain alleles of which confer increased susceptibility to type 2 diabetes in conjunction with obesity. We additionally observed moderate evidence for linkage to chromosome 1, near marker D1S3462; chromosome 4, near marker D4S2361; chromosome 5, near marker D5S1505; and chromosome 17, near marker D17S1301.
Published: 2001

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