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 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. Among the older antidiabetes agents, most, including the insulin secretagogues and sensitizers, can lead to weight gain, except for metformin, which is weight-neutral. Among the newer agents, the dipeptidyl peptidase-4 inhibitors generally are weight-neutral in addition to lowering glucose, while the glucagon-like peptide-1 receptor agonists lead to weight reduction. Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.
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PMID:The impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus. 1982 Feb 78

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.
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PMID:Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents. 1983 46

Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and induce slowing of gastric emptying and feelings of satiety - which result in reduced food intake and weight loss. Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1 receptor-dependent and -independent mechanisms. If these initial findings are confirmed in larger clinical trials, GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.
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PMID:Impact of glucagon-like peptide-1 on endothelial function. 1987 58

All forms of diabetes are increasing in prevalence, but with the advent of the obesity epidemic, we now face the prospect of an increasing number of women conceiving whilst taking traditional oral antidiabetic agents (OADs). This is also further complicated by the availability of new incretin-based therapies, the dipeptidylpeptidase-4 (DPP-IV) inhibitors and glucagon-like-1 receptor (GLP-1R) analogues. Original concerns regarding the use of such OADs have meant that diet control and insulin has been the mainstay of treatment for hyperglycaemia during pregnancy. However, recent NICE guidelines have suggested a role for oral antidiabetic agents. Safety is of paramount concern, especially in pregnancy, and this review will discuss the evidence to date.
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PMID:Diabetic medications in pregnancy. 1992 89

GLP-1 (9-36)amide is the cleavage product of GLP-1(7-36) amide, formed by the action of diaminopeptidyl peptidase-4 (Dpp4), and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (9-36)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. In this paper, we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes.
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PMID:Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis. 2001 25

Glucagon-like peptide 1 (GLP-1) functions as an incretin hormone with antidiabetogenic properties. However, the role of GLP-1 in human bone marrow-derived mesenchymal stem cells (hMSCs), if any, remains unknown. The effects of GLP-1 on hMSCs were tested with regard to cell proliferation, cytoprotection, and cell differentiation into adipocytes. The signaling pathways involved in these processes were also analyzed. Cells were characterized with biochemical and morphological approaches before and after being induced to differentiate into adipocytes. PCNA protein levels were used as a proliferation index, whereas cell apoptosis was studied by deprivation of fetal bovine serum. Isolated hMSCs expressed stem cell markers as well as mRNA and GLP-1 receptor protein. GLP-1 increased the proliferation of hMSCs, which decreased when they were induced to differentiate into adipocytes. This process produced biochemical and morphological changes in cells expressing PPARgamma, C/EBPbeta, AP2, and LPL in a time-dependent pattern. Notably, GLP-1 significantly reduced the expression of PPARgamma, C/EBPbeta, and LPL. These effects were exerted at least through the MEK and PKC signaling pathways. In addition, GLP-1 significantly reduced cell apoptosis. Our data indicate that, in hMSCs, GLP-1 promotes cellular proliferation and cytoprotection and prevents cell differentiation into adipocytes. These latter findings underscore the potential therapeutic role of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and, additionally, could bolster the maintenance of hMSC stores by promoting the proliferation and cytoprotection of undifferentiated hMSC.
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PMID:Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow. 2004 Jun 95

Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive beta-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.
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PMID:Therapeutic options that provide glycemic control and weight loss for patients with type 2 diabetes. 2010 1

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 inhibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.
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PMID:Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide. 2011 29

Diabetes mellitus is a complex and increasingly common metabolic disease that is characterized by hyperglycemia and associated with microvascular and macrovascular complications. Approximately 90% of patients with diabetes have type 2 diabetes. Obesity and type 2 diabetes are intricately linked, with weight gain being a major contributor to the increasing incidence of type 2 diabetes. Both conditions are independent risk factors for cardiovascular disease, which is the cause of death for the majority (65%) of patients with diabetes. Data from recent large-scale outcomes trials continue to clarify the role of glucose-lowering therapy for patients with type 2 diabetes and increased risk of cardiovascular disease. This serves to further underscore the importance of an individualized treatment approach that takes duration of disease, presence of complications and comorbidities, and the potential adverse risks of therapy into consideration. Although the currently available antidiabetes medications are effective in lowering glucose, some of these agents, including insulin, sulfonylureas, and thiazolidinediones, are often limited by weight gain and/or hypoglycemia. Expert panel guidelines recommend a comprehensive approach that targets the traditional risk factors (glucose, weight, blood pressure, lipids) as the ideal treatment strategy to prevent complications of type 2 diabetes. Incretin-based therapies, including the glucagon-like peptide-1 receptor agonists, target the fundamental defects of type 2 diabetes, reduce glycosylated hemoglobin and body weight, and have potentially beneficial effects on blood pressure, lipids, and other surrogate markers, leading to reduced cardiovascular risk. Physicians should be encouraged to adopt a therapeutic approach with individualized patient goals. By reinforcing the role of patients with type 2 diabetes in treatment decisions, better compliance and achievement of treatment goals can be achieved.
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PMID:New perspectives in type 2 diabetes, cardiovascular risk, and treatment goals. 2046 14

A pathogenic relationship exists between type 2 diabetes and obesity. Over the last decade, the escalation in diabetes cases has paralleled the rapid increase in obesity rates, constituting a global health crisis. Environmental risk factors attributed to the global increase in obesity include the consumption of high-calorie, high-fat foods and inadequate physical activity. Obese individuals may also have a genetic predisposition for obesity. Both diabetes and obesity confer an elevated risk of developing a range of complications and comorbidities, including cardiovascular disease, hypertension and stroke, which can complicate disease management. This review examines the aetiology of the linkages between diabetes and obesity and the range of available therapies. Recent clinical evidence substantiating the efficacy and safety of incretin-based antidiabetic therapies is analysed, in addition to data on antiobesity therapeutic strategies, such as antiobesity agents, behaviour modification and bariatric surgery. Glucose control is often accompanied by weight-neutral or modest weight reduction effects with DPP-4 inhibitor treatment (sitagliptin, vildagliptin, saxagliptin) and weight loss with GLP-1 receptor agonist therapy (exenatide, liraglutide). Studies of antiobesity agents including orlistat, sibutramine and rimonabant have shown attrition rates of 30-40%, and the long-term effects of these agents remain unknown. Bariatric surgical procedures commonly performed are laparoscopic adjustable banding of the stomach and the Roux-en-Y gastric bypass, and have produced type 2 diabetes remission rates of up to 73%. Therapeutic strategies that integrate glycaemic control and weight loss will assume greater importance as the prevalence of diabetes and obesity increase.
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PMID:Diabesity: therapeutic options. 2051 2


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