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Background: More children are now surviving severe acute malnutrition (SAM), but evidence suggests that early-life malnutrition is associated with increased risk of long-term cardio-metabolic disorders. To better understand potential mechanisms, we studied the metabolite profiles of children seven years after treatment for SAM. Methods: We followed-up children (n=352) treated for SAM in 2006-2007, at Queen Elizabeth Central Hospital, in Malawi. Using nuclear magnetic resonance spectroscopy, tandem mass spectrometry and enzyme-linked immunosorbent assay, we measured circulating metabolites in fasting blood in a subset of SAM survivors (n = 69, 9.6 +/- 1.6 years), siblings (n = 44, 10.5 +/- 2.7 years), and age and sex-matched community controls (n = 37, 9.4 +/- 1.8 years). Data were analysed using univariate and sparse partial least square (sPLS) methods. Differences associated with SAM survival, oedema status, and anthropometry were tested, adjusting for age, sex, HIV, and wealth index. Findings: Based on 194 measured metabolites, the profiles of SAM survivors were similar to those of siblings and community controls. IGF1, creatinine, and FGF21, had loading values >0.3 and ranked stably in the top 10 distinguishing metabolites, but did not differ between SAM survivors and controls with univariate analysis. Current stunting was associated with IGF1 (beta = 15.2, SE = 3.5, partial R-2 = 12%, p

Background: Studies have shown that the prevalence of children born with high birth weight or large for gestational age (LGA) is increasing. This is true for spontaneous pregnancies; however, children born after frozen embryo transfer (FET) as part of assisted reproductive technology (ART) also have an elevated risk. In recent years, the practice of FET has increased rapidly and while the perinatal and obstetric risks are well-studied, less is known about the long-term health consequences. Objective: The aim of this systematic review was to describe the association between high birth weight and LGA on long-term child outcomes. Data Sources: PubMed, Scopus, and Web of Science were searched up to January 2021. Exposure included high birth weight and LGA. Long-term outcome variables included malignancies, psychiatric disorders, cardiovascular disease, and diabetes. Study Selection: Original studies published in English or Scandinavian languages were included. Studies with a control group were included while studies published as abstracts and case reports were excluded. Data Extraction: The methodological quality, in terms of risk of bias, was assessed by pairs of reviewers. Robins-I (www.methods.cochrane.org) was used for risk of bias assessment in original articles. For systematic reviews, AMSTAR (www.amstar.ca) was used. For certainty of evidence, we used the GRADE system. The systematic review followed PRISMA guidelines. When possible, meta-analyses were performed. Results: The search included 11,767 articles out of which 173 met the inclusion criteria and were included in the qualitative analysis, while 63 were included in quantitative synthesis (meta-analyses). High birth weight and/or LGA was associated with low to moderately elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, and type 1 and 2 diabetes. Conclusions: Although the increased risks for adverse outcome in offspring associated with high birth weight and LGA represent serious health effects in childhood and in adulthood, the size of these effects seems moderate. The identified risk association should, however, be taken into account in decisions concerning fresh and frozen ART cycles and is of general importance in view of the increasing prevalence in high birthweight babies. publishedVersion

Hypoglycaemia is common in patients with type 1 diabetes and type 2 diabetes and constitutes a major limiting factor in achieving glycaemic control among people with diabetes. While hypoglycaemia is defined as a blood glucose level under 70 mg/dL (3.9 mmol/L), symptoms may occur at higher blood glucose levels in individuals with poor glycaemic control. Severe hypoglycaemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions to assure neurologic recovery. Hypoglycaemia is the most important safety outcome in clinical studies of glucose lowering agents. The American Diabetes Association Standards of Medical Care recommends that a management protocol for hypoglycaemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan. A tailored approach, using clinical and pathophysiologic disease stratification, can help individualize glycaemic goals and promote new therapies to improve quality of life of patients. Data from recent large clinical trials reported low risk of hypoglycaemic events with the use of newer anti-diabetic drugs. Increased hypoglycaemia risk is observed with the use of insulin and/or sulphonylureas. Vulnerable patients with T2D at dual risk of severe hypoglycaemia and cardiovascular outcomes show features of “frailty.” Many of such patients may be better treated by the use of GLP-1 receptor agonists or SGLT2 inhibitors rather than insulin. Continuous glucose monitoring (CGM) should be considered for all individuals with increased risk for hypoglycaemia, impaired hypoglycaemia awareness, frequent nocturnal hypoglycaemia and with history of severe hypoglycaemia. Patients with impaired awareness of hypoglycaemia benefit from real-time CGM. The diabetes educator is an invaluable resource and can devote the time needed to thoroughly educate the individual to reduce the risk of hypoglycaemia and integrate the information within the entire construct of diabetes self-management. Conversations about hypoglycaemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycaemia among patients with diabetes and their family members. Optimizing insulin doses and carbohydrate intake, in addition to a short warm up before or after the physical activity sessions may help avoiding hypoglycaemia. Several therapeutic considerations are important to reduce hypoglycaemia risk during pregnancy including administration of rapid-acting insulin analogues rather than human insulin, pre-conception initiation of insulin analogues, and immediate postpartum insulin dose reduction.

Hypoglycemia is common in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) and constitutes a major limiting factor in achieving glycemic control among people with diabetes. While hypoglycemia is defined as a blood glucose level under 70 mg/dL (3.9?mmol/L), symptoms may occur at higher blood glucose levels in individuals with poor glycemic control. Severe hypoglycemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions to assure neurologic recovery. Hypoglycemia is the most important safety outcome in clinical studies of glucose lowering agents. The ADA Standards of Medical Care recommends that a management protocol for hypoglycemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan. A tailored approach, using clinical and pathophysiologic disease stratification, can help individualize glycemic goals and promote new therapies to improve quality of life of patients. Data from recent large clinical trials reported low risk of hypoglycemic events with the use of newer antidiabetic drugs. Increased hypoglycemia risk is observed with the use of insulin and/or sulfonylureas. Vulnerable patients with T2D at dual risk of severe hypoglycemia and Cardiovascular (CV) outcomes show features of ?frailty?. Many of such patients may be better treated by the use of GLP-1 receptor agonists or SGLT2 inhibitors rather than insulin. CGM should be considered for all individuals with increased risk for hypoglycemia, impaired hypoglycemia awareness, frequent nocturnal hypoglycemia and with history of severe hypoglycemia. Patients with impaired awareness of hypoglycemia (IAH) benefit from real-time continuous glucose monitoring (CGM). The diabetes educator is an invaluable resource and can devote the time needed to thoroughly educate the individual to reduce the risk of hypoglycemia and integrate the information within the entire construct of diabetes self-management. Conversations about hypoglycemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycemia among patients with diabetes and their family members. Optimizing insulin doses and carbohydrate intake, in addition to a short warm up before or after the physical activity sessions may help avoiding hypoglycemia. Several therapeutic considerations are important to reduce hypoglycemia risk during pregnancy including administration of rapid-acting insulin analogs rather than human insulin, pre-conception initiation of insulin analogs, and immediate postpartum insulin dose reduction. This article is protected by copyright. All rights reserved.

Objective We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity. Methods Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A) and zinc transporter 8 (ZnT8A) and genotyped for HLA DR/DQ alleles. In the DIPP study autoantibodies were regularly analyzed from birth up to 15 years of age. Results In the DIPP cohort 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268 and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR. Conclusions These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response. This article is protected by copyright. All rights reserved.

Microvascular and metabolic physiology are tightly linked. This Perspective reviews evidence that 1) the relationship between hyperglycemia and microvascular dysfunction (MVD) is bidirectional and constitutes a vicious cycle; 2) MVD in diabetes affects many, if not all, organs, which may play a role in diabetes-associated comorbidities such as depression and cognitive impairment; and 3) MVD precedes, and contributes to, hyperglycemia in type 2 diabetes (T2D) through impairment of insulin-mediated glucose disposal and, possibly, insulin secretion. Obesity and adverse early-life exposures are important drivers of MVD. MVD can be improved through weight loss (in obesity) and through exercise. Pharmacological interventions to improve MVD are an active area of investigation.

Objective: The aim of this study was to produce and validate a Turkish version of the University of Virginia Parent Low Blood Sugar Survey (P-LBSS). The P-LBSS is used to assess parental fear of their diabetic children’s hypoglycemia. Methods: Linguistic, content and face validity of the translated P-LBSS was tested. Afterwards, explanatory and confirmatory factor analyses were conducted in order to evaluate construct validity. Results: The sample included 390 parents of type 1 diabetic adolescents aged 12-17 years. Results of the factor analysis showed that the Turkish P-LBSS had 2 subscales (behavior and worry) as in the original. The Cronbach’s alpha coefficient of the Turkish version of the total P-LBSS was found to be 0.803, and the value was 0.865 for the behavior and 0.790 for the worry subscales. Psychometric investigation of the Turkish version of P-LBSS indicated high reliability and good retestability, content and construct validity. Conclusion: The Turkish P-LBSS is a valid and reliable instrument to measure the fear of hypoglycemia experienced by parents of diabetic adolescents aged between 12-17 years in the Turkish population. © 2018 by Turkish Pediatric Endocrinology and Diabetes Society.

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMT(mean) and IMT(max) (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.

During the sensitization phase of allergic contact dermatitis, the proinflammatory cytokine tumour necrosis factor (TNF) plays an important role by promoting epidermal Langerhans cell migration to draining lymph nodes. It also plays a role during the elicitation phase. The TNF gene (TNF) is located within themajor histocompatibility complex region. Many single-nucleotide variants exist in the promoter region of TNF, and these may either increase or decreasemRNAtranscription and therefore lead to higher or lower levels of TNF. The most extensively studied single-nucleotide variant of TNF is a base pair substitution in the promoter region at location - 308 relative to the transcription start site (rs1800629, TNF - 308G>A), which is believed to increase transcription and lead to higher TNF levels. The role of TNF in allergic contact dermatitis and the functionality of TNF - 308G>A are reviewed in this article. The association between genetic variants and disease can be studied in a case-control design. Only a few case-control studies investigating the association between TNF - 308G>A and allergic contact dermatitis have been published, with contradictory results. These are reviewed critically, and suggestions for future case-control studies on this topic are made.

In this review article, we focus on the most recent applications of nuclear medicine techniques (mainly (99m)Tc/(111)In white blood cells (WBC) scan, [(18)F]-FDG-PET/CT, [(18)F]-FDG-PET/MRI, and (99m)Tc-IL-2 scintigraphy) in the study of children affected by peripheral bone osteomyelitis, fungal infections, inflammatory bowel diseases, and type 1 diabetes, owing to recent important published evidences of their role in the management of these diseases. For osteomyelitis in children, both bone scintigraphy and [(18)F]-FDG-PET have a major advantage of assessing the whole body in one imaging session to confirm or exclude multifocal involvement, whereas WBC scan has a limited role. In children with fungal infections, [(18)F]-FDG-PET can help in defining the best location for biopsy and can help in evaluating the extent of the infection and organs involved (also sites that were not yet clinically apparent), although its main role is for therapy monitoring. In inflammatory bowel diseases, and Crohn disease in particular, WBC scan has been successfully used for many years, but it is now used only in case of doubtful magnetic resonance (MR) or when MR cannot be performed and endoscopy is inconclusive. By contrast, there is an accumulating evidence of the role of [(18)F]-FDG-PET in management of children with Crohn disease, and PET/MR could be a versatile and innovative hybrid imaging technique that combines the metabolic information of PET with the high soft tissue resolution of MR, particularly for distinguishing fibrotic from active strictures. Finally, there are several new radiopharmaceuticals that specifically target inflammatory cells involved in the pathogenesis of insulitis aiming at developing new specific immunotherapies and to select children candidates to these treatments for improving their quality of life.

In this review article, we focus on the most recent applications of nuclear medicine techniques (mainly (99m)Tc/(111)In white blood cells (WBC) scan, [(18)F]-FDG-PET/CT, [(18)F]-FDG-PET/MRI, and (99m)Tc-IL-2 scintigraphy) in the study of children affected by peripheral bone osteomyelitis, fungal infections, inflammatory bowel diseases, and type 1 diabetes, owing to recent important published evidences of their role in the management of these diseases. For osteomyelitis in children, both bone scintigraphy and [(18)F]-FDG-PET have a major advantage of assessing the whole body in one imaging session to confirm or exclude multifocal involvement, whereas WBC scan has a limited role. In children with fungal infections, [(18)F]-FDG-PET can help in defining the best location for biopsy and can help in evaluating the extent of the infection and organs involved (also sites that were not yet clinically apparent), although its main role is for therapy monitoring. In inflammatory bowel diseases, and Crohn disease in particular, WBC scan has been successfully used for many years, but it is now used only in case of doubtful magnetic resonance (MR) or when MR cannot be performed and endoscopy is inconclusive. By contrast, there is an accumulating evidence of the role of [(18)F]-FDG-PET in management of children with Crohn disease, and PET/MR could be a versatile and innovative hybrid imaging technique that combines the metabolic information of PET with the high soft tissue resolution of MR, particularly for distinguishing fibrotic from active strictures. Finally, there are several new radiopharmaceuticals that specifically target inflammatory cells involved in the pathogenesis of insulitis aiming at developing new specific immunotherapies and to select children candidates to these treatments for improving their quality of life.

Background: More children are now surviving severe acute malnutrition (SAM), but evidence suggests that early-life malnutrition is associated with increased risk of long-term cardio-metabolic disorders. To better understand potential mechanisms, we studied the metabolite profiles of children seven years after treatment for SAM. Methods: We followed-up children (n=352) treated for SAM in 2006-2007, at Queen Elizabeth Central Hospital, in Malawi. Using nuclear magnetic resonance spectroscopy, tandem mass spectrometry and enzyme-linked immunosorbent assay, we measured circulating metabolites in fasting blood in a subset of SAM survivors (n = 69, 9.6 +/- 1.6 years), siblings (n = 44, 10.5 +/- 2.7 years), and age and sex-matched community controls (n = 37, 9.4 +/- 1.8 years). Data were analysed using univariate and sparse partial least square (sPLS) methods. Differences associated with SAM survival, oedema status, and anthropometry were tested, adjusting for age, sex, HIV, and wealth index. Findings: Based on 194 measured metabolites, the profiles of SAM survivors were similar to those of siblings and community controls. IGF1, creatinine, and FGF21, had loading values >0.3 and ranked stably in the top 10 distinguishing metabolites, but did not differ between SAM survivors and controls with univariate analysis. Current stunting was associated with IGF1 (beta = 15.2, SE = 3.5, partial R-2 = 12%, p

Objective: Low concentrations of insulin-like growth factor-I (IGFI) have been reported in type 1 diabetes mellitus (T1DM), suggested to be due to low insulin concentrations in the portal vein. The aim was to describe the long-term course of IGFI concentrations among T1DM subjects treated with continuous intraperitoneal (IP) insulin infusion (CIPII).Design: Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF-I measurements were performed at the start of the 2006 study, after the 6 month SC- and CIPII treatment phase in 2006 and during CIPII therapy in 2012. Z-scores were calculated to compare the IGF-I concentrations with age-specific normative range values of a non-DM reference population.Results: In 2012, IGF-I Z-scores (-0.7; 95% confidence interval -1.3, -0.2) were significantly higher than at the start of the 2006 study (-2.5; -33, -1.8), the end of the SC (-2.0; -2.6, -1.5) and CIPII (-1.6; -2.1, -1.0) treatment phase with a mean difference of: 1.8 (0.9, 2.7), 1.3 (0.5, 2.1) and 0.8 (0.1, 1.6), respectively.Conclusion: After 6 years of treatment with CIPII, IGF-I concentrations among T1DM patients increased to a level that is higher than during prior SC insulin treatment and is in the lower normal range compared to a non-DM reference population. The results of this study suggest that long-term IP insulin administration influences the IGF system in T1DM. (C) 2015 Elsevier Ltd. All rights reserved.

OBJECTIVE: Albuminuria is thought to be a biomarker of microvascular and macrovascular endothelial dysfunction. However, direct evidence for an association of microvascular endothelial dysfunction with albuminuria is limited. In addition, experimental data suggest a stronger association of microvascular endothelial dysfunction with albuminuria in individuals with than in those without diabetes.METHODS: We examined cross-sectional associations of flicker light-induced retinal arteriolar dilation (n = 2095) and heat-induced skin hyperemia (n = 1508) with 24-h albuminuria in the population-based, diabetes-enriched Maastricht Study. We used linear regression analyses to adjust for age, sex, type 2 diabetes, and cardiovascular disease risk factors. In addition, we tested for statistical interaction with type 2 diabetes.RESULTS: Median [interquartile range] albuminuria was 6.5 [3.9-11.6] mg/24 h and 8.2% had albuminuria at least 30 mg/24 h. After adjustment, albuminuria was 1.168 (95% confidence interval, 1.046-1.303) times greater in participants in the quartile with the smallest flicker light-induced retinal arteriolar dilation relative to those with the greatest dilation, and this association was stronger in participants with type 2 diabetes (Pinteraction CONCLUSION: This is the first population-based study that provides direct evidence that microvascular endothelial dysfunction is associated with albuminuria, and that this association is stronger in individuals with than in those without type 2 diabetes.

Microvascular and metabolic physiology are inextricably linked. Thus, metabolic dysfunction impairs microvascular function and microvascular dysfunction impairs normal metabolism. The relationship is therefore reciprocal, justifying the concept of a ‘Metabolic-Microvascular Dysregulation Syndrome’. For example, metabolic dysregulation (hyperglycaemia) causes microvascular dysfunction, diabetic retinopathy and diabetic nephropathy. Conversely, microvascular dysregulation impairs insulin-mediated glucose disposal, i.e. causes insulin resistance, impairs insulin secretion, and is associated with onset of type 2 diabetes in prospective studies. Obesity is a key driver of the Metabolic-Microvascular Dysregulation Syndrome, as it impairs insulin signal transduction in endothelial cells through adverse changes in adipokines such as adiponectin, free fatty acids and tumour necrosis factor-α. Microvascular dysfunction in obesity appears reversible by diet-induced weight loss. Next to obesity, other factors are also likely to play a role. Examples are microvascular dysfunction of adipose tissue as a primary cause of adipose tissue dysfunction; early life exposures, both antenatal and postnatal; and large artery stiffening. Large artery stiffening is unquestionably important for microvascular function in susceptible organs such as the brain, the eye and the kidney but whether it can cause microvascular dysfunction in metabolically crucial tissues such as skeletal muscle, pancreas and adipose tissue has not been studied. It is therefore not clear that arterial stiffening in and of itself is sufficient to cause the Metabolic-Microvascular Dysregulation Syndrome.

Extrahepatic transplantation of islets of Langerhans could aid in better survival of islets after transplantation. When islets are transfused into the liver 60-70% of them are lost immediately after transplantation. An important factor for a successful extrahepatic transplantation is a well-vascularized tissue surrounding the implant. There are many strategies known for enhancing vessel formation such as adding cells with endothelial potential, the combination with angiogenic factors and / or applying surface topography at the exposed surface of the device. Previously we developed porous, micropatterned membranes which can be applied as a lid for an islet encapsulation device and we showed that the surface topography induces human umbilical vein endothelial cell (HUVEC) alignment and interconnection. This was achieved without the addition of hydrogels, often used in angiogenesis assays. In this work, we went one step further towards clinical implementation of the device by combining this micropatterned lid with Mesenchymal Stem Cells (MSCs) to facilitate prevascularization in vivo. As for HUVECs, the micropatterned membranes induced MSC alignment and organization in vitro, an important contributor to vessel formation, whereas in vivo (subcutaneous rat model) they contributed to improved implant prevascularization. In fact, the combination of MSCs seeded on the micropatterned membrane induced the highest vessel formation score in 80% of the sections. [Figure not available: see fulltext.].

Background and aims Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT., Highlights • Identification of a novel proinsulin-associated locus on chromosome 15. • Lead chromosome 15 SNP rs8029765 influences expression of UNC45A in liver. • Proinsulin effects on carotid intima-media thickness are segment-specific. • Proinsulin-increasing SNP scores had limited effects on carotid intima-media thickness. • Proinsulin is unlikely to have causal effects on intima-media thickness.

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.

Background:\ud The glycaemic index (GI) is a physiological measure of the ability of a carbohydrate to affect blood glucose. Interest is growing in this area for the clinical management of people at risk of, or with, established cardiovascular disease. There is a need to review the current evidence from randomised controlled trials (RCTs) in this area. This is an update of the original review published in 2008.\ud \ud Objectives:\ud To assess the effect of the dietary GI on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible randomised controlled trials.\ud \ud Search methods:\ud We searched CENTRAL, MEDLINE, Embase and CINAHL in July 2016. We also checked reference lists of relevant articles. No language restrictions were applied.\ud \ud Selection criteria:\ud We selected RCTs that assessed the effects of low GI diets compared to diets with a similar composition but a higher GI on cardiovascular disease and related risk factors. Minimum trial duration was 12 weeks. Participants included were healthy adults or those at increased risk of cardiovascular disease, or previously diagnosed with cardiovascular disease. Studies in people with diabetes mellitus were excluded.\ud \ud Data collection and analysis:\ud Two reviewers independently screened and selected studies. Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using GRADE, and extracted data following the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. Analyses were checked by a second reviewer. Continuous outcomes were synthesized using mean differences and adverse events were synthesized narratively.\ud \ud Main results:Twenty-one RCTs were included, with a total of 2538 participants randomised to low GI intervention (1288) or high GI (1250). All 21 included studies reported the effect of low GI diets on risk factors for cardiovascular disease, including blood lipids and blood pressure.\ud \ud Twenty RCTs (18 of which were newly included in this version of the review) included primary prevention populations (healthy individuals or those at high risk of CVD, with mean age range from 19 to 69 years) and one RCT was in those diagnosed with pre-existing CVD (a secondary prevention population, with mean age 26.9 years). Most of the studies did not have an intervention duration of longer than six months. Difference in GI intake between comparison groups varied widely from 0.6 to 42.\ud \ud None of the included studies reported the effect of low GI dietary intake on cardiovascular mortality and cardiovascular events such as fatal and nonfatal myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and stroke. The unclear risk of bias of most of the included studies makes overall interpretation of the data difficult. Only two of the included studies (38 participants) reported on adverse effects and did not observe any harms (low-quality evidence).\ud \ud Authors' conclusions:\ud There is currently no evidence available regarding the effect of low GI diets on cardiovascular disease events. Moreover, there is currently no convincing evidence that low GI diets have a clear beneficial effect on blood lipids or blood pressure parameters.

Evidence is increasing that the postprandial state is an important factor contributing to the risk of chronic diseases. Not only mean glycemia, but also glycemic variability has been implicated in this effect. In this exploratory study, we measured 24-h glucose profiles in 25 overweight participants in a long-term diet intervention study (DIOGENES study on Diet, Obesity and Genes), which had been randomized to four different diet groups consuming diets varying in protein content and glycemic index. In addition, we compared 24-h glucose profiles in a more controlled fashion, where nine other subjects followed in random order the same four diets differing in carbohydrate content by 10 energy% and glycemic index by 20 units during three days. Meals were provided in the lab and had to be eaten at fixed times during the day. No differences in mean glucose concentration or glucose variability (SD) were found between diet groups in the DIOGENES study. In the more controlled lab study, mean 24-h glucose concentrations were also not different. Glucose variability (SD and CONGA1), however, was lower on the diet combining a lower carbohydrate content and GI compared to the diet combining a higher carbohydrate content and GI. These data suggest that diets with moderate differences in carbohydrate content and GI do not affect mean 24-h or daytime glucose concentrations, but may result in differences in the variability of the glucose level in healthy normal weight and overweight individuals.

Increasing evidence supporting the correlation between bovine beta-casein and disorders in milk consumers has led to the development and popularity of A2 milk and milk products worldwide. The indigenous cattle population of India harbours the preferred A2 allele of beta casein; however, genetic improvement of this cattle population by crossbreeding with exotic breeds is spoiling the gene pool as most of the exotic breeds contain A1 allele of the gene. In this study, we aim at evaluating the status of beta-casein in the Indian dairy sector and provide a discussion of future implications to the A2 milk industry. Our results show that the genotypic frequencies of A1 and A2 genes in a sample cattle population were 0.365 and 0.635 respectively. Based on the pure nature of the A2 allele in indigenous cattle, the presence of the A1 allele was assumed to be attributable to crossbreeding with exotic cattle breeds. Current options to drift the frequency of herds towards A2 are highly limited, raising serious questions regarding breeding policies in India and the lack of availability of certified A2 semen straws. The absence of any official standards and certification procedures in the country for A2 milk and milk products aggravates the situation from a food safety perspective. The future focus of sorted sexed semen and embryo transfers by the Department of Animal Husbandry, Dairying and Fisheries in India for dairy development should include A2 certification as an integral component. The Food Safety and Standards Authority of India should define and establish standard protocols for certification of A2 milk and milk products to safeguard the rights of consumers against the potential food fraud.

Recurrent insulin-induced hypoglycaemia is a major limitation to insulin treatment in diabetes patients leading to a condition called hypoglycaemia-associated autonomic failure (HAAF). HAAF is characterised by reduced sympathoadrenal response to subsequent hypoglycaemia thereby predisposing the patients to severe hypoglycaemia that can lead to coma or even death. Despite several attempts being made, the mechanism of HAAF is yet to be clearly established. In order for the mechanism of HAAF to be elucidated, establishing a human/animal model of the phenomenon is the foremost requirement. Several research groups have attempted to reproduce the phenomenon in diabetic and nondiabetic humans and rodents and reported variable results. The success of the phenomenon is marked by a significant reduction in plasma adrenaline response to subsequent hypoglycaemic episode relative to that of the antecedent hypoglycaemic episode. A number of factors such as the insulin dosage, route of administration, fasting conditions, blood sampling methods and analyses, depth, duration, and number of antecedent hypoglycaemic episodes can impact the successful reproduction of the phenomenon and thus have to be carefully considered while developing the protocol. In this review, we have outlined the protocols followed by different research groups to reproduce the phenomenon in diabetic and nondiabetic humans and rodents including our own observations in rats and discussed the factors that have to be given careful consideration in reproducing the phenomenon successfully. Refereed/Peer-reviewed

Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD., Non-alcoholic fatty liver disease (NAFLD) is a risk factor for other types of liver diseases. Here, the authors integrate transcriptomic and metabolomic data from patients with NAFLD with a genome-scale metabolic model to paint a comprehensive picture of liver function in NAFLD.

Background & Aims: Ectopic fat in muscle and liver is linked to obesity and type 2 diabetes. Recently, pancreatic lipid accumulation has also been associated with beta-cell dysfunction and reduced insulin production, leading to the development of type 2 diabetes. Physical exercise training has been shown to attenuate beta-cell dysfunction in patients, but little is known about its effects on pancreatic and hepatic fat accumulation. In this study, we validated in-vivo proton magnetic resonance spectroscopy ((1)H MRS) in pancreatic fat measurement with biochemical measurements in a pig model. Thereafter, the effects of increased physical activity on the amounts of pancreatic and liver fat were studied in eight monozygotic twin pairs who have discordant physical activity and fitness.Methods: Pancreatic fat content was studied in 15 pigs using (1)H MRS and/or biochemical analyses. In addition, liver and pancreatic fat were assessed using (1)H MRS in eight monozygotic male twin pairs with 18% mean difference in VO(2max) between the twin brothers.Results: Twins with higher physical fitness had 23% less liver fat (1.3 +/- 1.3% vs. 2.1 +/- 2.6%, p = 0.022) but no such difference was observed in the pancreatic fat (8.2 +/- 9.3% vs. 9.8 +/- 8.5%, respectively, p = 0.3). Hepatic fat content was inversely associated with VO(2max). A positive association was found between pancreatic and liver fat contents (beta = 5.18, p = 0.012). Pancreatic fat content was also associated with insulin sensitivity indexes and plasma adiponectin and glutamyltransferase concentrations.Conclusions: Pancreatic fat content is associated with insulin resistance and hepatic fat content. An active lifestyle seems to beneficially influence hepatic fat metabolism. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Both the biology and the therapeutic potential of the phosphoinositide 3-kinase (PI3K) signalling axis have been the subject of intense investigation; however, little is known about the regulation of PI3K expression. Emerging evidence indicates that PI3K levels change in response to cellular stimulation with insulin and nuclear receptor ligands, and during various physiological and pathological processes including differentiation, regeneration, hypertension and cancer. Recently identified mechanisms that control PI3K production include increased gene copy number in cancer, and transcriptional regulation of the p110 alpha PI3K gene by FOXO3a, NF-kappa B and p53, and of the PI3K regulatory subunits by STAT3, EBNA-2 and SREBP. In most instances, however, the impact of alterations in PI3K expression on PI3K signalling and disease remains to be established.

5-hydroxytryptamine mechanisms in mediating the effects of small intestinal glucose on blood pressure and antropyloroduodenal motility in older subjects. Am J Physiol Gastrointest Liver Physiol 293: G692-G698, 2007. First published August 9, 2007; doi:10.1152/ajpgi.00199.2007.-Postprandial hypotension is an important clinical problem, particularly in the elderly. 5-Hydroxy-tryptamine(3) (5-HT3) mechanisms may be important in the regulation of splanchnic blood flow and blood pressure (BP), and in mediating the effects of small intestinal nutrients on gastrointestinal motility. The aims of this study were to evaluate the effects of the 5-HT3 antagonist granisetron on the BP, heart rate (HR), and antropyloroduodenal (APD) motility responses to intraduodenal glucose in healthy older subjects. Ten subjects (5 male, 5 female, aged 65-76 yr) received an intraduodenal glucose infusion (3 kcal/min) for 60 min (t = 0-60 min), followed by intraduodenal saline for a further 60 min (t = 60-120 min) on 2 days. Granisetron (10 mu g/kg) or control (saline) was given intravenously at t = -25 min. BP (systolic and diastolic), HR, and APD pressures were measured. Pressure waves in the duodenal channel closest ("local") to the infusion site were quantified separately. During intraduodenal glucose, there were falls in systolic and diastolic BP and a rise in HR (P

Background. The use of invasive procedures has mostly been studied in retrospective (multi)national registries. Limited evidence exists on the association between microalbuminuria and coronary artery disease (CAD).Methods: The incidence of major adverse cardiac events (MACE) and invasive cardiac procedures was registered between 1997 and 2003 in 8139 subjects, without prior documented CAD, in the PREVEND cohort study (the Netherlands), in which the focus is on microalbuminuria and cardiovascular risk. Qualitative coronary angio-graphic analysis was performed.Results. During 5.5 years of follow-up, a first MACE occurred in 271 (3.3%) and a first coronary angiography (CAG) was performed in 264 (3.2%) subjects. Of these, 216 CAGs were available for qualitative angiographic analysis. Indications for CAG were stable angina in 129, acute coronary syndrome (ACS) in 55 and ST-elevation myocardial infarction (STEMI) in 32 subjects. Obstructive coronary artery disease was present in 61, 53 and 30 subjects, respectively. A revascularisation was performed in 50 (39%), 50 (91%) and 25 (78%) subjects, respectively. Microalbuminuria was associated with a first MACE, after adjustment for established risk factors. Microalbuminuria was present at baseline in 9% of subjects with normal coronary arteries, in 21% of subjects with one- and two-vessel CAD and in 39% of subjects with three-vessel or left main CAD at CAG during follow-up (Ptrend=0.005).Conclusion: This large cohort study shows that two-thirds of diagnostic CAGs for stable angina were not followed by a revascularisation, in contrast to CAGs for STEMI or ACS. Furthermore, this study shows that microalbuminuria is associated with CAD.

Background: The purpose of this study was to examine the correlations between plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) and cardiovascular disease-related traits in a general population and whether these correlations differed between females and males. Methods: Plasma PAI-1 and t-PA antigen levels and C-reactive protein (CRP), HDL-cholesterol, triglycerides, total cholesterol, systolic blood pressure, diastolic blood pressure, urinary albumin excretion, and glucose were measured in the population-based PREVEND study in Groningen, the Netherlands (n = 2527). Results: Except for CRP and total cholesterol levels, all traits were significantly different between gender (P

Microalbuminuria has been shown to be a strong predictor of cardiovascular morbidity and mortality in diabetic and hypertensive patients, but also in the general population. Moreover, several reports suggest that reduction of urinary albumin excretion (UAE) is associated with improvement of cardiovascular prognosis. Reduction of UAE can be achieved by lowering arterial blood pressure, but blockers of the renin-angiotensin system (RAS) with their specific renal actions have demonstrated to be able to reduce UAE more than might be expected from reduction of blood pressure alone. Consequently, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also provide superior cardiovascular protection, especially in subjects with higher levels of albuminuria, but evidence is still scarce. The ability of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to reduce UAE and provide cardiovascular protection suggests that the RAS may play a central role. New developments in this area include the use of aldosterone antagonists in albuminuric/proteinuric subjects, and the development of oral renin inhibitors. Combinations of the aforementioned drugs may have the ability to fully block the RAS, potentially avoiding all detrimental effects of this hormonal cascade. However, combination therapy is expected to also increase the incidence of side effects, such as hyperkalaemia and acute renal insufficiency. The current knowledge of microalbuminuria represents the proverbial tip of the iceberg, and future studies should focus on the underlying pathophysiological mechanism of urinary albumin excretion in relation to cardiovascular protection. Only then can a better understanding of the problem be achieved and the optimal pharmacological approach be ascertained.

Microalbuminuria has been shown to be a strong predictor of cardiovascular morbidity and mortality in diabetic and hypertensive patients, but also in the general population. Moreover, several reports suggest that reduction of urinary albumin excretion (UAE) is associated with improvement of cardiovascular prognosis. Reduction of UAE can be achieved by lowering arterial blood pressure, but blockers of the renin-angiotensin system (RAS) with their specific renal actions have demonstrated to be able to reduce UAE more than might be expected from reduction of blood pressure alone. Consequently, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also provide superior cardiovascular protection, especially in subjects with higher levels of albuminuria, but evidence is still scarce. The ability of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to reduce UAE and provide cardiovascular protection suggests that the RAS may play a central role. New developments in this area include the use of aldosterone antagonists in albuminuric/proteinuric subjects, and the development of oral renin inhibitors. Combinations of the aforementioned drugs may have the ability to fully block the RAS, potentially avoiding all detrimental effects of this hormonal cascade. However, combination therapy is expected to also increase the incidence of side effects, such as hyperkalaemia and acute renal insufficiency. The current knowledge of microalbuminuria represents the proverbial tip of the iceberg, and future studies should focus on the underlying pathophysiological mechanism of urinary albumin excretion in relation to cardiovascular protection. Only then can a better understanding of the problem be achieved and the optimal pharmacological approach be ascertained.

A minor increase in urinary albumin excretion (microalbuminuria) is known to predict adverse renal and cardiovascular events in diabetic and hypertensive patients. Recent intriguing findings show that microalbuminuria is an early and sensitive marker of future cardiovascular events even in healthy subjects. The mechanisms linking microalbuminuria with end-organ damage have not been fully explained yet; however, generalized endothelial dysfunction might play an important role. Prevailing experimental and clinical data suggest that generalized endothelial dysfunction, frequently characterized by decreased nitric oxide bioavailability, actually precedes the development of microalbuminuria. This review summarizes the current knowledge about the intricate relationship between microalbuminuria and endothelial dysfunction. On the basis of the current evidence, we propose that microalbuminuria and endothelial dysfunction are an emerging target for primary prevention strategies in cardiovascular disease. In near future, dietary components improving nitric oxide bioavailability, such as cocoa-derived flavanols may play important role in these preventive strategies.

A minor increase in urinary albumin excretion (microalbuminuria) is known to predict adverse renal and cardiovascular events in diabetic and hypertensive patients. Recent intriguing findings show that microalbuminuria is an early and sensitive marker of future cardiovascular events even in healthy subjects. The mechanisms linking microalbuminuria with end-organ damage have not been fully explained yet; however, generalized endothelial dysfunction might play an important role. Prevailing experimental and clinical data suggest that generalized endothelial dysfunction, frequently characterized by decreased nitric oxide bioavailability, actually precedes the development of microalbuminuria. This review summarizes the current knowledge about the intricate relationship between microalbuminuria and endothelial dysfunction. On the basis of the current evidence, we propose that microalbuminuria and endothelial dysfunction are an emerging target for primary prevention strategies in cardiovascular disease. In near future, dietary components improving nitric oxide bioavailability, such as cocoa-derived flavanols may play important role in these preventive strategies.

Objective. Semicarbazide-sensitive amine oxidase (SSAO) is widely expressed in adipose tissue, where it may contribute to stimulation of glucose transport via GLUT4 recruitment. We tested the relationships of soluble SSAO, as reflected by its plasma activity, with insulin sensitivity and indices of body fat, and determined whether insulin is involved in regulating plasma SSAO activity. Material and methods. In 24 non-diabetic subjects, the relationships of plasma SSAO activity with insulin sensitivity (M-value and free fatty acid (FFA) suppression during a 3-h hyperinsulinemic (8.3 mu U kg(-1) s(-1)), euglycemic clamp), body mass index (BMI 25.5 +/- 3.1 kg m(-2)), waist- hip ratio and fat mass were assessed. In 16 subjects, the effect of insulin infusion, administered at a rate of 8.3 mu U kg(-1) s(-1) during 3 h, followed by 3-h insulin infusion at a high rate of 41.7 mu U kg(-1) s(-1) on plasma SSAO activity was determined. In the other 8 subjects, the response of plasma SSAO activity to 24- h insulin infused at 8.3 mu U kg(-1) s(-1) was assessed. Results. There were no relationships ( all p > 0.10) of plasma SSAO activity (215 +/- 60 mu U L-1) with the M-value or with any indices of body fat and FFA before and after insulin suppression. Plasma SSAO activity changed by 27.2 (95% CI, -14.5 to + 0.2)% after 3 h (NS) and decreased by 10.1 (95% CI, 19.2 to 1)% after 6 h of insulin infusion ( p

This review focuses on common and genetic risk factors such as HLA and other genes that may be involved in susceptibility for (pre)neoplastic cervical disease. The goal of this review is the evaluation of polymorphisms that are either associated with cervical intraepithelial neoplasia (CIN) and/or cervical cancer. A pooled analysis was performed for DQA1, DQB1 and DRB1 alleles and 10 other genes that have been evaluated in more than one study. An association, either an increased or a decreased risk, with CIN and cervical cancer at a 5% significance level was found for 15 HLA II alleles. Four polymorphisms (Tp53, IL-10, CYP2D6 and the MTHFR) exhibited an increased CIN and cervical cancer risk. However, only the pooled analysis of the DQB1 alleles, the HLA-DR specificities and Tp53 genes had sufficiently large sample sizes to confirm or exclude the proposed association. Our data indicate that further analysis in larger sample sizes, especially for genes other than the HLA genes, is neccesary to describe the exact relations between these genes and susceptibility for CIN and cervical cancer with an adequate power.

Background Several observational studies have shown that higher insulin levels are associated with an increased risk of cardiovascular disease. If higher endogenous insulin levels are causally related to cardiovascular disease, one might expect an increased risk of cardiovascular disease in patients treated with insulin, as this results in high circulating insulin levels. Such risk elevation might counteract the benefits of tight glucose control. Our objective was to explore the relationship between insulin therapy and cardiovascular disease in Type 1 and Type 2 diabetes mellitus using information from available literature.Summary of comment Several experimental studies in animals and humans support the presence of a harmful effect of insulin on the vascular endothelium. In prospective follow-up studies increased insulin dosage was associated with increased risks of cardiovascular disease, although confounding by indication could not be excluded. Randomized controlled trials in diabetic patients, comparing conventional with intensive glucose-lowering treatment, although showing a reduction in microvascular disease, showed no significant difference in the incidence of cardiovascular disease. The results with respect to exposure to insulin are, however, difficult to interpret due to insufficient information on exposure to insulin levels as well as confounding by glycaemic control and body mass index. In addition, these studies were not designed to address the question whether higher insulin use relates to increased cardiovascular risk.Conclusion Published research provides conflicting evidence as to whether exposure to high levels of exogenous insulin in diabetes mellitus affects the risk of cardiovascular disease. The currently available studies have a number of serious methodological restraints that limit accurate interpretation and conclusions in this area.

Background. Microalbuminuria has recently been identified as an independent risk factor for cardiovascular disease in the general population. Immunochemical urinary albumin assays only detect immunoreactive intact albumin. High performance liquid chromatography (HPLC) is able to detect both immunoreactive and immunounreactive intact albumin. We compared both measurement methods respectively in subjects with normo-, micro-, and macroalbuminuria in the general population.Methods. We used 24-hour urine samples that were collected within the framework of the second screening for the PREVEND Study, a prospective cohort study, on albuminuria in the city of Groningen, The Netherlands.Results. With nephelometry as immunochemical reference method, we classified 986 subjects as normoalbuminuric, 283 as microalbuminuric, and 43 subjects as macroalbuminuric. The mean+/-SD albumin concentration was 6.8+/-4.3 mg/L for nephelometry in the urine samples of the 998 subjects with a concentrationConclusion. The use of HPLC for determination of urinary albumin concentrations reveals higher values compared to nephelometry, especially in the lower concentration range, resulting in a higher prevalence of microalbuminuria. With HPLC compared to nephelometry, we found a 21% higher independent odds ratio for microalbuminuria with the presence of peripheral vascular disease, and a 30% higher independent odds ratio for macroalbuminuria.This higher prevalence of microalbuminuria, accompanied with a similar absolute risk for peripheral vascular disease compared to patients with microalbuminuria detected by nephelometry, suggests HPLC to identify more people at risk, which is of great importance, especially when screening in large populations is concerned.

Background. Microalbuminuria has recently been identified as an independent risk factor for cardiovascular disease in the general population. Immunochemical urinary albumin assays only detect immunoreactive intact albumin. High performance liquid chromatography (HPLC) is able to detect both immunoreactive and immunounreactive intact albumin. We compared both measurement methods respectively in subjects with normo-, micro-, and macroalbuminuria in the general population. Methods. We used 24-hour urine samples that were collected within the framework of the second screening for the PREVEND Study, a prospective cohort study, on albuminuria in the city of Groningen, The Netherlands. Results. With nephelometry as immunochemical reference method, we classified 986 subjects as normoalbuminuric, 283 as microalbuminuric, and 43 subjects as macroalbuminuric. The mean+/-SD albumin concentration was 6.8+/-4.3 mg/L for nephelometry in the urine samples of the 998 subjects with a concentration Conclusion. The use of HPLC for determination of urinary albumin concentrations reveals higher values compared to nephelometry, especially in the lower concentration range, resulting in a higher prevalence of microalbuminuria. With HPLC compared to nephelometry, we found a 21% higher independent odds ratio for microalbuminuria with the presence of peripheral vascular disease, and a 30% higher independent odds ratio for macroalbuminuria. This higher prevalence of microalbuminuria, accompanied with a similar absolute risk for peripheral vascular disease compared to patients with microalbuminuria detected by nephelometry, suggests HPLC to identify more people at risk, which is of great importance, especially when screening in large populations is concerned.

Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects.Methods. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age- and sex-matched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL).Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, pless than or equal to0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA(1)c of the previous year and creatinine levels.Conclusions/interpretation. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation.

Objective. Metformin has been associated with the serious side-effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in lactic acidosis. Design. A literature search of the Index Medicus (1959-66) and of the databases Embase, Medline, Medline Express (1966-99) was performed using the keywords metformin, biguanides and lactic acidosis. All articles of cases with metformin-induced lactic acidosis (MILA) were cross-referenced. Subjects. Cases were included for analysis if they met the following criteria: serum pH less than or equal to7.35, lactate concentration greater than or equal to5 mmol L-1. Intervention. A forum of six experts in intensive care medicine independently categorized the cases in MILA unlikely (score 0), possible MILA (score 1) or probable MILA (score 2). Main outcome measures. Statistical analysis included the paired interobserver agreement (kappa) and multivariate regression analysis. Results. Of 80 reported cases, 33 were excluded because of insufficient quality. The forum scores of the remaining 47 cases were distributed normally with a mean score of 7 (range 2-10). The kappa-value was 0.041 (SD = 0.24, range -0.514, 0.427). Neither lactate concentration nor mortality correlated with serum metformin concentrations. Conclusions. Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and lactic acidosis in diabetic patients has to be reconsidered.

Background Overweight and obesity are believed to be associated with renal damage. Whether this depends on fat distribution is not known. We hypothesize that in addition to overweight, fat distribution may be associated with renal function abnormalities. Methods: We studied the relation between body weight and fat distribution and microalbuminuria and elevated or diminished filtration in 7,676 subjects without diabetes. Microalbuminuria is defined as urinary albumin excretion (UAE) of 30 to 300 mg/24 h. Elevated and diminished filtration are defined as filtration plus or minus 2 SDs of a nondiabetic lean group with a peripheral fat distribution and UAE of 0 to 15 mg/24 h, corrected for age and sex. The total population was divided into six groups according to body weight (overweight is defined as body mass index [BMI] > 25 and less than or equal to 30 kg/m(2); obesity, as BMI > 30 kg/m(2)) and fat distribution. Results: In logistic regression analysis, obese subjects with central fat distribution had a greater risk for microalbuminuria (relative risk, 1.7; 95% confidence interval, 1.19 to 2.35). Obese subjects with either peripheral or central fat distribution had a greater risk for elevated filtration (relative risk, 3.2; 95% confidence interval, 1.19 to 8.47; relative risk, 2.6; 95% confidence interval, 1.59 to 4.28, respectively). Furthermore, subjects with central fat distribution, either lean, overweight, or obese, had a greater risk for diminished filtration (relative risk, 1.9; 95% confidence interval, 1.19 to 3.12; relative risk, 2.0; 95% confidence interval, 1.19 to 3.19; and relative risk, 2.7; 95% confidence interval, 1.46 to 4.85, respectively). Finally, by dividing waist-hip ratio (WHR) into quartiles, greater WHR was associated with a greater risk for diminished filtration, even when corrected for BMI. Conclusion: Not only overweight and obese subjects, but also lean subjects with central fat distribution are at risk for diminished filtration. Therefore, a central pattern of fat distribution, not overweight or obesity by itself, seems to be important for renal impairment. (C) 2003 by the National Kidney Foundation, Inc.

Data from recent clinical trials show that lowering of BP reduces the rate of renal function loss in chronic renal disease. There is evidence supporting the assertion that BP lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an additive renoprotective effect in both diabetic and nondiabetic renal diseases. However, to dissociate BP-dependent and non-BP-dependent action of RAAS blockade, the relevant trials are in many cases flawed by design, resulting in BP differences between the comparative anti hypertensive strategies. This review discusses whether the relevant literature allows for the conclusion that RAAS intervention has renoprotective effects in addition to its effects on BP. In particular, the main evidence for a specific renoprotective action of RAAS blockade is provided by its consistent antiproteinuric action, which cannot completely be attributed to the reduction in BP. Indeed, other strategies that lower proteinuria without having an antihypertensive effect, such as lowering dietary protein intake or the use of nonsteroidal antiinflammatory drugs, appear to have a renoprotective effect as well. Interestingly, a consistent finding across different intervention studies is that the more proteinuria is reduced the better the kidney appears to be protected. Therefore, it is concluded that agent-characteristics of RAAS intervention (i.e., antiproteinuric properties) independently influence renal function loss in addition to its BP-lowering effect. Future studies should further explore the renoprotective benefit of non-anti hypertensive intervention measures, alone and in combination with antihypertensive strategies.

Based on studies in diabetic and hypertensive populations it has been postulated that early endothelial dysfunction is the mechanism responsible for the increased cardiovascular risk in microalbuminuric Subjects. We evaluated the relation between microalbuminuria and endothelial dysfunction, assessed as flow-mediated dilation of the brachial artery, in an apparently healthy population. Within the framework of the PREVEND Intervention Trial non-hypertensive and non-hypercholesterolemic subjects were recruited on the basis of reproducible microalbuminuria. Using high-resolution ultrasound, flow-mediated dilation and nitroglycerin-mediated dilation of the brachial artery was assessed to measure endothelium-dependent and endothelium-independent responses, respectively. For the current study subjects with diabetes mellitus, clinical atherosclerosis, and macroalbuminuria were excluded from the analyses. We studied 421 men and 233 women (mean age (SD) 50 (12)). Increasing levels of urinary albumin excretion were accompanied by a significant increase in age, percentage men, systolic and diastolic blood pressure, body mass index. and serum triglycerides, whereas there was no decrease of flow-mediated vasodilation or nitroglycerin-mediated vasodilation. Adjusted for age and sex, urinary albumin excretion was significantly related to systolic (r=0.19, P

Background: The aim of our study was to determine which factors are associated with switching from oral hypoglycaemic agents to insulin therapy in patients with type 2 diabetes mellitus in general practice.Methods: Longitudinal, observational study in a Dutch general healthcare centre. All pharmacologically treated patients with type 2 diabetes mellitus were included (n=152). Comorbidity, laboratory results and medication use were obtained from the general practitioners' files.Results: A total of 31 (20.4%) patients switched from oral hypoglycaemic agents to insulin therapy; they were significantly younger at the onset of diabetes, 50.5 versus 57.7 years. Fasting blood glucose levels and HbA(IC) values were significantly higher after the switch compared with patients on oral treatment, 10.0 mmol/l versus 8.4 mmol/l and 8.8 versus 7.9%, respectively. Concerning comorbidity, they suffered more frequently from acute myocardial infarction, lipid disorders, depression, retinopathy and atrial fibrillation. Cardiovascular disease in general was more often present in patients who switched over to insulin, 77.4% versus 52.9% (OR 3.1; CI 1.2-7.6).Conclusions: Patients who switch over to insulin therapy are younger at diagnosis, suffer from more health problems besides diabetes, especially cardiovascular disease, and have worse metabolic control, compared with users of oral hypoglycaemic agents.

Diet composition and energy content modulate free fatty acid (FFA) release. The aim of this study was to evaluate the dose–response effects of euenergetic variations in dietary carbohydrate and fat content on postabsorptive FFA release. The rate of appearance (Ra) of palmitate was measured by infusion of [2,2-2H2]palmitate after an overnight fast in six healthy men on three separate occasions, i.e. after 7 d on euenergetic control, high-carbohydrate and high-fat diets. The protein content and composition was identical for each diet. Postabsorptive plasma fatty acid concentrations were not different between the high-carbohydrate and control diets (0·36 (SE 0·07) V. 0·43 (se 0·04) mmol/l), but were increased after the high-fat diet (0·75 (se 0·09) mmol/l, (Pa palmitate was not different between the high-carbohydrate and control diets (1·36 (se 0·20) v. 1·47 (se 0·15) μmol/kg per min). However, Ra palmitate was increased to 2·36 (se 0·26) μmol/kg per min after the high-fat diet (PP

The present review describes the knowledge of microalbuminuria as a cardiovascular risk indicator. Microalbuminuria is usually defined as a urinary albumin excretion rate of 30 to 300 mg, in a 24 h urine collection, or as a urinary albumin excretion rate of 20 to 200 mg/min in a timed overnight urine collection, although microalbuminuria was demonstrated to be a predictor for cardiovascular events at levels below these conventional cutoff values, More than one consecutive urine collection is preferred given the high day to day variability of urinary albumin excretion. Microalbuminuria is frequently present and a known cardiovascular risk indicator in diabetic populations, Also, in hypertensive and general populations, microalbuminuria is common and has been associated with all adverse atherogenic risk profile and a higher prevalence of cardiovascular disease. Moreover, evidence strongly suggests that microalbuminuria is also an independent predictor of cardiovascular disease in thee populations, However, more prospective studies are needed to elucidate fully the value of microalbuminuria as a cardiovascular risk indicator in hypertensive and general populations, Generalized endothelial dysfunction has been hypothesized to be the underlying factor for microalbuminuria on one hand and the underlying factor for increased cardiovascular risk on the other. In this respect, the loss of the glycosaminoglycan heparin sulphate might be an important pathophysiological mechanism, This hypothesis need., further clarification, especially in nondiabetic populations.

Accelerated atherosclerosis is often observed in patients with chronic renal failure. In the present review we summarize and discuss the recent literature on the pathogenic role of low-density lipoproteins modified by oxidative processes in atherosclerosis and the possible role in renal diseases. Pathogenetically, the oxidation of low-density lipoproteins is considered to be a key event in the development of atherosclerosis, in part by causing enhanced uptake of lipids by macrophages. In addition, oxidation of low-density lipoproteins exerts cytotoxic, proinflammatory and immunogenic properties, all of which could potentially contribute to the development and progression of atherosclerosis.

Background The Fisher to Lewis (F-L) model of renal transplantation (Rtx) is widely used. Rtx from F to L without immunosuppressive treatment results in 50% survival, whereas L to F results in survival rates similar to syngrafts. When treated with an angiotensin-converting enzyme (ACE) inhibitor or antihypertensive triple therapy, renal damage is markedly reduced in F-L allografts. Despite similar reductions in blood pressure, the ACE inhibitor (ACE-I) is more effective than antihypertensive triple therapy, suggesting that the inhibition of intrarenal ACE plays an additional role in the attenuation of renal damage. Methods In the present study, we investigated strain-related differences in intrarenal ACE activity between F and L rats and whether treatment with ACE-I in F-L allografted rats results in reduction of intrarenal ACE. Intrarenal ACE was measured by activity assays, immunohistochemistry and PCR. Results In control kidneys from healthy F rats (n=8), we found a four-fold higher ACE activity than in native L rats (n=8, p Conclusion In conclusion, intrarenal levels of ACE may play a role in the development of renal damage in experimental chronic renal transplant failure.