Search

Aims Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic beta-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. Methods Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. Results rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*10(-4)) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*10(-4)) but again not in men (P = 0.34). Conclusion The present data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene. Aims: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. Methods: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. Results: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*10 -4) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*10 -4) but again not in men (P = 0.34). Conclusion: The present data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene. What's new?: The rs1800497 single nucleotide polymorphism at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women but not in men. The rs6275 single nucleotide polymorphism in the DRD2 gene is associated with increased first-phase glucose-stimulated insulin secretion in women only. Our data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene.

Aims Since many type 2 diabetes patients experience postprandial hypotension, the aim of this study was to unravel meal-related changes in systemic hemodynamics and autonomic nervous system (ANS)-balance. Methods Forty-two age-matched males (15 type 2 diabetes; 12 metabolic syndrome; 15 controls) without overt autonomic neuropathy received a standardized high-fat mixed meal after an overnight fast. Hemodynamic variables were measured by finger plethysmography. Fourier analysis was used to calculate the low-/high-frequency (LF/HF)-ratio, a marker of autonomic nervous system-balance, and baroreceptor reflex sensitivity (BRS). Results Following the meal, diastolic blood pressure (DBP) decreased in type 2 diabetes patients only, paralleled by a significant decrement in systemic vascular resistance (SVR) and an increase in cardiac index. All groups showed an increase in postprandial heart rate. Controls, but not metabolic syndrome or type 2 diabetes patients, showed a meal-related increase in LF/HF-ratio. When combining all study subjects, homeostatic model assessment-insulin resistance (HOMA-IR) was inversely correlated with changes in DBP, SVR, LF/HF-ratio and BRS. Conclusions Based on these data, we hypothesize that in patients with uncomplicated type 2 diabetes, insulin resistance hampers adequate meal-induced sympathetic activation, leading to a decrease in SVR and resulting in a postprandial drop in DBP.

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, and is associated with a high risk of cardiovascular morbidity and mortality. Intensive control of glucose levels and blood pressure is currently the mainstay of both prevention and treatment of diabetic nephropathy. However, this strategy cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need remains for additional novel therapies. The incretin-based agents--agonists of glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades glucagon-like peptide 1--are novel blood-glucose-lowering drugs used in the treatment of type 2 diabetes mellitus (T2DM). Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic effects that ameliorate various phenotypic defects of T2DM that are beyond glucose control. Agonists of GLP-1R and inhibitors of DPP-4 reduce blood pressure, dyslipidaemia and inflammation, although only GLP-1R agonists decrease body weight. Both types of incretin-based agents inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in rodents and humans. In rodents, incretin-based therapies also prevent onset of the morphological abnormalities of diabetic nephropathy.

The recommended dose of vitamin D supplementation of 400 IU/day might be inadequate to treat obese children with vitamin D insufficiency. Therefore, we tested the efficacy and tolerability of a high loading dose vitamin D3 supplementation of 25,000 IU weekly in multiethnic obese children, 8-18 years of age, with vitamin D insufficiency/deficiency.Fasting blood samples were drawn for the assessment of vitamin D. Vitamin D-insufficient/-deficient children (50 nmol/l) were supplemented, using a high loading dose of 25,000 IU weekly, and measured again 9 weeks later. Vitamin D supplementation was considered effective and tolerable when an increase to vitamin D sufficiency (25(OH)D50 nmol/l) was reached in75% without side effects nor reaching toxic levels.In total, 109 children (mean ± SD age 11.1 ± 3.0, 34.2% boys, 90.8% obese) received vitamin D supplementation. In 84.4% of the children, the vitamin D status improved from insufficiency/deficiency (50 nmol/l) to sufficiency (≥50 nmol/l). The majority of children that did not reach vitamin D sufficiency reported non-compliance. No side effects were reported, and the highest level reached was far below the threshold for toxicity.A high loading dose vitamin D3 supplementation is effective and well-tolerated in our cohort of multiethnic obese children with vitamin D insufficiency/deficiency.

OBJECTIVE We investigated whether proliferative diabetic retinopathy in type 1 diabetic patients can be generalized to cerebral small vessel disease and whether it is associated with impaired peripheral microvascular function. RESEARCH DESIGN AND METHODS Thirty-three patients with proliferative diabetic retinopathy (PDR+), 34 patients without proliferative diabetic retinopathy, and 33 controls underwent magnetic resonance imaging to assess cerebral microangiopathy (cerebral microbleeds) and ischemic damage (white matter hyperintensities and lacunes). Peripheral microvascular function, i.e., skin capillary density and capillary recruitment, was assessed by capillary microscopy. RESULTS Cerebral microbleeds, but not ischemic damage, were more prevalent in PDR+ patients versus the other groups (P < 0.05). A trend was found across groups for the lowest baseline capillary density in PDR+ patients (P for trend = 0.05). In individuals with microbleeds, capillary recruitment was impaired compared with those without microbleeds (P = 0.04). CONCLUSIONS In PDR+ patients, cerebral microbleed prevalence was higher and seems part of generalized microangiopathy that may affect the skin and the brain.

Type 2 diabetes is associated with prolonged and exaggerated postprandial hyperglycemia and hypertriglyceridemia, endothelial dysfunction, and cardiovascular disease (CVD) (1–7). Endothelial dysfunction may link postprandial dysmetabolism to CVD (5–7). Since the postprandial state unveils the full scope of metabolic abnormalities in type 2 diabetes, previous studies (1) in fasting subjects may have underestimated the true risk. Currently, endothelial functions can only be estimated from indirect measurements, such as flow-mediated dilation (FMD) (6,8). Cell-derived microparticles are released by cells in response to stress. Increased numbers of microparticles of various cellular origin circulate in patients at risk of CVD (9,10). Recently, vascular-endothelial cadherin (CD144)-positive microparticles were demonstrated in type 2 diabetic patients with coronary artery disease and patients with end-stage renal disease (11,12). Since vascular-endothelial cadherin is exclusively expressed by endothelial cells, CD144-positive microparticles may be regarded as endothelium-derived microparticles (EMPs), directly reflecting endothelial damage. However, it is unknown whether circulating EMPs are cause or consequence of CVD, and whether their occurrence associates with CVD per se or, rather, with diabetes-related metabolic abnormalities. We hypothesized that in patients with uncomplicated type 2 diabetes, exposure to three consecutive high-fat mixed meals, given during a 24-h period, will disclose the full scope of their compromised metabolism and subsequent endothelial dysfunction, measured as FMD and circulating EMPs. After obtaining informed consent, 27 nonsmoking Caucasian male subjects ( n = 15 with uncomplicated type 2 diabetes and n = 12 healthy age-matched volunteers) were studied during a 24-h period. No drug use other than sulfonylureas and/or metformin was allowed. After an overnight fast, subjects received three consecutive, …

Background: Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is regarded as a key pathogenic factor and component of the metabolic syndrome. It was reported that administration of the incretin mimetic exenatide reversed hepatic steatosis in an obese mouse model. We had the opportunity to study the effect of additional exenatide administration on liver fat content in a patient with type 2 diabetes. Case report: A 59-year-old male with poorly controlled type 2 diabetes was treated with exenatide in addition to metformin monotherapy. Following 44 weeks of exenatide therapy, mean the liver fat measured by liver spectroscopy declined from 15.8% to 4.3%. This dramatic decrease in liver fat was accompanied by significant beneficial changes in several cardiovascular disease risk factors and improvement of all liver enzymes, in particular alanine aminotransferase, the most important marker of liver steatosis. Conclusion: This case report suggests that the incretin mimetic exenatide decreases hepatic fat accumulation and may play a role in the future treatment of NAFLD, and the associated insulin resistance and cardiovascular risk factors in an ever-growing high-risk population.

Background Activin A released from epicardial adipose tissue has been linked to contractile dysfunction and insulin resistance in cardiomyocytes. This study investigated the role of activin A in clinical diabetic cardiomyopathy by assessing whether circulating activin A levels associate with cardiometabolic parameters in men with uncomplicated type 2 diabetes (T2D), and the effects of treatment with pioglitazone versus metformin on these associations. Methods Seventy-eight men with uncomplicated T2D and fourteen healthy men with comparable age were included, in this randomized, double-blind, active comparator intervention study. All T2D men were on glimipiride monotherapy, and randomized to a 24-week intervention with either pioglitazone or metformin. Cardiac dimensions and -function were measured using magnetic resonance imaging, whilst myocardial glucose metabolism (MMRglu) was determined using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography during a hyperinsulinemic-euglycemic clamp. Results Circulating activin A levels were comparable in T2D men and controls. Activin A levels were independently inversely associated with MMRglu, and positively with left ventricular mass/volume (LVMV)-ratio in T2D men. Intervention with metformin decreased activin A levels, whereas pioglitazone did not alter activin A levels. The changes in plasma activin A levels were not correlated with the changes in MMRglu following either pioglitazone or metformin treatment. A borderline significant correlation (p = 0.051) of changes in plasma activin A levels and changes in LVMV-ratio was observed after pioglitazone treatment. Conclusions Circulating activin A levels are associated with impaired myocardial glucose metabolism and high LVMV-ratio in patients with uncomplicated T2D, reflecting a potential detrimental role in early human diabetic cardiomyopathy. Trial registration number Current Controlled Trials SRCTN53177482

This study evaluates the impact of hybrid imaging on referral for invasive coronary angiography (ICA) and revascularization rates.A total of 375 patients underwent hybrid (15)O-water positron emission tomography (PET)/computed tomography (CT)-based coronary angiography (CTCA) imaging for the evaluation of coronary artery disease (CAD). Downstream treatment strategy within a 60-day period after hybrid PET/CTCA imaging for ICA referral and revascularization was assessed. CTCA examinations were classified as showing no (obstructive) CAD, equivocal (borderline test result), or obstructive CAD, while the PET perfusion images were classified into normal or abnormal. On the basis of CTCA imaging, 182 (49%) patients displayed no (obstructive) CAD. Only 10 (5%) patients who showed no (obstructive) CAD on CTCA were referred for ICA, which were all negative. An equivocal CT study was observed in 80 (21%) patients, among whom 56 (70%) showed normal myocardial perfusion imaging (MPI), resulting in referral rates for ICA of 18% for normal MPI and 71% for abnormal MPI, respectively. No revascularizations were performed in the presence of normal MPI, while 59% of those with abnormal MPI were revascularized. CTCA indentified obstructive CAD in 113 (30%) patients accompanied in 59 (52%) patients with abnormal MPI. Referral rate for ICA was 57% for normal MPI and 88% for those with abnormal MPI, resulting in revascularization rates of 26% and 72%, respectively.Hybrid (15)O-water PET/CTCA imaging impacts clinical decision-making with regard to referral for ICA and revascularization procedures. Particularly, in the presence of an equivocal or abnormal CTCA, MPI could guide in the decision to refer for ICA and revascularization.

To compare cerebral blood flow (CBF) values measured using magnetic resonance imaging (MRI) arterial spin labeling (ASL) with those obtained with [(15)O]H2O positron emission tomography (PET), the gold standard for measuring CBF in vivo.Data were collected in 11 healthy men and in 20 age- and body mass index (BMI)-matched type 1 diabetic men. Pseudo-continuous ASL (PCASL) data were acquired at 3 T and [(15)O]H2O PET scans were acquired using a high-resolution PET scanner. Input functions were obtained using on-line arterial blood sampling. Whole brain and regional CBF values were compared.For both modalities, whole brain CBF was similar in both subject groups. In groups combined, average whole brain CBF was 0.30 ± 0.05 mL · cm(-3) · min(-1) for [(15)O]H2O PET and 0.34 ± 0.05 mL · cm(-3) · min(-1) for ASL MRI (P0.01). A significant correlation between methods was observed for whole brain, gray and white matter. In 12 out of 33 brain regions a significant difference between methods was observed.PCASL provides CBF values that correlate with [(15)O]H2O PET-derived values, but is less accurate. PCASL may be an attractive alternative when absolute quantification is not needed.

The proline-rich Akt substrate of 40-kDa (PRAS40) has been linked to the regulation of the activity of the mammalian target of rapamycin complex 1 as well as insulin action. Despite these cytosolic functions, PRAS40 was originally identified as nuclear phosphoprotein in Hela cells. This study aimed to detail mechanisms and consequences of the nucleocytosolic trafficking of PRAS40. Sequence analysis identified a potential leucine-rich nuclear export signal (NES) within PRAS40. Incubation of A14 fibroblasts overexpressing human PRAS40 (hPRAS40) resulted in nuclear accumulation of the protein. Furthermore, mutation of the NES mimicked the effects of leptomycin B, a specific inhibitor of nuclear export, on the subcellular localization of hPRAS40. Finally, A14 cells expressing the NES-mutant showed impaired activation of components of the Akt-pathway as well as of the mTORC1 substrate p70 S6 kinase after insulin stimulation. This impaired insulin signaling could be ascribed to reduced protein levels of insulin receptor substrate 1 in cells expressing mutant NES. In conclusion, PRAS40 contains a functional nuclear export signal. Furthermore, enforced nuclear accumulation of PRAS40 impairs insulin action, thereby substantiating the function of this protein in the regulation of insulin sensitivity.

OBJECTIVE To compare magnetic resonance imaging-derived right ventricular (RV) dimensions and function between men with type 2 diabetes and healthy subjects, and to relate these parameters to left ventricular (LV) dimensions and function. RESEARCH DESIGN AND METHODS RV and LV volumes and functions were assessed in 78 men with uncomplicated type 2 diabetes and 28 healthy men within the same range of age using magnetic resonance imaging. Steady-state free precession sequences were used to assess ventricular dimensions. Flow velocity mapping across the pulmonary valve and tricuspid valve was used to assess RV outflow and diastolic filling patterns, respectively. Univariate general linear models were used for statistical analyses. RESULTS RV end-diastolic volume was significantly decreased in patients compared with healthy subjects after adjustment for BMI and pulse pressure (177 ± 28 mL vs. 197 ± 47 mL, P < 0.01). RV systolic function was impaired: peak ejection rate across the pulmonary valve was decreased (433 ± 54 mL/s vs. 463 ± 71 mL/s, P < 0.01) and pulmonary flow acceleration time was longer (124 ± 17 ms vs. 115 ± 25 ms, P < 0.05). Indexes of RV diastolic function were impaired: peak filling rate and peak deceleration gradient of the early filling phase were 315 ± 63 mL/s vs. 356 ± 90 mL/s (P < 0.01) and 2.3 ± 0.8 mL/s2 × 10−3 vs. 2.8 ± 0.8 mL/s2 × 10−3 (P < 0.01), respectively. All RV parameters were strongly associated with its corresponding LV parameter (P < 0.001). CONCLUSIONS Diabetic cardiomyopathy affects the right ventricle, as demonstrated by RV remodeling and impaired systolic and diastolic functions in men with type 2 diabetes, in a similar manner as changes in LV dimensions and functions. These observations suggest that RV impairment might be a component of the diabetic cardiomyopathy phenotype.

OBJECTIVE A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone. RESEARCH DESIGN AND METHODS A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500–2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio. RESULTS After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was −0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (−0.91 mg/dL and −7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo. CONCLUSIONS Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.

Objective: Glucocorticoids (GCs) are well known to induce insulin resistance; however, mechanisms that cause the impairement of the insulin signaling pathway have not yet been identified. In this study we measured whether GC-induced insulin resistance in humans is related to changes in muscle ceramide, GM3, and muscle mitochondrial function. Methods: In a randomized, placebo-controlled, double-blind, dose-response intervention study, 32 healthy males (aged 22 ± 3 years; body mass index 22.4 ± 1.7 kg/m(-2)) were allocated to prednisolone (PRED) 7.5 mg once daily (n = 12), PRED 30 mg once daily (n = 12), or placebo (n = 8) for 2 weeks using block randomization. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp before and after treatment. Muscle biopsies were performed to measure ceramide, monosialodihexosylganglioside (GM3), and mitochondrial function. Results: Peripheral insulin sensitivity was dose dependently decreased after the PRED treatment. Muscle ceramide and GM3 concentration and mitochondrial function were not altered by 2 weeks of PRED treatment. Conclusion: Short-term GC treatment dose dependently impaired whole-body insulin sensitivity in healthy males, without concomitant changes in muscle ceramide, GM3, or mitochondrial function. These findings suggest that other mechanisms play a role in GC-related impairment of insulin sensitivity

Background Contrasting data exist regarding the relationship between thyroid-stimulating hormone (TSH) and obesity-related risk factors in children. In the present study, we investigated the association between TSH, free T4 (fT4) and cardiometabolic risk factors in euthyroid obese children and adolescents. Methods A retrospective analysis of patient records was performed on data from 703 multi-ethnic obese children and adolescents who visited an obesity-outpatient clinic. We performed anthropometric measurements, an oral glucose tolerance test, and measured serum TSH, fT4 and lipid levels. Results A positive association between TSH and the standard deviation score of the body mass index (BMI-Z) was found. After adjustment for ethnicity, sex, pubertal stage and BMI-Z, logistic regression analysis showed significant associations between TSH levels and impaired fasting glucose, impaired glucose tolerance, high total cholesterol, high low-density lipoprotein cholesterol and high triglycerides. No significant associations between fT4 levels and cardiometabolic risk factors were found in linear/logistic regression analysis. Conclusion In our multi-ethnic cohort of euthyroid obese children and adolescents increasing TSH was associated with impaired glucose metabolism and dyslipidemia.

During lipid oversupply, the heart becomes insulin resistant, as exemplified by defective insulin-stimulated glucose uptake, and will develop diastolic dysfunction. In the healthy heart, not only insulin, but also increased contractile activity stimulates glucose uptake. Upon increased contraction both AMP-activated protein kinase (AMPK) and protein kinase D (PKD) are activated, and mediate the stimulation of glucose uptake into cardiomyocytes. Therefore, each of these kinases is a potential therapeutic target in the diabetic heart because they may serve to bypass defective insulin-stimulated glucose uptake. To test the preventive potential of these kinases against loss of insulin-stimulated glucose uptake, AMPK or PKD were adenovirally overexpressed in primary cultures of insulin resistant cardiomyocytes for assaying substrate uptake, insulin responsiveness and lipid accumulation. To induce insulin resistance and lipid loading, rat primary cardiomyocytes were cultured in the presence of high insulin (100 nM; HI) or high palmitate (palmitate/BSA: 3/1; HP). HI and HP each reduced insulin responsiveness, and increased basal palmitate uptake and lipid storage. Overexpression of each of the kinases prevented loss of insulin-stimulated glucose uptake. Overexpression of AMPK also prevented loss of insulin signaling in HI- and HP-cultured cardiomyocytes, but did not prevent lipid accumulation. In contrast, overexpression of PRO prevented lipid accumulation, but not loss of insulin signaling in HI- and HP-cultured cardiomyocytes. In conclusion, AMPK and PKD prevent loss of insulin-stimulated glucose uptake into cardiomyocytes cultured under insulin resistance-inducing conditions through different mechanisms. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

Contains fulltext : 118105.pdf (Publisher’s version ) (Open Access) CONTEXT: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. METHODS: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. RESULTS: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P

Development of cardiovascular disease is one of the major complications of type 2 diabetes mellitus (T2DM). The chronic hyperglycaemic state is often accompanied by dyslipidaemia, hypertension, low-grade systemic inflammation and oxidative stress which collectively result in a high risk of micro- and macrovascular complications. Current glucose-lowering agents do not sufficiently address fore-mentioned macrovascular-risk factors. Recently, new therapeutic agents were introduced, based on the incretin hormone glucagon-like peptide-1 (GLP-1), that is, the GLP-1 receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 (DPP-4) inhibitors. Beside its effect on pancreatic insulin secretion, GLP-1 exerts several extra-pancreatic effects such as slowing down gastric emptying, promoting satiety and reducing food intake and weight loss. Also, GLP-1 and GLP-1RA were shown to improve cardiovascular-risk profiles, by reducing body fat content, blood pressure, circulating lipids and inflammatory markers in patients with T2DM. This review summarizes the presently known evidence with regard to extra-pancreatic effects of the incretin-based agents, focusing on the actions that improve the cardiovascular-risk profile. We present available data from clinical trials of at least 24 week duration, but also findings from small-sized clinical 'proof of principle' studies. We conclude that GLP-1 RA and to a lesser extent DPP-4 inhibitors are promising agents with regard to their effects on body weight, blood pressure and lipids, which collectively ameliorate the cardiovascular-risk profile and as such may have added value in the treatment of T2DM. However, large-sized long-term outcome studies are warranted to show the true added value of these agents in the treatment of patients with T2DM.

The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances β-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30–40%) on GLP-1–stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 × 10−7). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.

Background The role of diet in inflammatory bowel disease (IBD) is supported by migration studies and increasing incidences in line with Westernisation. Aim To give a complete overview of studies associating habitual diet with the onset or relapses in ulcerative colitis (UC) or Crohn's disease (CD). Methods A structured search in Pubmed, the Cochrane Library and EMBASE was performed using defined key words, including only full text papers in English language. Results Forty-one studies were identified, investigating onset (n = 35), relapses (n = 5) or both (n = 1). Several studies reported high intake of sugar or sugar-containing foods (n = 7 UC, n = 12 CD), and low intake of fruits and/or vegetables (n = 5 UC, n = 10 CD) to be associated with an increased onset risk. However, these findings could not be confirmed by similar or higher numbers of other studies. A possible protective role was found for grain-derived products in CD onset, but results were inconsistent for dietary fibre in UC and CD and grain-derived products in UC. No definite conclusions could be drawn for unsaturated fatty acids (UFA), protein and energy intake due to limited and/or inconsistent results. Six studies reported on diet and relapse risk, of which only two (n = 1 UC, n = 1 CD) had a prospective follow-up. Conclusions The current evidence is not sufficient to draw firm conclusions on the role of specific food components or nutrients in the aetiology of IBD. Furthermore, large prospective studies into the role of habitual diet as a trigger of relapses are needed, to identify new therapeutic or preventive targets

Aims/hypothesis We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control. We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. Methods Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peakvalley respiratory sinus arrhythmia [pvRSA], and highfrequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine). Results Serum insulin level was positively associated with HR at all time points during the clamps except the firstphase hyperglycaemic clamp. Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log10HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and insulin sensitivity. Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. Conclusion/interpretation Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control.

Glucocorticoids (GCs) are widely used anti-inflammatory agents that frequently induce side effects, including insulin resistance, diabetes and hypertension. Here, we investigated the contribution of microvascular dysfunction to the development of these adverse effects in healthy men.In a randomised, placebo-controlled, dose-response intervention study, 32 healthy normoglycaemic men (age: 21 ± 2 years; BMI: 21.9 ± 1.7 kg/m(2)) were allocated to receive prednisolone 30 mg once daily (n = 12), prednisolone 7.5 mg once daily (n = 12) or placebo (n = 8) for 2 weeks using block randomisation. A central office performed the treatment allocation, and medication was dispersed by the hospital pharmacy that was also blinded. Treatment allocation was kept in concealed envelopes. Participants, study personnel conducting the measures and assessing the outcome were blinded to group assignment. The study was conducted at a university hospital. Primary endpoint was prednisolone-induced changes in microvascular function, which was assessed by capillary microscopy. Insulin sensitivity was determined by hyperinsulinaemic-euglycaemic clamp and postprandial glycaemic excursions by standardised meal tests.Compared with placebo, prednisolone 7.5 mg and 30 mg decreased insulin-stimulated capillary recruitment by 9 ± 4% and 17 ± 3%, respectively (p0.01). In addition, prednisolone 7.5 mg and 30 mg reduced insulin sensitivity (M value) by -11.4 ± 4.5 μmol kg(-1) min(-1) and -25.1 ± 4.1 μmol kg(-1) min(-1) (p0.001) and increased postprandial glucose levels by 11 ± 5% and 27 ± 9% (p0.001), respectively. Only high-dose prednisolone increased systolic blood pressure (6 ± 1.2 mmHg, p = 0.006). Prednisolone-induced changes in insulin-stimulated capillary recruitment were associated with insulin sensitivity (r = +0.76; p0.001), postprandial glucose concentrations (r = -0.52; p0.03) and systolic blood pressure (r = -0.62; p0.001). Prednisolone increased resistin concentrations, which were negatively related to insulin-stimulated capillary recruitment (r = -0.40; p = 0.03). No effects were noted on adiponectin and leptin concentrations. Prednisolone treatment was well tolerated; none of the participants left the study.Prednisolone-induced impairment of insulin-stimulated capillary recruitment was paralleled by insulin resistance, increased postprandial glucose levels, hypertension and increased circulating resistin concentrations in healthy men. We propose that GC-induced impairments of microvascular function may contribute to the adverse effects of GC treatment on glucose metabolism and blood pressure.isrctn.org ISRTCN 78149983.The study was funded by the Dutch Top Institute Pharma T1-106.

Background: Depressive and anxiety disorders are highly overlapping, heterogeneous conditions that both have been associated with an increased risk of cardiovascular disease (CVD). Cognitive vulnerability traits for these disorders could help to specify what exactly drives CVD risk in depressed and anxious subjects. Our aim is to examine sensitivity to depression or anxiety in association with indicators of subclinical CVD.Methods: Data from 635 participants (aged 20-66 years) of the Netherlands Study of Depression and Anxiety were analyzed. Depression sensitivity was measured by the revised Leiden Index of Depression Sensitivity. Anxiety sensitivity was measured by the Anxiety Sensitivity Index. Subclinical CVD was measured as (1) carotid intima-media thickness and plaque presence using B-mode ultrasonography and (2) central arterial stiffness (augmentation index) using calibrated radial applanation tonometry.Results: After adjustment for sociodemographics, blood pressure, and LDL cholesterol, higher scores of anxiety sensitivity were associated with both increased likelihood of carotid plaques (OR per SD increase=1.34, 95%CI=1.06-1.68) and increased arterial stiffness (beta=.06, p=.01). No significant associations were found with carotid intima-media thickness nor for depression sensitivity.Limitations: The cross-sectional design precludes causal inference. Current mood state could have influenced the self-reported sensitivity data.Conclusions: The presence of carotid plaques and central arterial stiffness was especially increased in subjects who tend to be highly fearful of anxiety-related symptoms. These observations suggest that vulnerability to anxiety, rather than to depression, represents a correlate of subclinical CVD. (C) 2012 Elsevier B.V. All rights reserved.

Small LDL size is common in patients with type 2 diabetes and is associated with an increased risk of cardiovascular disease (1). LDL size is determined by various constituents of lipoprotein metabolism, such as lipoprotein lipase (LPL) and hepatic lipase (HL) activities, cholesteryl ester transfer protein (CETP), as well as triglyceride concentrations (2–4). Although abnormalities in LPL, HL, and CETP levels are associated with a diabetic lipoprotein profile, a relation to insulin resistance has been found only with lipase activities (5–7) but not with CETP (8,9). In this cross-sectional study, we investigated the relationship of LPL and HL activities and CETP mass with LDL size in 426 subjects with normal and impaired glucose metabolism or type 2 diabetes. The Hoorn Study is a population-based cohort study of glucose metabolism and cardiovascular risk factors among 2,484 inhabitants of the municipality of Hoorn, which started in 1989. In 2000–2001, a follow-up was conducted in selected subjects then aged 60–87 years, as previously described (10). We invited all surviving subjects with type 2 diabetes ( n = 176) and …

Altered skeletal muscle fatty acid (FA) metabolism contributes to insulin resistance. Here, we compared skeletal muscle FA handling between subjects with impaired fasting glucose (IFG; n = 12 (7 males)) and impaired glucose tolerance (IGT; n = 14 (7 males)) by measuring arterio-venous concentration differences across forearm muscle. [H-2(2)]-palmitate was infused intravenously, labeling circulating endogenous triacylglycerol (TAG) and free fatty acids (FFA), whereas [U-C-13]-palmitate was incorporated in a high-fat mixed-meal, labeling chylomicron-TAG. Skeletal muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid content, their fractional synthetic rate (FSR) and degree of saturation, and gene expression. Insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. Net skeletal muscle glucose uptake was lower (p = 0.018) and peripheral insulin sensitivity tended to be reduced (p = 0.064) in IGT as compared to IFG subjects. Furthermore, IGT showed higher skeletal muscle extraction of VLDL-TAG (p = 0.043), higher muscle TAG content (p = 0.025), higher saturation of FFA (p = 0.004), lower saturation of TAG (p = 0.017) and a tendency towards a lower TAG FSR (p = 0.073) and a lower saturation of DAG (p = 0.059) versus IFG individuals. Muscle oxidative gene expression was lower in IGT subjects. In conclusion, increased liver-derived TAG extraction and reduced lipid turnover of saturated FA, rather than DAG content, in skeletal muscle accompany the more pronounced insulin resistance in IGT versus IFG subjects.

OBJECTIVE Heart failure is common in individuals with type 2 diabetes, and early detection of individuals at risk may offer opportunities for prevention. We aimed to explore 1) prospective associations of B-type natriuretic peptide (BNP) levels in a non–heart failure range with changes in markers of left ventricular (LV) function and 2) possible effect modification by type 2 diabetes in a population-based cohort. RESEARCH DESIGN AND METHODS Echocardiographic measurements were performed at baseline (2000–2001) and follow-up (2007–2009), together with standardized physical examinations and BNP measurements on 300 individuals (mean age 66 years, 32% with type 2 diabetes) of the longitudinal Hoorn Study. Multivariate linear regression analyses were performed to investigate associations of baseline BNP (

Hyperinsulinaemia-induced whole-body glucose uptake during a euglycaemic-hyperinsulinaemic clamp is partly mediated by increased capillary density. We hypothesised that physiological insulinaemia in response to a mixed meal may also enhance microvascular function, and that this may be impaired in insulin-resistant individuals and patients with type 2 diabetes.Twelve men with uncomplicated type 2 diabetes, 13 with metabolic syndrome and 12 age-matched healthy normoglycaemic controls, mean age 57 ± 6 years, underwent skin capillary video microscopy before and 60 and 120 min following a standardised mixed meal to measure baseline capillary density (BCD) and capillary density during post-occlusive peak reactive hyperaemia (PRH), also termed capillary recruitment. Oral glucose insulin sensitivity (Matsuda index) and postprandial hyperglycaemia (2 h AUC(glucose)) were calculated.Fasting BCD was similar among groups, but fasting PRH was lowest in diabetes (p0.05). Postprandially, both BCD and PRH increased in all groups (p0.001); however, the meal-related increase in BCD was significantly lower in diabetes and metabolic syndrome vs controls (both p0.05). At all time points, postprandial PRH was lower in both diabetes and metabolic syndrome vs controls (both p0.05). In pooled analysis, postprandial mean PRH correlated with Matsuda index (r = 0.386, p = 0.018) and inversely with 2 h AUC(glucose) (r = -0.336, p = 0.042).Gradual deterioration in meal-related capillary recruitment was paralleled by decreasing insulin sensitivity and postprandial hyperglycaemia, as assessed in healthy normoglycaemic men, men with the metabolic syndrome and those with type 2 diabetes. These findings suggest that in both impaired glucose tolerance and in overt diabetes microvascular dysfunction might contribute to postprandial dysglycaemia.ClinicalTrials.gov NCT00721552.

Background: Low serum 25-hydroxyvitamin D (25OHD) levels have been associated with increased risk of cardiovascular disease. Dysfunction of the vitamin D-parathyroid hormone (PTH)-calcium axis may play a role in the pathogenesis of heart failure. Hypothesis: We investigated whether lower serum 25OHD levels and higher PTH levels are associated with higher B-type natriuretic peptide (BNP) levels in older individuals both cross-sectionally and after 8 years of follow-up. Methods: We measured baseline serum 25OHD, PTH and BNP in 502 subjects in 2000–2001 in the Hoorn Study, a population-based cohort. Follow-up BNP was measured in 2007–2009 in 278 subjects. Subjects were categorized according to season and sex-specific 25OHD and PTH quartiles at baseline. We studied the association of 25OHD and PTH quartiles with BNP using linear regression analyses adjusting for confounders. Effect-modification by kidney function and CVD presence was examined. Results: Subjects had a mean age of 70 years, mean 25OHD level of 52±19.5 (nmol/L) and mean PTH of 6.1±2.4 (pmol/L). The lowest 25-OHD quartile was cross-sectionally associated with higher BNP, in subjects with low kidney function only (eGFR2 )(=sample median). The association attenuated after adjustment for PTH. PTH was cross-sectionally associated with BNP in subjects with low kidney function only (p-for-trend < 0.05), even after adjustment for 25OHD (Figure 1). Neither 25OHD nor PTH was associated with BNP in longitudinal analyses. Conclusion: This study showed no strong association between 25OHD and BNP. However, PTH - a potential mediator in the relation between 25OHD and BNP, was associated with BNP in subjects with low kidney function.

Reperfusion limits myocardial necrosis, however induces reperfusion injury leading to additional necrosis and apoptosis. Glucagon Like Peptide-1 (GLP-1), an incretin hormone, has anti-apoptotic properties and proved to be cardioprotective in experimental studies. This pilot study assessed the safety and feasibility of the GLP-1 receptor agonist exenatide in patients with acute MI undergoing primary PCI. Methods: Seventy-one non-diabetic patients with acute MI undergoing primary PCI were randomized to placebo or exenatide 5μg bolus administered in 30 minutes prior to PCI, followed by continuous infusion of 20μg/ 24 hours for 72 hours. Blood samples were obtained including enzymatic infarct size and glucose levels. Magnetic resonance imaging and echocardiography were conducted 3-5 days and 4 months post MI for measurements including infarct size, cardiac function and myocardial salvage index (MSI), a predictor for mortality and major adverse cardiac events. Results: Forty out of 71 randomized patients completed the full protocol. Exclusion was mainly due to angiographic criteria. Patient characteristics were well balanced between the groups. An equal amount of hypo- and hyperglycemic episodes (glucose 10 mmol/L) were observed in both groups. No deaths, CABG or re-infarction occurred during the 4-month follow-up. Although more patients in the exenatide group experienced nausea (58% v 20%, p = 0.015), no decrease or cessation of exenatide was required. Infarct size, cardiac function and MSI at 4 months did not differ signiicantly. However, a trend towards a higher MSI was seen in patients with TIMI 0 and 1 low receiving exenatide (0.65 ± 0.14 (n = 12) v 0.53 ± 0.17 (n = 11), p = 0.09). Conclusions: We demonstrated that administering exenatide in patients with acute MI undergoing primary PCI is feasible and safe. Although not powered for this analysis, Exami phase l seems to show a trend towards a higher MSI in the exenatide group. A large randomized placebo controlled study is required to assess the eficacy of exenatide on myocardial salvage.

Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1-2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes.

Purpose The perfusable tissue index (PTI) is a marker of myocardial viability. Recent technological advances have made it possible to generate parametric PTI images from a single [15O]H2O PET/CT scan. The purpose of this study was to validate these parametric PTI images. Methods The study population comprised 46 patients with documented or suspected coronary artery disease who were studied with [15O]H2O PET and late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR). Results Of the 736 myocardial segments included, 364 showed some degree of LGE. PTI and perfusable tissue fraction (PTF) diminished with increasing LGE. The areas under the curve of the PTI and PTF, used to predict (near) transmural LGE on CMR, were 0.86 and 0.87, respectively. Optimal sensitivity and specificity were 91 % and 73 % for PTI and 69 % and 87 % for PTF, respectively. Conclusion PTI and PTF assessed with a single [15O]H2O scan can be utilized as markers of myocardial viability in patients with coronary artery disease.

Background: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. Methodology: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. Principal Findings: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. Conclusions: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism. © 2012 van Vliet-Ostaptchouk et al.

Background Positron emission tomography (PET) allows for the measurement of cerebral blood flow (CBF; based on [15O]H2O) and cerebral metabolic rate of glucose utilization (CMRglu; based on [18 F]-2-fluoro-2-deoxy-d-glucose ([18 F]FDG)). By using kinetic modeling, quantitative CBF and CMRglu values can be obtained. However, hardware limitations led to the development of semiquantitive calculation schemes which are still widely used. In this paper, the analysis of CMRglu and CBF scans, acquired on a current state-of-the-art PET brain scanner, is presented. In particular, the correspondence between nonlinear as well as linearized methods for the determination of CBF and CMRglu is investigated. As a further step towards widespread clinical applicability, the use of an image-derived input function (IDIF) is investigated. Methods Thirteen healthy male volunteers were included in this study. Each subject had one scanning session in the fasting state, consisting of a dynamic [15O]H2O scan and a dynamic [18 F]FDG PET scan, acquired at a high-resolution research tomograph. Time-activity curves (TACs) were generated for automatically delineated and for manually drawn gray matter (GM) and white matter regions. Input functions were derived using on-line arterial blood sampling (blood sampler derived input function (BSIF)). Additionally, the possibility of using carotid artery IDIFs was investigated. Data were analyzed using nonlinear regression (NLR) of regional TACs and parametric methods. Results After quality control, 9 CMRglu and 11 CBF scans were available for analysis. Average GM CMRglu values were 0.33 ± 0.04 μmol/cm3 per minute, and average CBF values were 0.43 ± 0.09 mL/cm3 per minute. Good correlation between NLR and parametric CMRglu measurements was obtained as well as between NLR and parametric CBF values. For CMRglu Patlak linearization, BSIF and IDIF derived results were similar. The use of an IDIF, however, did not provide reliable CBF estimates. Conclusion Nonlinear regression analysis, allowing for the derivation of regional CBF and CMRglu values, can be applied to data acquired with high-spatial resolution current state-of-the-art PET brain scanners. Linearized models, applied to the voxel level, resulted in comparable values. CMRglu measurements do not require invasive arterial sampling to define the input function. Trial registration ClinicalTrials.gov NCT00626080

Aims: Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-exenatide antibodies and potential effects on efficacy and safety. Methods: Data from intent-to-treat patients in 12 controlled (n = 2225,12-52weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52weeks) were analysed. Results: Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, exenatide BID; -1.6% and -1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres. Conclusions: Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide. © 2012 Blackwell Publishing Ltd.

Purpose To test whether improvement in glycosylated haemoglobin (HbA(1c)) as a marker of glycaemic control, following intensifying insulin therapy, is associated with improvements in HRQoL. Methods Dutch sub-optimally controlled (HbA(1c) > 7%) type 2 diabetes patients (N = 447, mean age 59 +/- 11) initiated insulin glargine therapy. Data were collected at baseline, 3 and 6 months, and included HbA1c and measures of HRQoL: diabetes symptom distress (Diabetes Symptom Checklist-revised; DSC-r), fear of hypoglycaemia (Hypoglycaemia Fear Survey; HFS-w) and emotional well-being (WHO-5 wellbeing index). Results HbA(1c) decreased from 8.8 +/- 1.4% to 8.0 +/- 1.2% and 7.7 +/- 1.3% at 3 and 6 months follow-up, respectively (P

Objective:To determine insulin sensitivity and skeletal muscle fatty acid (FA) handling at baseline and after a high-fat mixed meal in impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG/IGT and normal glucose tolerance (NGT) subjects.Design:In this multi-center study, insulin sensitivity and beta-cell function were assessed (n=102), using a euglycemic-hyperinsulinemic and hyperglycemic clamp with additional arginine stimulation and a 75 g oral glucose tolerance test. Fasting and postprandial skeletal muscle FA handling was examined in a substudy using the forearm balance technique (n=35).Subjects:A total of 102 subjects with IFG (n=48), IGT (n=12), IFG/IGT (n=26) and NGT (n=16).Results:IFG, IGT and IFG/IGT subjects had lower insulin sensitivity with no differences between groups, and lower impaired beta-cell function compared with NGT controls. The early postprandial increase in triacylglycerol (TAG) concentration was higher (iAUC(0-2 h) IFG: 238.4+/-26.5, IGT: 234.0+/-41.0 and NGT: 82.6+/-13.8 mumol l(-1) min(-1), both P

In the present article, we aimed to compare the cardiometabolic risk between overweight children with and without type 1 diabetes (T1DM). Therefore, data with regard to cardiometabolic risk parameters of 44 overweight Caucasian children (3-18 years) with T1DM were matched with 44 overweight peers without T1DM for sex, ethnicity, age and standard deviation score of BMI (Z-BMI). Detailed history was taken, information regarding anthropometrics and family history were collected and blood pressure was measured. Blood samples were collected for evaluation of lipid profiles (fasting in controls, non-fasting in T1DM children), alanine aminotransferase and HbA1c (in children with T1DM). It was found that overweight children with T1DM had lower median standard deviation score of waist circumference (Z-WC) as compared to the overweight control group [median, 2.0 (interquartile range, IQR, 1.5-2.3) vs. 2.6 (IQR, 2.0-2.9), P

Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available,1–5 mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications.6–9 Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations10 and by other societies and federations.2,11–15 However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes,16,17 the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care.18,19 This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular risk factors (blood pressure and lipid therapy, antiplatelet treatment, and smoking cessation) is likely to have even greater benefits. View this table: Table 1. Properties of Currently Available Glucose-Lowering Agents That May Guide Treatment Choice in Individual Patients With Type 2 Diabetes Mellitus These recommendations should be considered within the context …

Background Blockade of the renin-angiotensin system (RAS) reduces the incidence of type 2 diabetes mellitus. In rodents, it has been demonstrated that RAS blockade improved adipose tissue (AT) function and glucose homeostasis. However, the effects of long-term RAS blockade on AT function have not been investigated in humans. Therefore, we examined whether 26-wks treatment with the angiotensin II type 1 receptor blocker valsartan affects AT function in humans with impaired glucose metabolism (IGM). Methodology/Principal Findings We performed a randomized, double-blind, placebo-controlled parallel-group study, in which 38 subjects with IGM were treated with valsartan (VAL, 320 mg/d) or placebo (PLB) for 26 weeks. Before and after treatment, an abdominal subcutaneous AT biopsy was collected for measurement of adipocyte size and AT gene/protein expression of angiogenesis/capillarization, adipogenesis, lipolytic and inflammatory cell markers. Furthermore, we evaluated fasting and postprandial AT blood flow (ATBF) (133Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (P

Liraglutide is a GLP-1 receptor agonist, a novel medication for type 2 diabetes. We describe a case of pustules in a patient recently started on liraglutide. Common side effects of liraglutide are gastrointestinal disorders. Skin and tissue reactions are less well-known side effects. Liraglutide could be the cause of skin eruptions in this patient, possibly by immunogenicity.

Objective: Angiopoietin-like protein 4 (Angptl4) is a circulating inhibitor of plasma triglyceride clearance via inhibition of lipoprotein lipase. The aim of the present study was to examine the regulation of Angptl4 by glucocorticoids and insulin in vivo in humans, since these factors regulate Angptl4 expression in vitro. Research design and methods: In a randomized, placebo-controlled, double-blind, dose-response intervention study, 32 healthy males (age: 22 +/- 3 years; BMI 22.4 +/- 1.7 kg m(-2)) were allocated to prednisolone 30 mg once daily (n = 12), prednisolone 7.5 mg once daily (n = 12), or placebo (n = 8) for 2 weeks. Angptl4 levels and lipid metabolism were measured before and at 2 weeks of treatment, in the fasted state and during a 2-step hyperinsulinemic clamp. Additionally, human hepatoma cells were treated with dexamethasone and/or insulin. Results: Compared to placebo, prednisolone treatment tended to lower fasting Angptl4 levels (P = 0.073), raised fasting insulin levels (P = 0.0004) and decreased fasting nonesterified fatty acid concentrations (NEFA) (P = 0.017). Insulin infusion reduced Angptl4 levels by 6 % (plasma insulin similar to 200 pmol/l, P = 0.006) and 22 % (plasma insulin similar to 600 pmol/l, P

Pharmacological augmentation of glucagon-like peptide 1 receptor signalling by dipeptidyl peptidase 4 (DPP-4) inhibition reduced intestinal lipoprotein secretion in experimental studies, suggesting that DPP-4 inhibitors may ameliorate dyslipidaemia and thus reduce cardiovascular risk in patients with type 2 diabetes. We assessed the effects of alogliptin (Alo) and Alo co-administered with pioglitazone (Pio) vs placebo (Pbo) on triacylglycerol (TG)-rich lipoproteins in type 2 diabetes before and following a high-fat meal.Seventy-one patients (age 18-70 years), who did not reach HbA(1c) 6.5% (48 mmol/mol) with lifestyle and/or metformin, sulfonylurea or glinide therapy, participated in this 16 week, double-centre (university hospitals) Pbo-controlled parallel-group study. All participants, people doing measurements or examinations, and people assessing the outcomes were blinded to group assignment. Fasting TG 1.7-5.0 mmol/l was among the entry criteria. Patients received a high-fat mixed meal before and 4 and 16 weeks after randomisation (allocation by central office) to Alo (n = 25), Alo/Pio (n = 22) or Pbo (n = 24). Blood was sampled at pre-specified intervals, starting at 15 min before and ending 8 h after meal ingestion.At week 16, Alo (n = 25) and Alo/Pio (n = 21) vs Pbo (n = 24) produced similar significant reductions in total postprandial TG response (incremental AUC [iAUC]; p 0.001), as well as in chylomicron TG (p 0.001) and VLDL1 TG iAUCs (p 0.001 and p = 0.012, respectively). Postprandial chylomicron apolipoprotein B-48 iAUC showed a significant decrease after Alo treatment (p = 0.028), and a non-significant trend towards a decrease with Alo/Pio (p = 0.213). The incidence of adverse events was low and consistent with previous studies.Treatment with Alo and Alo/Pio produced significant reductions in postprandial TG and TG-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. The data support the concept that incretins not only modulate glucose metabolism but also influence chylomicron metabolism in intestinal cells.ClinicalTrials.gov number NCT00655863.

The aim of this study was to identify characteristic features in bronchoalveolar lavage fluid (BALF) samples of patients with tuberculosis, non-Hodgldn's or Hodgkin's disease and to investigate whether these differences facilitate the distinction of those disorders from sarcoidosis presenting with a similar clinical picture. Nonsmoker patients with histologically verified sarcoidosis (n = 29), tuberculosis (n = 6) proven by positive culture, non-Hodgkin's disease, (n = 6) or Hodgkin's disease (n = 7), both histologically verified, were investigated by BAL. A control group consisted of subjects without any pulmonary history. The presence of CD4 + and CD8 + T lymphocytes, as well as the CD4/ CD8 ratio in BALF, aided in the differentiation between the various groups. Patients with malignant lymphomas had the lowest CD4/CD8 ratio in BALF, as well as in peripheral blood, and occasionally, plasma cells were present in BALF samples. The most important feature of BALF analysis in tuberculosis was detection of the causal microbial agent. In conclusion, although malignant lymphomas and tuberculosis require histologic evaluation and a positive culture, respectively, for diagnosis, BALF analysis may be of additional value in distinguishing those disorders from sarcoidosis.

Two series of experiments were done to investigate the mechanism underlying arginine 8 -vasopressin (AVP)-induced barrel rotation in rats. In the first series, the effect of intracerebroventricular (ICV) administration of various neurohypophyseal hormone antagonists on AVP-induced barrel rotation was studied. The more vasopressin was given, the more the rats exhibited barrel rotation. ICV pretreatment with a V 1 vasopressin receptor antagonist, d(CH 2 ) 5 [Tyr(Me) 2 ]AVP, prevented barrel rotation, while similar treatment with a V 2 -antagonist, d(CH 2 ) 5 [dIle 2 Ile 4 ]AVP, did not affect vasopressin-induced barrel rotation. However, Des-Gly,NH 2 d(CH 2 ) 5 [Tyr)Me 2 )Thr 4 Orn 8 ]-vasotocin, a specific oxytocin antagonist, potentiated the effect of AVP on barrel rotation. The second experiment was performed in rats equipped with a telemetry system to measure heart rate (HR), core temperature (CT), and gross locomotor activity. Also, in this experiment the incidence of AVP-induced barrel rotation was dose-dependent, as was the number of rats that died. Barrel rotation was accompanied by a significant decrease in CT and HR, while rats that did not develop hypothermia did not show barrel rotation. These results suggest that a V 1 receptor is involved in barrel rotation. Since AVP-induced hypothermia is also mediated by a V 1 receptor, it is postulated that hypothermia is a prerequisite for barrel rotation to occur. Further experiments are needed to substantiate this hypothesis.

Item does not contain fulltext Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2alpha. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death. 01 november 2011

Bone metabolism is a dynamic process that is influenced by food ingestion. Endogenous incretins have been shown to be important regulators of bone turnover. The aim of the present study was to assess whether a dipeptidylpeptidase (DPP)-4 inhibitor affects markers of bone resorption and calcium homeostasis.The present study was a single-center, double blind, randomized clinical trail. Fifty-nine drug-naïve patients with type 2 diabetes (T2D) were randomized to either 1 year treatment with the DPP-4 inhibitor vildagliptin (100 mg, once daily; n = 29) or placebo (n = 30). Patients received a standardized breakfast after measurement of serum concentrations of cross-linked C-terminal telopeptide (s-CTx), a bone resorption marker influenced by food intake, before and after 50 weeks treatment.Vildagliptin did not change postprandial s-CTx concentrations compared with pretreatment levels (between-group ratio 1.15 ± 0.17; P = 0.320). Fasting serum alkaline phosphatase, calcium, and phosphate were also unaffected y 1 year treatment with vildagliptin.Treatment with vildagliptin for 1 year was not associated with changes in markers of bone resorption and calcium homeostasis in drug-naïve patients with T2D and mild hyperglycemia.