Changes in Prandial Glucagon Levels After a 2-Year Treatment With Vildagliptin or Glimepiride in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

OBJECTIVE - To determine if the dipeptidyl peptidase-4 inhibitor vildagliptin more effectively inhibits glucagon levels than the sulfonylurea glimepiride during a meal. RESEARCH DESIGN AND METHODS - Glucagon responses to a standard meal were measured at baseline and study end point (mean 1.8 years) in a trial evaluating add-on therapy to metformin with 50 mg vildagliptin bid. compared with glimepiride up to 6 mg q.d. in type 2 diabetes (baseline MC 7.3 +/- 0.6%). RESULTS - A1C and prandial glucose area under the curve (AUC)(0-2 h) were reduced similarly in both groups, whereas prandial insulin AUC(0-2 h) increased to a greater extent by glimepiride. Prandial glucagon AUC(0-2 h) (baseline 66.6 +/- 2.3 pmol . h(-1) . l(-1)) decreased by 3.4 +/- 1.6 pmol . h(-1) . l(-1) by vildagliptin (n = 137) and increased by 3.8 +/- 1.7 pmol . h(-1) . l(-1) by glimepiride (n = 121). The between-group difference was 7.3 +/- 2.1 pmol . h(-1) . l(-1) (P < 0.001). CONCLUSIONS - Vildagliptin therapy but not glimepiride improves postprandial a-cell function, which persists for at least 2 years

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms

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Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion

Funding Information: Source of funding The study received partial support from FTC (Fundação para a Ciência e a Tecnologia - Portuguese Foundation for Science and Technology) under the project PTDC/DTP-EPI/0207/2012. Other funds came from resources made available by other funded studies.Aims/hypothesis: Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. Methods: Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester (l-NAME, at rates of 2.5, 5, 10 and 20 μg min-1 kg-1) infusion. Another five volunteers underwent an OGTT with either saline or l-NAME (20 μg min-1 kg-1) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. Results: Compared with saline, l-NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (-12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity (M/I index) was unchanged. During the OGTT, l-NAME raised 2 h plasma glucose by 1.8 mmol/l (p < 0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. Conclusions/interpretation: In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.publishersversionpublishe

Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver

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Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

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 organizations (10) 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

Advantages of the single delay model for the assessment of insulin sensitivity from the intravenous glucose tolerance test

The Minimal Model, (MM), used to assess insulin sensitivity (IS) from Intra-Venous Glucose-Tolerance Test (IVGTT) data, suffers from frequent lack of identifiability (parameter estimates with Coefficients of Variation (CV) less than 52%). The recently proposed Single Delay Model (SDM) is evaluated as a practical alternative

A simple intravenous glucose tolerance test for assessment of insulin sensitivity

<p>Abstract</p> <p>Background</p> <p>The aim of the study was to find a simple intravenous glucose tolerance test (IVGTT) that can be used to estimate insulin sensitivity.</p> <p>Methods</p> <p>In 20 healthy volunteers aged between 18 and 51 years (mean, 28) comparisons were made between kinetic parameters derived from a 12-sample, 75-min IVGTT and the M_bw(glucose uptake) obtained during a hyperinsulinemic euglycemic glucose clamp. Plasma glucose was used to calculate the volume of distribution (<it>V</it>_d) and the clearance (<it>CL</it>) of the injected glucose bolus. The plasma insulin response was quantified by the area under the curve (AUC_ins). Uptake of glucose during the clamp was corrected for body weight (M_bw).</p> <p>Results</p> <p>There was a 7-fold variation in M_bw. Algorithms based on the slope of the glucose-elimination curve (<it>CL/V</it>_d) in combination with AUC_insobtained during the IVGTT showed statistically significant correlations with M_bw, the linearity being r²= 0.63-0.83. The best algorithms were associated with a 25-75^thprediction error ranging from -10% to +10%. Sampling could be shortened to 30-40 min without loss of linearity or precision.</p> <p>Conclusion</p> <p>Simple measures of glucose and insulin kinetics during an IVGTT can predict between 2/3 and 4/5 of the insulin sensitivity.</p

Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity