1,721,059 research outputs found
Pharmacogenetics in Type 2 Diabetes. Polymorphisms in Candidate Genes Affecting Responses to Antidiabetic Oral Treatment
No full textType 2 diabetes is a complex and heterogeneous metabolic condition that has reached epidemic proportions, affecting more than 150 million individuals worldwide. Maintenance of near-normal glucose control in patients with type 2 diabetes been shown to be associated with a reduced risk of microvascular complications as well as a trend toward reduction of macrovascular events. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary to restore acceptable glycemic control for many patients. The molecular reasons for the different responses to antidiabetic therapy
are not clear, and the possibility that genetic factors may predispose to failure to respond adequately to oral antidiabetic agents remains an open question. Pharmacogenetics is an emerging discipline that involves the search for genetic polymorphisms, commonly observed among the general population, which influence drug response. Interesting candidate genes belong to three main groups: 1) genes encoding for drug metabolizing enzymes and/or transporters that influence pharmacokinetics; 2) genes encoding for targets and/or receptors of drugs that influence pharmacodynamics; and 3) genes encoding for proteins that are involved in the causal pathway of disease and are able to modify the effects of drugs. In this
review, we will discuss our current understanding of genetic polymorphisms that may affect responses of patients with type 2 diabetes to antidiabetic oral treatment as well as the main challenges, which should be addressed in order to translate pharmacogenetics principles into widespread clinical practice
Glucagon-like peptide-1 analogs in the treatment of Type 2 diabetes. a review of the Phase II and III trials
No full textGlucagon-like peptide-1 (GLP-1) analogs-based therapies are a new option for Type 2 diabetes treatment that hold the promise of overcoming the major limitations of traditional treatments, including the increased risk for hypoglycemia and weight gain. GLP-1 is a naturally occurring hormone that potentiates glucose-dependent insulin secretion. The clinical utility of native GLP-1 is, however, limited by its short half-life; these observations led to the generation of GLP-1 analogs, which mimic GLP-1 action in vivo in humans. Here, we review the data from clinical trials that have assessed mechanism of action, efficacy and safety of GLP-1 agonists; these trials have demonstrated the efficacy of GLP-1 analogs in reducing glycosylated hemoglobin and fasting plasma glucose levels. The use of these drugs was associated with weight loss and reductions in blood pressure, with a low risk of hypoglycemia, GLP-1 agonists were generally well tolerated with the most frequent adverse effects being nausea
Liraglutide, the once-daily human GLP-1 analog, in the treatment of Type 2 diabetes
No full textType 2 diabetes is a progressive disorder characterized by continuous deterioration in beta-cell function requiring an escalation of therapeutic efforts in order to maintain glycaemic control. Recent studies have demonstrated that the current antidiabetic treatments, including metformin, sulfonylureas and thiazolidinediones, are not durable resulting in an increase of HbA1c over time with all three therapies. Many current antidiabetic treatments (sulfonylureas, thiazolidinediones and insulin) are associated by the undesirable feature of weight gain. In addition, sulfonylureas and insulin are associated with an increased risk for hypoglycaemia. The unsatisfactory results with the current pharmacological therapies for type 2 diabetes have encouraged the development of a number of novel treatments. Among these are the incretin-based therapies, which include GLP-1 receptor agonists; this review focuses on one of these agonists the human GLP-1 analogue liraglutide. Liraglutide has been approved for use in type 2 diabetic individuals in several countries, including Europe, USA and Japan
Glucagon-like peptide-1 analogues: effects on body weight and glycemia
No full textGlucagon-like peptide-1 (GLP-1) analogues-based therapies are a new option for type 2 diabetes treatment that hold the promise of overcoming the major limitations of traditional treatments, including the increased risk for hypoglycemia and weight gain. Herein, we review the data from clinical trials that have assessed the mechanism of action, the efficacy, and safety of exenatide and liraglutide, two analogues already available for therapy. The data of these trials showed that exenatide and liraglutide induced an improvement in glycemic control comparable with type 2 diabetes traditional treatments, as insulin, thiazolidinediones and sulfonylurea. GLP-1 analogues-based therapy was also associated with progressive weight reduction and a very low risk for hypoglycemia
Role of C Reactive Protein (CRP) in Leptin Resistance
No full textIncreased plasma levels of both leptin and C reactive protein (CRP) have been reported in a number of conditions, including obesity, and have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk; interestingly these two biomarkers appear to be able to reciprocally regulate their bioavailability, through complex mechanisms that have not been completely clarified yet. Here we first review clinical evidence suggesting not only that the circulatory levels of CRP and leptin show an independent correlation, but also that assessing them in tandem may result in an increased ability to predict cardiovascular disease. We summarize also molecular studies showing that leptin is able to promote CRP production from hepatocytes and endothelial cells in vitro and discuss
the studies addressing the possibility that in vivo leptin administration may be able to modulate plasma CRP levels. Furthermore, we describe two studies demonstrating that CRP directly binds leptin in extra-cellular settings, thus impairing its biological actions. Finally we report genetic evidence that common variations at the leptin receptor locus are associated with CRP blood levels. Overall, the data reviewed here show that the chronic elevation of CRP observed in obese subjects may worsen leptin resistance, contributing to the pathogenesis of cardiovascular disease, and highlight a potential link between conditions, such as leptin resistance and endothelial dysfunction, that may be amenable of pharmacological treatment targeted to the disruption of leptin-CRP interaction
Association of hepatic insulin resistance indexes to nonalcoholic fatty liver disease and related biomarkers.
No full textElevated 1 h postload plasma glucose levels identify adults with normal glucose tolerance but increased risk of non-alcoholic fatty liver disease
No full textLow plasma insulin-like growth factor-1 levels are associated with reduced insulin sensitivity and increased insulin secretion in nondiabetic subjects
No full textPlasma complement C3 levels are associated with insulin secretion independently of adiposity measures in non-diabetic individuals
No full textBACKGROUND AND AIMS:
To evaluate if complement C3 is associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders including adiposity measures.
METHODS AND RESULTS:
1010 nondiabetic subjects were stratified into quartiles according to complement C3 values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT) in the whole study group and from intravenous glucose tolerance test (IVGTT) in a subgroup (n = 110). Significant differences between quartiles of C3 were observed in body mass index (BMI), waist, fat mass, blood pressure, total cholesterol, high density lipoprotein (HDL), triglycerides, fasting and 2-h post-load glucose, fasting insulin, C reactive protein (hsCRP), fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), complement C4, and insulin sensitivity with C3 quartiles exhibiting graded increases in cardio-metabolic risk factors. Differences in insulin secretion indexes between C3 quartiles remained significant after adjustment for age, gender, BMI, insulin sensitivity, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, and complement C4 levels (P < 0.0001). A multivariable regression analysis revealed that complement C3 is a contributor of insulin secretion, explaining 2.4% and 1.9% of variation of the Stumvoll index for first-phase and second-phase insulin secretion, respectively, and 2.1% of variation of the InsAUC30/GluAUC30 index, independently of gender, age, BMI, waist, fat mass, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, AST, ALT.
CONCLUSIONS:
Complement C3 concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, subclinical inflammation, and insulin sensitivity.
Copyright © 2015 Elsevier B.V. All rights reserved
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