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Liraglutide is associated with blood pressure reduction in patients with type 2 diabetes. However, it is not known whether this blood pressure reduction can be predicted prior to treatment initiation, and to what extent it correlates with weight loss and with improved glycemic control during follow‐up. We analyzed data from a double‐blind, placebo‐controlled trial, in which 124 insulin‐treated patients with type 2 diabetes were randomized to liraglutide or placebo. We evaluated various baseline variables as potential predictors of systolic blood pressure (SBP) reduction, and evaluated whether changes in SBP correlated with weight loss and with improved glycemic control. A greater reduction in SBP among liraglutide‐treated patients was predicted by higher baseline values of SBP (P

Background Increased urinary excretion of IgM and low-grade albuminuria are associated with increased risk of cardiovascular morbidity and mortality. The objective of this study was to investigate the association between urinary IgM, albuminuria, and vascular parameters reflecting arterial structure and function. Methods Subjects of the present study were from the Malmö Offspring study (MOS) cohort, and included 1531 offspring (children and grand-children) to first-generation subjects that participated in the Malmö Diet Cancer-Cardiovascular Arm study cohort. At baseline, technical measurements of arterial stiffness (carotid-femoral pulse wave velocity; c-f PWV), carotid arterial morphology, 24-h ambulatory blood pressure recordings, ankle-brachial-index (ABI), and evaluation of endothelial function (reactive hyperemia index, RHI) were performed. Urinary (U) IgM, U-albumin, and U-creatinine were measured. Multivariate adjusted logistic regression was used to test whether U-IgM excretion and increasing urinary albumin excretion were related to vascular parameters. Results Detectable U-IgM was independently associated with higher systolic blood pressure, odds ratio (OR) 1.021, 95% confidence interval (CI, 1.003–1.039), p = 0.025 and lower ABI; ABI dx: OR 0.026, 95% CI (0.002–0.381), p = 0.008, ABI sin: OR 0.040, 95% CI (0.003–0.496), p = 0.012. Low-grade albuminuria was independently associated with systolic and diastolic blood pressure, aortic blood pressure, the c-f PWV and the number of carotid intima plaques (p Conclusions In young to middle-aged, mostly healthy individuals, increased U-IgM excretion and low-grade albuminuria are associated with adverse vascular parameters. Increased U-IgM excretion may reflect subclinical peripheral atherosclerosis, whereas increased U-albumin excretion is associated with a wide range of cardiovascular abnormalities. This may reflect different pathophysiological mechanisms.

Risk stratification of patients presenting with acute chest pain is crucial for immediate and long-term management. Traditional predictors are suboptimal; therefore inflammatory biomarkers are studied for clinical assessment of patients at risk. Recently, we reported the association of IgM-uria with worse cardiovascular outcome in patients with acute chest pain. In this study, in the same cohort of patients with chest pain, we compared the value of IgM-uria to pro-inflammatory cytokines in predicting the occurrence of subsequent cardiovascular events.A total of 178 consecutive patients presenting with acute chest pain to the emergency department at the University Hospital of Lund, were recruited. Twenty-seven of 57 patients with acute coronary syndrome (ACS), and 18 of 118 patients with non-specific chest pain at baseline developed a subsequent major cardiovascular event during the 18 months follow-up. Urinary proteins (IgM-uria and Microalbuminuria) and plasma inflammatory markers (IL-6, Il-8, IL-10, IFN-γ and TNF-α) were measured at time of admission.Using the receiver operating characteristic curves, the area under the curve for predicting cardiovascular events was 0.71 (95%CI 0.61-0.81) for IgM-uria, 0.61 (95%CI 0.51-0.71) for IL-6, 0.63 (95%CI 0.53-0.72) for IL-8, 0.65 (95%CI 0.56-0.74) for IL-10, and 0.64 (95% CI 0.54-0.74) for TNF-α. In multivariate Cox-regression analysis adjusted for age, microalbuminuria, IgM-uria, IL-10, TNF-α, troponin T, hsCRP and ACS at baseline; IgM-uria was the only biomarker that remained an independent predictor of outcome (HR = 4.2, 95%CI 2.2-7.8, p0.001).In patients with chest pain with or without acute coronary syndrome, IgM-uria could better predict the occurrence of cardiovascular events than plasma pro-inflammatory cytokines.

The purpose of this study was to investigate the preferences of people with diabetes for liraglutide vs other glucose lowering drugs, based on outcomes of clinical trials.Willingness to pay (WTP) for diabetes drug treatment was assessed by combining results from a recent WTP study with analysis of results from the Liraglutide Effect and Action in Diabetes (LEAD) programme. The LEAD programme included six randomised clinical trials with 3967 participants analysing efficacy and safety of liraglutide 1.2 mg (LEAD 1-6 trials), rosiglitazone (LEAD 1 trial), glimepiride (LEAD 2-3 trials), insulin glargine (LEAD 5 trial), and exenatide (LEAD 6 trial). The WTP survey used discrete choice experimental (DCE) methodology to evaluate the convenience and clinical effects of glucose lowering treatments.People with type 2 diabetes were prepared to pay an extra €2.64/day for liraglutide compared with rosiglitazone, an extra €1.94/day compared with glimepiride, an extra €3.36/day compared with insulin glargine, and an extra €0.81/day compared with exenatide. Weight loss was the largest component of WTP for liraglutide compared with rosiglitazone, glimepiride, and insulin glargine. Differences in the administration of the two drugs was the largest component of WTP for liraglutide (once daily anytime) compared with exenatide (twice daily with meals). A limitation of the study was that it was based on six clinical trials where liraglutide was the test drug, but each trial had a different comparator, therefore the clinical effects of liraglutide were much better documented than the comparators.WTP analyses of the clinical results from the LEAD programme suggested that participants with type 2 diabetes were willing to pay appreciably more for liraglutide than other glucose lowering treatments. This was driven by the relative advantage of weight loss compared with rosiglitazone, glimepiride, and insulin glargine, and administration frequency compared with exenatide.

Aims: To evaluate the effects of adding glucagon-like peptide-1 (GLP-1) analogue therapy to insulin on glycated hemoglobin (HbA1c), weight, insulin dosage, treatment satisfaction, and risk of hypoglycaemia. Methods: Type 2 diabetes patients with insulin therapy receiving a GLP-1 analogue at 4 Swedish centers were studied. Hypoglycemia was evaluated using glucometers and patient self-report. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was used to evaluate treatment satisfaction. Results: Among 65 patients studied, 4 discontinued therapy, none due to hypoglycemia, and there were no suspected severe adverse events. Among 61 patients who remained on therapy over a mean of 7.0 months, 40 were treated with liraglutide and 21 with exenatide. HbA1c decreased from a mean of 8.9% (82.4 mmol/mol) to 7.9% (71.9 mmol/mol) (p < 0.001), weight decreased from 111.1 kg to 104.0 kg (p

This study investigated whether metabolic derangement at diagnosis of diabetes mellitus affects the function of the basement membrane and the excretion of several components and whether insulin treatment can normalize this. It was designed to evaluate urinary excretion rates of transforming growth factor-beta(1) (TGF-beta(1)), the carboxy-terminal domain of collagen IV (NC1) and albumin in children during the first 20 days of treatment after diagnosis of type 1 diabetes.Thirty-four newly diagnosed diabetic children between 4 and 16 years of age and 26 healthy children of matching age were studied with timed overnight urine collections. Urine was collected during the first 20 days of treatment.Urinary excretion of albumin and TGF-beta(1) in diabetic children were significantly increased at entry but normalized during 20 days of treatment with insulin compared with control children. In contrast, the non-significant high NC1 excretion at diagnosis did not change but became significantly increased after 20 days of insulin treatment. Overall, the kidney size was within normal limits and unaffected by treatment. The largest kidneys had less NC1 excretion (R= - 0.67, p0.05, n=13) and a lower glomerular filtration rate (R= - 0.77, p0.01, n=10) than the smallest kidneys. After 20 days of treatment TGF-beta(1) excretion had decreased in children with kidney size8.5 cm.Correction of the metabolic derangement with insulin decreased excretion of albumin and TGF-beta(1), but had no effect on kidney size and urine NC1 excretion, presumably because the observation period was too short.

In a previous study, we found urinary excretion of Tamm-Horsfall protein (THP) to be persistently decreased in 25% of patients during the first year after diagnosis of diabetes mellitus. We thus wanted to study another marker for distal tubular function, pi glutathione S-transferase (pi-GST) and compare this and THP with proximal tubular function evaluated with alpha-GST and alpha-1-microglobulin (HC) in patients with longer duration of diabetes. One hundred and eighty-four diabetic and 16 control children were studied with timed overnight urine collections. Median age was 14 years, and median age at diagnosis was 8 years. The urinary excretion of alpha- and pi-GST was significant lower in diabetic than control children. There were no differences in the excretion of HC and THP. Diabetic children with decreased alpha-GST had higher albumin excretion, HbA 1c levels, and longer diabetes duration but decreased THP excretion and cystatin-C clearance compared with those with normal excretion. In contrast, a decreased pi-GST or THP excretion was not associated with such differences. Diabetic children with increased HC excretion had increased HbA 1c levels. Diabetic children, before the stage of microalbuminuria, may have signs of both proximal and distal tubular dysfunction, which is related to diabetes duration and poor metabolic control. Alpha-GST and pi-GST seem to be more sensitive than other parameters studied.

Objective. The first changes in the diabetic kidney are glycogen deposits in the epithelial cells of the thick ascending limb of Henle. These cells produce Tamm-Horsfall protein (THP). Is low excretion of THP associated with the development of renal insufficiency or cardiovascular disease? Material and methods. Urine samples were collected at baseline in patients with type 1 (n=131) and type 2 (n=108) diabetes who were followed for a mean of 14 years (range 1-20 years) and 4.5 years (range 1-15 years), respectively. Results. Twenty percent of type 1 and 54% of type 2 diabetic patients died and 24% and 29%, respectively developed uraemia. A decreased urinary concentration of THP (u-THP) was associated with an eight-fold increased risk of renal failure and cardiovascular death in type 1 but not in type 2 diabetic patients, irrespective of the degree of albuminuria and glycosylated haemoglobin and blood pressure levels. There were no differences in the degrees of albuminuria, serum creatinine or u-THP between the two types of diabetic patients at baseline. Low u-THP occurred in 8% and 9% of normoalbuminuric type 1 and type 2 diabetic patients, respectively. Conclusion. A decreased u-THP was associated with an eight-fold increased risk of cardiovascular death and uraemia in type 1 but not in type 2 diabetic patients. (Less)

Objective: To investigate the relationship between early-onset retinopathy and urinary markers of renal dysfunction. Research Design and Methods: The Diabetes Incidence Study in Sweden (DISS) aims to register all new cases of diabetes in young adults (15-34 years). In 1987-1988, 806 patients were reported and later invited to participate in a follow-up study focusing on microvascular complications after similar to 10 years of diabetes. In the present study, 149 patients with type I diabetes, completed eye examination, and urine sampling were included. Results: The patients with retinopathy (n=58, 39%) had higher HbA(1c), (P

Introduction: A state of hypercoagulation and fibrinolytic dysfunction is present in individuals with diabetes, which may contribute to disturbed skin microcirculation and impaired ulcer heating. We have previously reported an improved outcome of chronic diabetic foot ulcers during treatment with dalteparin. In the present study we investigated the effects of dalteparin on skin microcirculation and haemostatic function. Materials and methods: 87 patients with diabetes, peripheral arterial obliterative disease and chronic foot ulcers were investigated in a prospective, randomised, double-blind and placebo-controlled study. They were randomised to treatment with subcutaneous injections of 5000 U dalteparin (n = 44) or placebo (n = 43), once daily until ulcer heating or for a maximum of six months. Plasma fibrinogen, fibrin get structure [permeability coefficient (Ks) and fiber mass/length ratio (mu)], prothrombin fragment 1 +2 (F1 +2) antigen, plasminogen activator inhibitor-1 (PAI-1) activity and tissue plasminogen activator (tPA) antigen were analysed before randomization (baseline value), and at the end of the treatment period. The skin microcirculation of the foot was investigated by transcutaneous oxygen tension (TcPO2) and laser Doppler ftuxmetry (LDF). Results: The changes (A-values) of Ks, mu, tPA and TcPO2 were higher (p

Study question What are the effects of liraglutide, an incretin based treatment, on glycaemic control in people with type 2 diabetes treated with multiple daily insulin injections? Methods The study was a randomised, double blind, placebo controlled trial with a parallel group design carried out at 13 hospital based outpatient clinics and one primary care unit in Sweden. Patients were considered eligible for inclusion if they had type 2 diabetes and inadequate glycaemic control (HbA1c concentrations ≥58 mmol/mol (7.5%) and ≤102 mmol/mol (11.5%)), a body mass index of 27.5-45 kg/m2, and required multiple daily insulin injections. Overall, 124 participants were randomised 1:1 to subcutaneous liraglutide or placebo by minimisation allocation. The main outcome measure was change in HbA1c level from baseline to week 24. Study answer and limitations Liraglutide was associated with a significant reduction of 16.9 mmol/mol (1.5%) in HbA1c versus 4.6 mmol/mol (0.4%) for placebo, difference −12.3 mmol/mol (95% confidence interval −15.8 to −8.8 mmol/mol; −1.13%, −1.45 to −0.81 mmol/mol). Body weight was significantly reduced in participants in the liraglutide compared with placebo group (3.8 v 0.0 kg, difference −3.8, −4.9 to −2.8 kg), and total daily insulin doses were significantly reduced, by 18.1 units and 2.3 units (difference −15.8, −23.1 to −8.5 units). Reductions in mean and standard deviation of glucose levels estimated by masked continuous glucose monitoring were significantly greater in the liraglutide group than placebo group (−1.9 and −0.5 mmol/L). Neither group experienced severe hypoglycaemic events nor were there any significant differences in symptomatic or asymptomatic non-severe hypoglycaemia (

Background. Renal function at diagnosis is a strong predictor not only of renal survival but also of patient survival of those with anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis (ASVV). Apart from the renal function at diagnosis, there are no other established risk factors for renal outcome in ASVV. We have previously reported that in other forms of glomerular diseases, an increased urine excretion of IgM is an early marker of poor renal outcome. Methods. In this single-centre observational study, the prognostic significance of urine IgM excretion and other selected prognostic markers was studied in 83 consecutive patients (49 males, 34 females) with ASVV with renal involvement. Results. Patient survival at 1 and 5 years was 93 and 77%, respectively, and the corresponding figures for renal survival censored for death were 84 and 76%. Univariate analysis indicated that patient survival was inversely associated with age, male sex, serum creatinine, low serum albumin and high urine IgM excretion. Renal survival was inversely associated with serum creatinine, albuminuria and urine IgM. Multivariate analysis determined that only old age and high urine IgM excretion were independent predictors of patient survival [odds ratio (OR) ¼ 11.2 and 4.4, respectively, P

Background/aims To investigate possible relationships between ambulatory blood pressure (BP) and renal structure and function in type 2 diabetic patients. Methods Renal biopsies were performed on 39 patients with urine albumin concentrations above 100 mg/l. BP was investigated with a 24-h, automated, portable BP device. Results None of the patients in the study had signs of other renal disease than nephrosclerosis or diabetic nephropathy. Ten patients had slight, 13 intermediate, and 6 severe diabetic nephropathy on the renal biopsy. Among the remaining patients, 4 had normal microscopy findings and 6 had nephrosclerosis. The degree of albuminuria correlated to the systolic BP during the day ( r =.43; P r =.49; P r =−.32; P r =−.47; P P Conclusions We have demonstrated that degree of albuminuria and GFR was significantly associated with daytime and nocturnal BP and glomerular structure with daytime BP. Furthermore, no renal disease other than diabetic nephropathy was found.

Background/Aims: Increased salt intake and enhanced salt sensitivity are implicated in the pathogenesis of hypertension. The aim of the present study was to investigate whether the urinary excretion rate of Tamm-Horsfall protein (THP) is dependent on salt intake in healthy, genetically hypertension-prone individuals. Methods: Thirty unrelated subjects (13 men and 17 women, mean age 48.1 ± 6.7 years) with at least one first-degree relative with primary hypertension were studied. After a baseline investigation, the study subjects were put on a low-salt diet (10 mmol of sodium and 70 mmol of potassium per day) for 1 week. During the second week, sodium chloride capsules (230 mmol/day) were added to the diet to achieve a high-salt intake of 240 mmol/day. Urine samples (24-hour and overnight collections) were collected before the baseline investigation and at the end of the high- and low-salt diet weeks. The salt sensitivity was calculated as the difference between the blood pressure during high salt intake and the blood pressure during low salt intake. Results: A low salt intake induced a decrease in the urinary excretion rate of THP during the night (11.7 µg/min) compared with baseline (19.5 µg/min; p < 0.05) and high salt intake (23.1 µg/min; p < 0.01). Furthermore, a greater response in blood pressure to a high salt intake, i.e. high salt sensitivity, was associated with increased excretion of THP in urine during the change to high salt intake (r = 0.38, p < 0.05). Conclusion: We were able to confirm that urinary excretion of THP is dependent on sodium intake. Patients with a high salt sensitivity, i.e. an exaggerated blood pressure response to high salt intake, responded to the high salt intake with an even greater increase in the urinary excretion rate of THP. The mechanism underlying this response is still unknown, but it might indicate that distal nephron function in healthy, genetically hypertension-prone individuals is altered.

OBJECTIVE—To estimate the occurrence of early-onset renal involvement in a nationwide population-based cohort of young adults with diabetes in Sweden and relate the findings to glycemic control, type of diabetes, sex, smoking, and blood pressure. RESEARCH DESIGN AND METHODS—The Diabetes Incidence Study in Sweden aims to register all incident cases of diabetes in the age-group 15–34 years. In 1987–1988, 806 patients were reported and invited to participate in a follow-up study focusing on microvascular complications. Of them, 469 subjects participated. The assessment was based on questionnaires (n = 469), blood samples (n = 424), urine samples (n = 251) and, when appropriate, medical records (n = 186). RESULTS—During the follow-up time, median 9 years (range 6–12), 31 of 469 patients (6.6%) with incipient or overt diabetic nephropathy (i.e., micro- or macroalbuminuria) were found, 24 of 426 (5.6%) in type 1 and 7 of 43 (16%) in type 2 diabetic subjects (P = 0.016). Additionally, 24 of 31 patients (77%) had microalbuminuria and 7 (23%) had macroalbuminuria, which mainly occurred in patients with type 2 diabetes. In a Cox regression analysis, high mean HbA1c during the follow-up period and high blood pressure at follow-up increased the risk of developing signs of nephropathy (P = 0.020 and P = 0.003, respectively). Compared with patients with type 1 diabetes, those with type 2 diabetes tended to have an increased risk of renal involvement (P = 0.054) when adjusting for sex, tobacco use, glycemic control, and blood pressure. CONCLUSIONS—Despite modern treatment and self-monitoring of blood glucose, young adult patients with diabetes may still develop renal involvement during the first 10 years of diabetes duration. Inadequate HbA1c, high blood pressure, and type 2 diabetes appear to be risk markers for early occurrence of diabetic nephropathy.

OBJECTIVE—Chronic foot ulcers are a common, severe, and expensive complication threatening life and limb in patients with diabetes. The aim of the present study was to investigate the effect of dalteparin on ulcer outcome in patients with diabetes, peripheral arterial occlusive disease, and chronic foot ulcers. RESEARCH DESIGN AND METHODS—A total of 87 patients were investigated in a prospective, randomized, double-blind, placebo-controlled trial. Participants were randomized to treatment with subcutaneous injection of 5,000 units dalteparin (Fragmin, Pharmacia Corporation; n = 44) or an equivalent volume of physiological saline (n = 43) once daily until ulcer healing or for a maximum of 6 months. Ulcer outcome was investigated by evaluating the number of patients 1) who healed with intact skin; 2) in whom the study ulcer was improved, unchanged, or impaired; or 3) who were amputated above or below the ankle level, as compared with control subjects. RESULTS—Two patients, one on dalteparin and one on placebo, dropped out of the study. Ulcer outcome was significantly better (P = 0.042, two-sided χ2 test for trend) in the dalteparin group (n = 43) compared with the placebo group (n = 42). A total of 29 patients healed with intact skin (n = 14) or decreased the ulcer area ≥50% (n = 15) in the dalteparin group compared with 20 (n = 9 and 11, respectively) in the placebo group. Five patients in each group showed impaired ulcer healing, i.e., the ulcer area increased ≥50%. Two patients in the dalteparin group were amputated compared with eight in the placebo group. Time to healing with intact skin was 17 ± 8 weeks in the dalteparin group compared with 16 ± 7 weeks in placebo group (NS). CONCLUSIONS—The results of the present study indicate that dalteparin improves the outcome of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease.

Purpose: To examine whether panretinal photocoagulation for severe nonproliferative retinopathy in type 1 diabetes patients could halt the progression of retinopathy with subsequent vitreous haemorrhages and visual impairment. Methods: During a 10-year follow-up study period of 344 type 1 diabetes patients, 81 subjects went through panretinal photocoagulation. Forty patients were treated for severe non-proliferative retinopathy (age at onset of diabetes 14 � 8 years, diabetes duration 18 þ 10 years) and 41 for proliferative retinopathy (age at onset 15 � 10 years, diabetes duration 22 þ 13 years). One randomly selected eye per patient forms the basis for the study. Metabolic control, systolic and diastolic blood pressure, serum creatinine and urinary albumin levels were measured and analysed yearly during the follow-up period. Results: A total of 35% (14/40) of eyes treated for severe non-proliferative retinopathy developed neovascularizations during a mean time of 2.9 � 1.5 years. Vitreous haemorrhages were more frequent in eyes with proliferative retinopathy at treatment than in eyes with severe non-proliferative retinopathy (12/41 versus 2/40; p ¼ 0.007). The number of vitrectomies due to vitreous haemorrhages in eyes treated for severe non-proliferative retinopathy tended to be lower (1/40 versus 6/41; p ¼ 0.052). Before photocoagulation, visual acuity (VA) was similar in eyes with severe non-proliferative retinopathy and in those with proliferative retinopathy (1.0, 0.4–1.0 versus 1.0, 0.1–1.0; median and range). Visual impairment and blindness tended to develop more often in eyes treated for proliferative retinopathy compared to those treated for severe non-proliferative retinopathy (10/40 versus 4/40; p ¼ 0.056). Eyes with neovascularizations at follow-up were more often visually impaired (VA < 0.5) than eyes without neovascularizations (15/55 versus 1/26; p ¼ 0.016). Conclusion: In type 1 diabetes, panretinal photocoagulation may be beneficial even at the severe non-proliferative retinopathy stage in terms of preventing vitreous haemorrhage, subsequent vitrectomy and visual impairment.

Objective: Do exaggerated increases in blood pressure and albuminuria during exercise occur earlier than microalbuminuria and which type of test is most predictive of diabetic nephropathy? Material and Methods: A total of 33 insulin-dependent normoalbuminuric men (mean duration of diabetes 14 years; mean age 28 years) and 34 age-matched apparently healthy control subjects were studied. Urinary albumin excretion, heart rate and blood pressure were measured during fixed workload (150 W) and fixed heart rate (155 beats/min) tests. Mean follow-up time was 13.1 +/- 3.2 years. A urinary albumin level in early-morning urine persistently >30 mg/l was considered a sign of diabetic nephropathy. Results: Sixteen patients reached the endpoints of the study. Eleven had developed microalbuminuria and five macroalbuminuria (persistent levels of urinary albumin >300 mg/l). Of the latter patients, two needed dialysis. Systolic blood pressure and albumin excretion during the fixed heart rate test were higher in diabetic patients who developed signs of nephropathy than in control subjects and diabetic subjects with persistent healthy kidneys. Such differences were not found in the fixed workload test. There were no differences in glycated haemoglobin, blood pressure levels or albumin excretion at baseline between the two diabetic groups. Conclusions: To predict the development of diabetic nephropathy it seems important to choose a fixed heart rate test. High levels of systolic blood pressure in such a test were associated with the development of micro- and macroalbuminuria. (Less)

We investigated whether aminoguanidine (AG), an inhibitor of advanced glycated end product formation, or probucol (PB), a free radical scavenger, could influence signs of glomerular and distal tubular function and morphological changes in kidneys of male Wistar rats after 6 months of streptozocin (STZ)-induced diabetes. Diabetic rats had a higher kidney weight/body weight ratio (P

AIMS: Can a cut-off blood pressure level for major complications be identified? METHODS: A 10 years observation study in 385 type 2 diabetic patients. RESULTS: 158 patients were affected with myocardial infarction, stroke, renal failure or death, which occurred in 68, 55, 19 and 109 patients, respectively. No patient with a blood pressure below 140 mmHg and/or a diastolic blood pressure below 75 mmHg developed uraemia during the observation period. No such cut-off level was seen for myocardial infarction, stroke or death. CONCLUSIONS: This study shows that there seems to be a cut-off level for blood pressure for development of renal failure, while no level was found for cardio- or cerebrovascular disorders.

Aims Patients with type 2 diabetes are generally treated in primary care setting and as a final treatment step to obtain good glycaemic control, multiple daily insulin injections (MDI) are generally used. The aim of this study is to evaluate the effect of GLP-1 analogue liraglutide on glycaemic control in patients with type 2 diabetes treated with MDI with inadequate glycaemic control. Methods Overweight and obese patients with type 2 diabetes and impaired glycaemic control treated with MDI were randomised to liraglutide or placebo over 24 weeks. Masked continuous glucose monitoring was performed at baseline and during the trial. The primary endpoint was the change in haemoglobin A1c from baseline to week 24. Additional endpoints include changes in weight, fasting glucose, glycaemic variability, treatment satisfaction, insulin dose, hypoglycaemias, blood pressure and blood lipid levels. Results Recruitment occurred between February 2013 and February 2014. A total of 124 patients were randomised. Study completion is anticipated in August 2014. Conclusions It is expected that the results of this study will establish whether adding liraglutide to patients with type 2 diabetes treated with MDI will improve glycaemic control, lower body weight, and influence glycaemic variability.

The aim of the present study was to find clinical parameters affecting incidence and progression of nephropathy in type 2 diabetic patients. A prospective study for 10 years was performed in 385 type 2 diabetic patients (diabetes diagnosis > or =30 years) attending a hospital-based outpatient clinic. Medical risk indicators like diabetes duration, HbA(1c), and blood pressure were related to the development and progression of diabetic nephropathy. The 10-year incidence of microalbuminuria was 38% (n=95) and that of macroalbuminuria was 10% (n=26). Out of 103 patients with microalbuminuria, 38 developed macroalbuminuria. In 252 normoalbuminuric patients, the mean of the HbA(1c) (P

The transport of large proteins across the glomerular capillary wall (GCW) may increase several fold in glomerular diseases. The occurrence of IgM in urine is a consequence of the presence of large defects or shunts in the GCW, whereas albuminuria is probably a result of an altered charge- and size-selectivity of the GCW. In order to examine whether patho-morphological differences influence the renal outcome in proteinuric glomerulopathies, we examined urinary excretion of IgM and albumin as prognostic markers of glomerular disease.An observational study over a median of 41 (+/-3) months was conducted in 84 patients with biopsy-verified glomerular disease. The patients were subdivided into groups with low (or =0.002) and high (0.002) proteinuria selectivity index based upon IgM (IgM-SI), and into groups with low (or =200 mg/mmol) and high (200 mg/mmol) albumin creatinine index (ACI).In the high IgM-SI group, the median creatinine clearance (Ccr) decreased by 26%, and 62% of the patients decreased in Ccr by5 ml/ min/year during the follow-up time. In comparison, the median Ccr decreased by 8% in the low IgM-SI group (P0.001) and only 18% of the patients in this group deteriorated by5 ml/min/year in the Ccr. Eleven (21%) of the 51 patients in the high IgM-SI group developed end-stage renal failure compared with none of the 33 patients in the low IgM-SI group. All the patients that progressed to uraemia had decreased Ccr (60 ml/min) at entry into the study. However, among all these patients, only those with high IgM-SI, and none with low IgM-SI, developed end stage renal failure. The fall in Ccr did not differ significantly between the patients in high (12%) and low (16%) ACI groups.The results of this study indicate that an increased IgM-SI value is a stronger predictor of clinical outcome in proteinuric glomerulopathies than baseline albuminuria. This finding may reflect different patho-histological mechanisms influencing renal survival in glomerular diseases.

The objective was to study the development and progression of heart disease in type 2 diabetic patients and to evaluate the influence of revascularisation procedures on its outcome. A 10-year observation study in 385 patients attending a hospital-based outpatient clinic was performed. A total of 156/385 patients developed myocardial infarction (n=68), angina (n=44), heart failure (n=34) or died (n=109). A high mortality was seen in patients with myocardial infarction (73%) and heart failure (71%), in contrast, to patients with angina (25%). Thirty patients had a coronary angiography because of angina, out of which 23 were revascularised. Four (17%) of patients with bypass surgery or angioplasty died compared with 57 (67%) of the patients with no intervention (p

Alterations of the charge-selective properties of the glomerular capillary wall are important constituents of the pathogenesis of many glomerular diseases. Thus, differences in the degree of such changes could be of help in understanding the mechanisms governing the transport of macromolecules across the glomerular capillary wall.The ratio between urine concentrations of neutral IgG2 and negatively charged IgG4 (IgG2/IgG4-ratio) was measured in 150 proteinuric patients and 21 healthy controls. The patients were subdivided into seven biopsy verified diagnostic groups.The study revealed decreased IgG2/ IgG4-ratio in membranous glomerulonephritis (0.57) compared to healthy controls (2.09) and to all other diagnosis groups; crescentic necrotizing glomerulonephritis (1.28), diffuse proliferative glomerulonephritis (1.10), IgA nephropathy (1.11), mesangial proliferative glomerulonephritis (1.55), minimal change nephropathy (1.00), and nephrosclerosis secondary to hypertension (1.06). Although not statistically significant, there was a tendency towards lower IgG2/IgG4-ratio values in all the studied glomerular diseases compared to healthy controls.Since IgG is transported entirely through the large pores of the glomerular basement membrane decreased IgG2/IgG4-ratio implies that this pathway is strongly influenced by the charge-selective properties of the glomerular capillary wall. The conclusion that could be drawn from that is that the large pore radius must be discrete, in the order of 80-90 A, and thus not non-discriminatory to macromolecules as previously thought.

OBJECTIVE: The study was performed in order to evaluate to what extent hypertension or diabetes mellitus may affect the urinary excretion rate of Tamm-Horsfall protein. MATERIALS AND METHOD: The urinary excretion rates of albumin and Tamm-Horsfall protein, a measure of glomerular and distal tubular function, respectively were measured in patients with essential hypertension (n = 17) and in type 1 diabetes with (n = 20) or without nephropathy (n = 8) and in apparently healthy subjects (n = 10). RESULTS: Mean 24-h ambulatory blood pressure measurements showed higher blood pressure levels in the hypertensive (167/ 106 mmHg, p < 0.001) than in the diabetic patients with (136/84 mmHg) and without nephropathy (121/74 mmHg) and in healthy subjects (122/76 mmHg). Day and night ratios of systolic and diastolic blood pressure levels were not different among the four groups. Urinary albumin excretion rate was increased in patients with hypertension (30.8 x/ 3.4 microg/min; geometric mean x/tolerance factor; p < 0.001) and diabetes with nephropathy (462 x/ 3.5 microg/min; p < 0.001) compared with diabetic patients without nephropathy and healthy subjects (4.6 x/ 1.9 and 3.7 x/ 1.5 microg/min, respectively). The Tamm-Horsfall protein excretion rate was decreased in patients with diabetic nephropathy (11.6 x/ 3.5 microg/min) compared to patients with hypertension (36.3 x/2.1 1g/min; p < 0.01), diabetes without nephropathy (39.2 x/ 2.0 microg/min; p < 0.05) and healthy subjects (63.0 x/ 1.4 microg/min; p < 0.001), whereas no differences were found among the latter three groups. CONCLUSION: These data indicate that high blood pressure may be associated with albuminuria, while a decrease in excretion rate of Tamm-Horsfall protein may be associated with diabetic nephropathy. These associations need to be studied in a larger population. (Less)

In diabetic nephropathy there is a decrease in glycosaminoglycans (GAG) in basement membranes and in Tamm-Horsfall protein (THP) in the distal tubules of the kidneys. Since GAG is present in both glomerular and tubular basement membranes, and the synthesis of both GAG and THP involves glycosylation, this study was carried out in order to investigate whether urinary excretion of these substances is interrelated.24-h urinary collections were analysed. A total of 94 diabetic patients were grouped in accordance with the urinary albumin excretion rate as normo- (20 microg/min) (n = 35), micro- (20-200 microg/min) (n = 30) and macroalbuminuria (200 microg/min) (n = 29).In comparison with 26 control subjects, the excretion rate of GAG was decreased in patients with micro- and macroalbuminuria and excretion of Tamm-Horsfall protein in patients with macroalbuminuria. The excretion rates of GAG and THP were associated (r = 0.64, p0.001) and correlated with creatinine clearance (r= 0.46 and r= 0.53, p0.001; respectively) but not with levels of HbA1c.In conclusion, albuminuria was associated with decreased urinary excretion of sulphated GAGs, which was associated with the excretion rate of Tamm-Horsfall protein, indicating that excretion of GAG was associated with distal tubular dysfunction in diabetic patients.

Background: In diabetic nephropathy, a reduction in negative membrane charge in the glomerular filter, i.e., the number of sulphated groups of glycosaminoglycans, has been argued to lead to increases in excretion of negatively charged molecules, such as albumin and IgG4. However, albuminuria and an increased excretion rate of IgG may also be caused by an increase in radius or number of glomerular large pores. Methods: Timed urinary excretion rates of sulphated glycosaminoglycans, albumin, and IgG2, IgG4, and IgM were analyzed in 94 patients with insulin-dependent diabetes mellitus with different degrees of nephropathy and compared with the excretion rates in 26 control subjects. Sulphated glycosaminoglycans were measured spectrophotometrically after addition of 1,9-dimethylmethylene blue. Albumin and immunoglobulins were measured by immunoassays. Results: With increases in the albumin excretion rate the excretion of IgG2, IgG4, and IgM also increased, in contrast to a decrease in glycosaminoglycans and the ratio between IgG2 and IgG4 (selectivity index). This index decreased from 6.2 to 0.7 (median; p < 0.01). However, with linear regression analysis the excretion rates of albumin and immunoglobulins were not associated with those of glycosaminoglycans. Conclusion: In diabetic nephropathy changes in both large-pore number and in charge selectivity may be pathogenic mechanisms for albuminuria.

Proteinuria selectivity index based upon α 2 -macroglobulin or IgM is superior to the IgG based index in differentiating glomerular diseases. Technical Note. Background The proteinuria selectivity index (SI) may be used to describe changes of the glomerular permeability for macromolecules in glomerular diseases. Proteins the size of α 2 -macroglobulin (α 2 M) or IgM cannot normally pass the glomerular barrier, whereas IgG can pass through the large pores of glomerular basement membrane. Comparison of the clearance of the three high-molecular-weight proteins to that of albumin may be useful in characterization and diagnosis of different glomerular diseases as well as in understanding of the permeability characteristics of the glomerular filter. Methods Three types of SI, each calculated as a ratio of clearance of either IgG, α 2 M or IgM to that of albumin, were measured in 199 proteinuric patients. The patients were subdivided into eight different biopsy-verified glomerular diseases. Results Two diagnoses could be clearly distinguished using SI based on α 2 M (α 2 M SI) or IgM (IgM SI). Both α 2 M SI and IgM SI were significantly lower in minimal change nephropathy and higher in crescentic necrotizing glomerulonephritis than in all the other diagnoses. The SI based on IgG (IgG SI) was less useful in determining specific diagnoses, since patients with minimal change nephropathy could not be distinguished from those with other types of primary glomerulonephritis and patients with crescentic necrotizing glomerulonephritis did not differ from those with diabetic nephropathy. Conclusions The findings of this study indicate that α 2 M SI and IgM SI are superior to IgG SI in characterization of glomerular disorders and might replace the IgG SI for this purpose.

Tamm-Horsfall protein (THP) and epidermal growth factor (EGF) are both synthesized by tubular cells in the distal part of the nephron and excreted with the urine. The present study examines the urinary excretion rates of the two peptides in relation to functional tubular markers in patients with chronic nephropathy. Four groups of patients with moderate to severely reduced renal function were studied: glomerulonephritis (n = 10), diabetic nephropathy (n = 11), tubulointerstitial nephropathy (n = 13), and polycystic kidney disease (n = 8). The renal function was evaluated by glomerular filtration rate (GFR) as an indicator for the general renal function, lithium clearance (CLi) as an indicator for proximal tubular function, and absolute distal reabsorption of sodium (ADRNa) as an indicator for distal tubular function. The excretion rate of EGF was rather closely correlated with GFR, CLi and ADRNa (Spearman coefficients of variation 0.88, 0.69, and 0.74, respectively). The correlations between the excretion rate of THP and GFR, CLi and ADRNa were weaker (Spearman coefficients of variation 0.68, 0.42, and 0.44). When the effect of GFR had been accounted for by multiple variance analyses, the excretion rates of the two peptides were still associated with ADRNa but not with CLi. In conclusion, the urinary excretion rates of especially EGF but also those of THP were correlated with renal function and distal tubular reabsorption of sodium in patients with chronic nephropathy.

The effect of 50 days of streptozotocine-induced diabetes mellitus (blood glucose 20 mmol/l) on contraction and relaxation of isolated renal and intrarenal arteries in rats were examined. Strong and similar contractions were induced by potassium (60 mM), 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) in renal and intrarenal arteries in diabetic and control rats. The vasodilatory reactivity, after precontraction with 5-HT, of neuropeptide Y (NPY) was similar to that of acetylcholine (ACh), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and was similar in diabetic and control rats. The relaxing effect of NPY was decreased (40%) only in the diabetic group by blockade of nitric oxide synthase with NG-nitro-L-arginine methyl ester (10(-4) M) and by blockade (50%) of NPY with alpha-trinositol (10(-6) M). In conclusion, the present study showed that diabetes mellitus in the rat is associated with normal vasoconstrictive and vasodilatory capacities. However, the vasodilatory response to NPY was largely eliminated by blockade of nitric oxide synthesis only in the diabetic animals. This indicates that the vasodilatory effect of NPY in diabetes mellitus may be dependent on nitric oxide synthesis.

The aim of the present study was to examine mean HbA1c and blood pressure levels during a 5 year period in 442 type 1 adult diabetic patients in relation to the incidence and progression of retinopathy, nephropathy and to cardiovascular morbidity and mortality. The study showed, that in patients under routine care at a diabetic unit with four visits to the out-patient clinic per year, the intraindividual coefficient of variation for HbA1c values was 11 +/- 4% (mean +/- S.D.), and 7 +/- 3 and 8 +/- 2% for systolic and diastolic blood pressure, respectively. In 121 patients without retinopathy at entry, the 5 year incidence of any retinopathy was 47% (n = 57). Patients who developed retinopathy had higher mean HbA1c levels (P0.01), as well as mean systolic (P0.01) and diastolic (P0.05) blood pressure levels. In 123 patients with background retinopathy at entry, progression to severe retinopathy, i.e. clinically significant macular oedema, severe non-proliferative or proliferative retinopathy, occurred in 41% (n = 51). In those patients, the degree of metabolic control was worse (P0.001), the systolic (P0.05) and diastolic (P0.01) blood pressure levels were higher. The patients were stratified into four groups according to their urinary albumin concentration at entry: (1) normal albuminuria (12.5 mg/l), (2) borderline albuminuria (12.5-30 mg/l), (3) microalbuminuria (31-299 mg/l), i.c. incipient nephropathy and (4) clinical nephropathy (or = 300 mg/l). An increase of urinary albumin concentration in patients who had normoalbuminuria or borderline albuminuria at entry was associated with mean HbA1c levels (r = 0.24, P0.01 and r = 0.27, P0.01, respectively). No such association was seen in patients with microalbuminuria or clinical nephropathy at entry. There was no association between the increase of urinary albumin level and mean systolic blood pressure levels in patients who had normoalbuminuria and microalbuminuria at entry. In contrast, there was an association between the increase of urinary albumin level in patients with borderline albuminuria (r = 0.36, P0.001), clinical nephropathy (r = 0.26, P0.05) and mean systolic blood pressure (P0.05). There was no association between the increase of urinary albumin levels and mean diastolic blood pressure in any of the albuminuria groups. As for the incidence of cardiovascular disease, renal insufficiency or death, the duration of diabetes (P0.01), urinary albumin concentration at entry (P0.001), mean systolic blood pressure (P0.05) and treatment with loop diuretics (P0.001) were but age, age at onset of diabetes, mean levels of HbA1c and diastolic blood pressure as well as treatment with beta- or Ca-blockers or ACE inhibitors were not related to these end-points. In conclusion, the present study showed that there was an association between the degree of metabolic control and both development and progression of retinopathy and progression of nephropathy of early stages in type 1 diabetic patients treated under routine conditions. Moreover, both the incidence and progression of retinopathy and progression of nephropathy at later stages were also associated with the long-term blood pressure levels. However, HbA1c levels were not associated with morbidity and mortality in cardiovascular disease or development of renal insufficiency.

Diabetic cardiovascular autonomic neuropathy increases the risk of deterioration in renal function and is associated with increased mortality in patients with renal failure. Type 1 diabetic patients with long diabetes duration, matched for age (38 +/- 9 years) and diabetes duration (28 +/- 8 years) were studied regarding the association between cardiovascular autonomic nerve function and different degrees of diabetic nephropathy. Eighteen patients were normo- (30 mg/l), six micro- (30-300 mg/l), and 13 macroalbuminuric (300 mg/l) based on urinary albumin concentrations in three separate morning samples. They were compared with 33 control subjects with similar age. Autonomic nerve function was evaluated by measuring the response of heart rate to deep breathing and active standing. Beat-to-beat finger artery blood pressure (Finapres) was tested during active standing. During deep breathing both change in heart rate (17 +/- 11, 9 +/- 7 and 4 +/- 3 beats/min) and ratio between expiratory and inspiratory R-R intervals (1.32 +/- 0.24, 1.14 +/- 0.15 and 1.05 +/- 0.04) decreased from normo- over micro- to macroalbuminuria (p0.05 vs normoalbuminuric and control subjects [17 +/- 5 beats/min and 1.28 +/- 0.10, respectively]). Similar results were obtained during active standing with respect to change in systolic arterial blood pressure (3 +/- 8, 2 +/- 13 and -6 +/- 11 mmHg; p0.05 vs control subjects [8 +/- 11 mmHg]). However, the response of diastolic arterial blood pressure or mean heart rate to standing up did not differ between any of the groups. The ratio of maximum to minimum R-R interval during the dynamic response of heart rate to active standing decreased with the degree of nephropathy (1.27 +/- 0.17, 1.11 +/- 0.11 and 1.05 +/- 0.06) with significantly higher values in patients with normo- compared with patients with macroalbuminuria (p0.05). All patients groups had significantly lower values than control subjects (1.46 +/- 0.22, p0.05). The overshoot of the blood pressure after an initial fall during active standing decreased with the degree of diabetic nephropathy. In conclusion, type 1 diabetic patients with long duration of diabetes have signs of cardiovascular autonomic neuropathy, the severity of which is related to the degree of nephropathy.

Background Micro-albuminuria is a recognized predictor of cardiovascular morbidity and mortality in patients with coronary artery disease. We have previously reported, in diabetic and non-diabetic patients, that an increased urinary excretion of IgM is associated with higher cardiovascular mortality. The purpose of this study was to investigate the pattern of urinary IgM excretion in patients with acute coronary syndrome (ACS) and its correlation to cardiovascular outcome. Methods Urine albumin, and IgM to creatinine concentration ratios were determined in 178 consecutive patients presenting with chest pain to the Department of Emergency Medicine (ED) at the University Hospital of Lund. Fifty eight (23 female) patients had ACS, 55 (19 female) patients had stable angina (SA), and 65 (35 female) patients were diagnosed as non-specific chest pain (NS). Results Urine albumin and IgM excretions were significantly higher in patients with ACS (p = 0.001, and p = 0.029, respectively) compared to patients with NS-chest pain. During the 2 years follow-up time, 40 (19 female) patients suffered a new major cardiovascular event (ACS, acute heart failure, stroke) and 5 (4 male/1 female) patients died of cardiovascular cause. A high degree of albuminuria and IgM-uria significantly predicted cardiovascular mortality and morbidity (HR = 2.89, 95% CI: 1.48 - 5.66, p = 0.002). Microalbuminuric patients (≥3 mg/mmol) with high IgM-uria (≥0.005 mg/mmol) had a 3-fold higher risk for cardiovascular new events compared to patients with low IgM-uria (RR = 3.3, 95% CI: 1.1 - 9.9, p = 0.001). Conclusion In patients with chest pain, an increased urine IgM excretion, is associated with coronary artery disease and long-term cardiovascular complications. Measuring urine IgM concentration could have a clinical value in risk stratification of patients with ACS.

The effect of the non-ionic contrast medium iohexol (Omnipaque) on renal function was investigated in diabetic patients with signs of peripheral ischaemia. Forty-six patients, 70 +/- 11 years (mean +/- SD) old, age at diabetes diagnosis 53 +/- 17 years, and with varying degrees of diabetic nephropathy were studied before 1, 2, and 30 days after aortobifemoral arteriography. Serum creatinine, creatinine clearance, urinary excretion of immunoglobulin G, albumin collagen IV (NC1), kappa and lambda chains, alpha-1 microglobulin and Tamm-Horsfall protein were evaluated. Within 1 month before and 30 days after arteriography, the glomerular filtration rate was measured by clearance of iohexol. The acute effect of the radiocontrast medium was an increase in the serum creatinine level in 41 (89%) patients, with a more than 25% increase in 12 (26%) patients. The excretion rates of immunoglobulin G and albumin decreased, whereas the proximal and distal tubular function and the excretion of collagen IV did not change. The increment in serum creatinine was associated with the preangiographic renal function (p < 0.05), a history of heart failure (p < 0.01), but not with age, duration and type of diabetes, gender, systolic or diastolic blood pressure, glycated haemoglobin (HbAlc) or blood glucose levels. The increase of serum creatinine was associated with a pre-existing proximal tubular dysfunction and a worsening of distal tubular function. No changes in the parameters measured persisted 30 days after angiography. In summary, a transient increment in serum creatinine level after arteriography occurred in 89% of diabetic patients. It was associated with the preangiographic renal function, a history of heart failure and signs of preexisting proximal tubular dysfunction and worsening of distal tubular function. However, these changes were reversible.

Objectives: What is the prognostic significance of achieving a systolic blood pressure of

Fifty-four type 2 diabetic patients with neuroischemic foot ulcers were randomised to treatment with 5000 IU of dalteparin, (n=28), or physiological saline, (n=26), once daily until ulcer healing or for a maximum of 6 months. Thirty-three patients had normo-, 15 micro-, and 6 macroalbuminuria. The urinary levels of IgM and IgG2were elevated in 47 and 50 patients, respectively. Elevated urinary levels of IgM and IgG2indicate decreased glomerular size selectivity. Urine IgM levels were associated with IGF-1/IGFBP-1 and IGFBP-1 levels. Dalteparin treatment increased urinary levels of glycosaminoglycans (P<0.001) and serum IGFBP-1 (P<0.05) while no significant effects were seen in any of the other studied parameters. In conclusion, dalteparin therapy in patients with type 2 diabetes had no effects on urinary levels of albumin, IgM, or IgG2despite significantly increased glycosaminoglycans in urine. Elevated urinary levels of IgM and IgG2might be more sensitive markers of renal disease than albuminuria in patients with type 2 diabetes and antihypertensive therapy.

Out of 369 diabetic patients with an age at onset of diabetes > or = 30 years previously studied, 325 (88%) were included in an ophthalmological follow-up examination 4 years later. In patients treated with oral drugs at baseline, the incidence of any type of retinopathy was 30.8% and of severe retinopathy 5.7%. All patients who developed severe retinopathy received insulin during the follow-up period. At baseline, duration of diabetes, diastolic blood pressure, and signs of nephropathy (p < 0.05 in all cases) as well as degree of metabolic control (p < 0.01) differed between patients who developed retinopathy and those who did not. At follow-up, there were no longer any differences regarding degree of metabolic control and diastolic blood pressure. In patients treated with insulin at baseline, the incidence of any type of retinopathy was 41.0% and of severe retinopathy 16.1%. At baseline, duration of diabetes (p < 0.01), degree of metabolic control, and insulin dosage (p < 0.05 in both cases) differed between patients who developed retinopathy and those who did not. At follow-up, there was no longer any difference in insulin dosage.

OBJECTIVES. The aim of the present study was to describe the 5-year incidence of retinopathy in type 1 diabetes mellitus and to characterize risk indicators for the development and progression of retinopathy. DESIGN. A cross-sectional study of type 1 diabetic patients taken care of at a medical department. SETTING. All type 1 diabetic patients attending the Department of Internal Medicine, University Hospital, Lund, during a 2-year period were offered ophthalmological examination. SUBJECTS. A total of 396 out of 461 (85.9%) initially examined type 1 diabetic patients formed the basis for this 5-year follow-up study. MAIN OUTCOME MEASURES. The degree of retinopathy was based on fundus photography or biomicroscopy. Degree of metabolic control was assessed by HbA1c levels, signs of nephropathy by albumin creatinine clearance ratio and urinary albumin levels. Blood pressure was measured in the supine position. Duration of diabetes, age, and insulin dosage were registered. RESULTS. The incidence of retinopathy was 47.2% and progression from background to severe retinopathy occurred in 41%. Risk indicators for the development of retinopathy were duration of diabetes (P < 0.001), degree of metabolic control (P < 0.001), insulin dosage (P < 0.05) and signs of nephropathy based on measurements of albumin creatinine clearance ratio (P < 0.01) and urinary albumin concentration (P < 0.05). Two risk indicators could be identified for progression of retinopathy, i.e. the degree of metabolic control (P < 0.01) and diastolic blood pressure (P < 0.05). CONCLUSIONS. The results suggest that apart from poor metabolic control, development of retinopathy in type 1 diabetes is associated with long diabetes duration and clinical signs of diabetic nephropathy. Progression of retinopathy is associated with poor metabolic control and elevated diastolic blood pressure levels. (Less)

Although the clinical manifestations of type 2 diabetic nephropathy and decline in kidney function are similar to those in type 1, the clinical course and the renal structural changes are more heterogeneous in type 2 diabetic patients. Previous studies have shown that an increased urine IgM excretion in patients with type 1 diabetic nephropathy was associated with poor outcome. In the present follow-up study we examine the prognostic value of baseline urine IgM excretion in patients with type 2 diabetes mellitus. METHODS: A cohort of 106 (74 male and 32 female) patients with type 2 diabetes regularly attending our diabetes out-patient clinic at Skane University Hospital in Lund. They were recruited prospectively under the period between 1992 and 2004. Patients were followed-up until January 2009. The end point was cardiovascular (CV) death or end-stage renal disease (ESRD). The median follow-up time was 5 years (0.5-13 years). Participants were divided according to degree of albuminuria and IgM-uria. RESULTS: During follow-up time, 28 (19 male and 9 female) patients died of CV events and 41 (26 male and 15 female) developed ESRD. The risk of CV mortality was 2.4 fold, and the risk of renal failure 4.9 fold higher in patients with increased urine IgM excretion compared to patients with low urine IgM excretion. Stratified analysis showed that an increased urine IgM excretion was an independent predictor of renal and cardiovascular death irrespective of the degree of albuminuria (HR=3.6, 95% CI: 2.1-6.0, P

The objective was to study ambulatory blood pressure and heart rate variability between day and night in patients with type 1 (insulin-dependent) diabetes mellitus with different degrees of diabetic nephropathy, and to evaluate the influence of autonomic neuropathy and type of antihypertensive treatment. Twenty type 1 diabetic patients with diabetic nephropathy and antihypertensive treatment were studied with 24-h ambulatory blood pressure monitoring using an oscillometric method. They were compared with eight insulin-treated diabetic patients with short duration of diabetes (1-5 years) and with 10 apparently healthy subjects. The degree of autonomic neuropathy was evaluated by measuring the RR-interval during deep breathing and uprising. The 24-h blood pressure was generally higher in patients with diabetic nephropathy compared to those other two groups. These patients also had a lower ratio between day and night in diastolic blood pressure compared to the control subjects (1.15 +/- 0.12 vs. 1.25 +/- 0.76, P < 0.05) and heart rate compared to the diabetic patients without nephropathy, as well as the control subjects (1.15 +/- 0.08 vs. 1.26 +/- 0.09 vs. 1.27 +/- 0.08, P < 0.01, respectively). All patients with diabetic nephropathy had clinical signs of autonomic neuropathy as judged by RR-interval measurements during deep breathing and uprising.

A 5-year follow-up study of 476 type I adult diabetic patients previously studied cross sectionally revealed that, during the observation period, 19 patients died and 30 developed cardiovascular or renal disease, such as myocardial infarction (n = 8), cerebrovascular disease (n = 3), amputation (n = 6), and renal insufficiency (n = 13). The patients were registered by one and the most-severe event only. The yearly death rate was 8.0 per 1000, compared with the expected death rate of 2.0 for people with corresponding age and sex in the general population. In patients with renal insufficiency, one also had myocardial infarction, and one had had an amputation. The ages of patients who died, with myocardial infarction, cerebrovascular disease, amputation, or renal insufficiency, were 44.2 +/- 12.7, 41.3 +/- 6.6, 43.7 +/- 13.2, 45.3 +/- 15.7, and 40.8 +/- 9.8 years, respectively. Urinary albumin concentration in a single early morning urine sample was found to be a strong prognostic marker for the development of cardiovascular disease or death. In contrast, age, gender, age at onset and duration of diabetes, levels of blood pressure, serum creatinine, and HbA1c, or presence of hypertension, as well as changes in blood pressure and hBa1c, during the observation period did not influence the survival or incidence of cardiovascular disease. However, blood pressure and HbA1c were associated with increased urinary albumin concentrations during the follow-up period.