glucagon-like-peptide-1 and Diabetes-Mellitus

Psoriasis is a chronic recurrent inflammatory skin disease with a high risk of diabetes based on disease severity.. The aim of the study was to evaluate the efficacy of different hypoglycemic medications in patients with psoriasis.. A systematic review and meta-analysis of studies were conducted to evaluate the efficacy of hypoglycemic medications in patients with psoriasis. The primary outcome was of changes in the psoriasis area and severity index (PASI) score, and a 75% improvement in PASI from baseline (PASI75). Subgroup analysis was used to investigate associations among the types of hypoglycemic medicines, combination therapy, patient characteristics, course of treatment, and curative effect.. We included 3,286 patients from 19 studies to explore the effects of hypoglycemic medications. Patients randomized to receive hypoglycemic medicines showed a more significant decrease in the PASI score (standard mean difference = -0.55, 95% confidence interval (CI): -0.87 to -0.23, p = 0.0007) and a higher PASI75 ratio (RR: 1.80, 95% CI: 1.20-2.71, p = 0.0046). Patients consuming thiazolidinediones (TZDs) were more likely to reach PASI75 than those consuming glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 inhibitors. The combined use of hypoglycemic medicines had an add-on effect on the standard psoriasis treatment, and the proportion of PASI75 in the combination group was nearly four times that in the noncombination group (p = 0.0216). In addition, hypoglycemic medications can reduce body weight, waist circumference, triglyceride, total cholesterol, low-density lipoprotein, and systolic blood pressure.. Certain hypoglycemic drugs, such as GLP-1 RAs and TZDs, are beneficial for treating psoriasis. Multidisciplinary collaboration is recommended for the management of systemic inflammation in patients with psoriasis and diabetes.

Topics: Chronic Disease; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Psoriasis; Randomized Controlled Trials as Topic; Thiazolidinediones

Acute myocardial infarction (AMI) reperfusion is associated with ischemia/reperfusion (I/R) injury, which leads to enlarged myocardial infarction size, poor healing of the infarcted myocardium, and poor left ventricular remodeling, thus increasing the risk of major adverse cardiovascular events (MACEs). Diabetes increases myocardial susceptibility to I/R injury, decreases myocardial responsiveness to cardioprotective strategies, exacerbates myocardial I/R injury, and expands the infarct size of AMI, thereby increasing the incidence of malignant arrhythmias and heart failure. Currently, evidence regarding pharmacological interventions for diabetes combined with AMI and I/R injury is lacking. Traditional hypoglycemic drugs have a limited role in the prevention and treatment of diabetes combined with I/R injury. Current evidence suggests that novel hypoglycemic drugs may exert a preventive effect on diabetes combined with myocardial I/R injury, especially glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-dependent glucose transporter protein 2 inhibitors (SGLT2i), which may increase coronary blood flow, reduce acute thrombosis, attenuate I/R injury, decrease myocardial infarction size, inhibit structural and functional remodeling of the ischemic heart, improve cardiac function, and reduce the occurrence of MACEs of diabetes patients combined with AMI via mechanisms such as reduction of inflammatory response, inhibition of oxidative stress, and improvement of vascular endothelial function. This paper will systematically elaborate the protective role and molecular mechanisms of GLP-1 RA and SGLT2i in diabetes combined with myocardial I/R injury, aiming to provide clinical assistance.

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Myocardial Infarction; Myocardial Reperfusion Injury

Management of diabetic kidney disease (DKD) has evolved in parallel with our growing understanding of the multiple interrelated pathophysiological mechanisms that involve hemodynamic, metabolic, and inflammatory pathways. These pathways and others play a vital role in the initiation and progression of DKD. Since its initial discovery, the blockade of the renin-angiotensin system has remained a cornerstone of DKD management, leaving a large component of residual risk to be dealt with. The advent of sodium-glucose cotransporter 2 inhibitors followed by nonsteroidal mineralocorticoid receptor antagonists and, to some extent, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has ushered in a resounding paradigm shift that supports a pillared approach in maximizing treatment to reduce outcomes. This pillared approach is like that derived from the approach to heart failure treatment. The approach mandates that all agents that have been shown in clinical trials to reduce cardiovascular outcomes and/or mortality to a greater extent than a single drug class alone should be used in combination. In this way, each drug class focuses on a specific aspect of the disease's pathophysiology. Thus, in heart failure, β-blockers, sacubitril/valsartan, a mineralocorticoid receptor antagonist, and a diuretic are used together. In this article, we review the evolution of the pillar concept of therapy as it applies to DKD and discuss how it should be used based on the outcome evidence. We also discuss the exciting possibility that GLP-1 RAs may be an additional pillar in the quest to further slow kidney disease progression in diabetes.

Topics: Diabetes Mellitus; Diabetic Nephropathies; Glucagon-Like Peptide 1; Heart; Heart Failure; Humans; Kidney

Obesity is a prevalent chronic disorder and a well-known risk factor for cardiovascular disease. However, the evidence of treating obesity for primary prevention of major cardiovascular events is still scarce and controversial. In this review, we provided a comprehensive description of the current evidence in treating obesity regarding cardiovascular protection. Bariatric surgery appears to be the most robust method to reduce events in people without established cardiovascular disease. High compliance to lifestyle interventions can further reduce cardiovascular risk. Concerning pharmacological therapies, a post hoc analysis from SUSTAIN-6 and a meta-analysis from STEP trials suggest that semaglutide, a GLP-1 receptor agonist, could reduce cardiovascular events in people without established cardiovascular disease. The first study addressed specifically a high-risk population with diabetes and, the second, low- or intermediary-risk individuals without diabetes. Tirzepatide, a novel dual GIP/GLP-1 agonist, although not yet tested in specific cardiovascular outcomes trials, could be an alternative since it induces loss in weight similar to the achieved by bariatric surgery. Therefore, extrapolated data in distinct baseline cardiovascular risk populations suggest that these two drugs could be used in primary prevention with the aim of preventing cardiovascular events, but the grade of this evidence is still low. Specifically designed studies are needed to address this specific topic.

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Obesity; Primary Prevention

Reactive oxygen species (ROS) have emerged as essential signaling molecules regulating cell survival, death, inflammation, differentiation, growth, and immune response. Environmental factors, genetic factors, or many pathological condition such as diabetes increase the level of ROS generation by elevating the production of advanced glycation end products, reducing free radical scavengers, increasing mitochondrial oxidative stress, and by interfering with DAG-PKC-NADPH oxidase and xanthine oxidase pathways. Oxidative stress, and therefore the accumulation of intracellular ROS, determines the deregulation of several proteins and caspases, damages DNA and RNA, and interferes with normal neuronal function. Furthermore, ROS play an essential role in the polymerization, phosphorylation, and aggregation of tau and amyloid-beta, key mediators of cognitive function decline. At the neuronal level, ROS interfere with the DNA methylation pattern and various apoptotic factors related to cell death, promoting neurodegeneration. Only few drugs are able to quench ROS production in neurons. The cross-linking pathways between diabetes and dementia suggest that antidiabetic medications can potentially treat dementia. Among antidiabetic drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been found to reduce ROS generation and ameliorate mitochondrial function, protein aggregation, neuroinflammation, synaptic plasticity, learning, and memory. The incretin hormone glucagon-like peptide-1 (GLP-1) is produced by the enteroendocrine L cells in the distal intestine after food ingestion. Upon interacting with its receptor (GLP-1R), it regulates blood glucose levels by inducing insulin secretion, inhibiting glucagon production, and slowing gastric emptying. No study has evidenced a specific GLP-1RA pathway that quenches ROS production. Here we summarize the effects of GLP-1RAs against ROS overproduction and discuss the putative efficacy of Exendin-4, Lixisenatide, and Liraglutide in treating dementia by decreasing ROS.

Topics: Amyloid beta-Peptides; Dementia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Oxidation-Reduction; Reactive Oxygen Species; Transcription Factors

The medical applications of glucagon-like peptide-1 receptor (GLP-1R) agonists is evergrowing in scope, highlighting the urgent need for a comprehensive understanding of the mechanisms through which GLP-1R activation impacts physiology and behaviour. A new area of research aims to elucidate the role GLP-1R signalling in glia, which play a role in regulating energy balance, glycemic control, neuroinflammation and oxidative stress. Once controversial, existing evidence now suggests that subsets of glia (e.g. microglia, tanycytes and astrocytes) and infiltrating macrophages express GLP-1Rs. In this review, we discuss the implications of these findings, with particular focus on the effectiveness of both clinically available and novel GLP-1R agonists for treating metabolic and neurodegenerative diseases, enhancing cognition and combating substance abuse. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Topics: Astrocytes; Diabetes Mellitus; Glaucoma; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity

Glucagon-like peptide-1 (GLP-1) receptor-based therapies have been developed and extensively applied in clinical practice. GLP-1 plays an important role in improving glycemic homeostasis by stimulating insulin biosynthesis and secretion, suppressing glucagon activity, delaying gastric emptying, and reducing appetite and food ingestion. Furthermore, GLP-1 has positive effects on β-cell function by promoting β-cell proliferation and neogenesis while simultaneously reducing apoptosis. Here, we summarize possible mechanisms of action of GLP-1 upon pancreatic islets as well as describe phytochemicals that modulate pancreatic islet β cell function through glucagon-like peptide-1-related mechanisms. Together, this information provides potential lead compound candidates against diabetes that function as GLP-1 receptor-based pharmacotherapy.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Insulin-Secreting Cells; Islets of Langerhans; Phytochemicals

Because of the beneficial actions of the hormone glucagon-like peptide-1 on glucose metabolism and appetite, food intake and eventually body weight, and because of the observation that the similar metabolic effects of gastric bypass surgery are associated with excessive secretion of GLP-1, attempts are now being made to stimulate the endogenous secretion of this hormone. By targeting the natural cellular origin of GLP-1 it is anticipated that also the physiological pathways of hormone action (which may include neural mechanisms) would be engaged, which might generate fewer side effects. In addition, release of other products of the responsible intestinal endocrine cells, the L-cells, namely the appetite inhibitory hormone, PYY 3-36, and the dual glucagon-GLP-1 co-agonist, oxyntomodulin, would also be promoted. Here, the normal mechanisms for stimulation of L-cell secretion are reviewed, and the potential of identified secretagogues is discussed. Paracrine regulation of L-cell secretion is also discussed and the potential of somatostatin receptor antagonists is emphasized. A therapeutic approach based on stimulation of endogenous secretion of GLP-1/PYY still seems both attractive and potentially feasible.

Topics: Animals; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity

Our aim was to study the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) on the risk of any cardiovascular event in adults with overweight or obesity and without diabetes. We conducted a random-effects meta-analysis of placebo-controlled randomized controlled trials. Nine trials were eligible and, in total, 11 430 patients were included, of which 7702 (67%) were submitted to treatment with GLP-1 RA. During follow-up, 673 participants receiving GLP-1 RA treatment (8.7%) and 416 participants receiving placebo (11.2%) had a cardiovascular event. Treatment with GLP-1 RA versus placebo resulted in a reduction in the risk of any cardiovascular event (RR = 0.81, CI 0.70-0.92; p = .001). In overweight or obese adults without diabetes, treatment with GLP-1 RA reduced the risk of cardiovascular events. Our findings support the use of GLP-1 RA for reducing the cardiovascular risk of these patients.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Overweight; Randomized Controlled Trials as Topic

The complications of macrovascular atherosclerosis are the leading cause of disability and mortality in patients with diabetes. It is generally believed that the pathogenesis of diabetic vascular complications is initiated by the imbalance between injury and endogenous protective factors. Multiple endogenous protective factors secreted by endothelium, liver, skeletal muscle and other tissues are recognized of their importance in combating injury factors and maintaining the homeostasis of vasculatures in diabetes. Among them, glucagon-like peptide-1 based drugs were clinically proven to be effective and recommended as the first-line medicine for the treatment of type 2 diabetic patients with high risks or established arteriosclerotic cardiovascular disease (CVD). Some molecules such as irisin and lipoxins have recently been perceived as new protective factors on diabetic atherosclerosis, while the protective role of HDL has been reinterpreted since the failure of several clinical trials to raise HDL therapy on cardiovascular events. The current review aims to summarize systemic endogenous protective factors for diabetes-associated atherosclerosis and discuss their mechanisms and potential therapeutic strategy or their analogues. In particular, we focus on the existing barriers or obstacles that need to be overcome in developing new therapeutic approaches for macrovascular complications of diabetes.

Topics: Atherosclerosis; Diabetes Mellitus; Diabetic Angiopathies; Glucagon-Like Peptide 1; Humans; Protective Factors

There is growing interest in the health benefits of natural plant pigments such as anthocyanins and curcumin. In this review, we introduce how these pigments can contribute to the prevention of diabetes and obesity by stimulating glucagon-like peptide-1 (GLP-1) secretion or inducing beige adipocyte formation. Of the anthocyanins, delphinidin 3-rutinoside (D3R) was shown to increase GLP-1 secretion. Pre-administered D3R-rich blackcurrant extract (BCE) significantly ameliorated glucose tolerance after intraperitoneal glucose injection in rats by stimulating the secretion of GLP-1 and subsequently inducing insulin secretion. D3R did not break down significantly in the gastrointestinal tract for at least 45-60 min after BCE administration. An increase in endogenous GLP-1 secretion induced by food-derived factors may help to reduce the dosages of diabetic medicines and prevent diabetes. Curcumin has various biological functions, including anti-obesity and anti-diabetic properties. However, high doses of curcumin have been administered in most animal and human trials to date, due mainly to the poor solubility of native curcumin in water and its low oral bioavailability. We demonstrated that a highly dispersible and bioavailable curcumin formulation (HC), but not native curcumin, induces the formation of beige adipocytes. Furthermore, co-administration of HC and artepillin C (a characteristic constituent of Brazilian propolis) at lower doses significantly induces beige adipocyte formation in mice, but administration of the same dose of HC or artepillin C alone does not. Our studies demonstrate that curcumin formulations or the co-administration of curcumin with other food-derived factors provide effects that native curcumin alone does not.

Topics: Adipocytes, Beige; Animals; Anthocyanins; Curcumin; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Humans; Mice; Obesity; Rats; Ribes

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been observed in several large cardiovascular outcome trials to significantly reduce the incidence of major cardiovascular event (MACE) with type 2 diabetic patients. The clinical trials of GLP-1 RAs, including lixisenatide, exenatide, liraglutide, semaglutide, albiglutide, and dulaglutide, are associated with a significantly 14% lower risk of MACE in patients with T2DM and a history of CV disease, and with a nonsignificantly 6% lower risk in patients without history of CV disease. Some of the interpretation with GLP-1 RA trials suggested the possible role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in primary prevention of cardiovascular diseases in nondiabetic individual, echoed by a recent editorial redefining the role of GLP-1 RAs being beyond glycaemic control. The narrative review provides an in-depth insight into GLP-1 RA use guideline in different countries and regions of the world and examines the safety and concern of GLP-1 RA use. The narrative review draws the comparison of GLP-1 RA use between diabetic and nondiabetic individual in terms of cardiovascular and metabolic benefits and points out the direction of future clinical trials of GLP-1 RAs in nondiabetic individuals. The focus of the review is on GLP-1 RAs' preventive roles in nondiabetic individuals with cardiovascular disease, chronic kidney diseases, obesity, dyslipidaemia, hypertension, nonalcoholic fatty liver diseases, polycystic ovarian syndrome (PCOS), and perioperative complications of bariatric surgery, albeit in small studies and subset analysis of clinical trials of diabetic patients.

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Humans

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF.

Topics: Aged; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Heart Failure; Humans; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume

Loss or dysfunction of the pancreatic beta cells or insulin receptors leads to diabetes mellitus (DM). This usually occurs over many years; therefore, the development of methods for the timely detection and clinical intervention are vital to prevent the development of this disease. Glucagon-like peptide-1 receptor (GLP-1R) is the receptor of GLP-1, an incretin hormone that causes insulin secretion in a glucose-dependent manner. GLP-1R is highly expressed on the surface of pancreatic beta cells, providing a potential target for bioimaging. In this review, we provide an overview of various strategies, such as the development of GLP-1R agonists (e.g., exendin-4), and GLP-1 sequence modifications for GLP-1R targeting for the diagnosis and treatment of pancreatic beta cell disorders. We also discuss the challenges of targeting pancreatic beta cells and strategies to address such challenges.

Topics: Animals; Diabetes Mellitus; Drug Development; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells

Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus; Dyslipidemias; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Intestines; Lipids; Receptors, G-Protein-Coupled; Secretory Pathway; Signal Transduction; Taste

GLP-1 was described as an incretin over 30 years ago. GLP-1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP-1 activates GLP-1 receptors (GLP-1r) on the β-cell to induce insulin secretion in a glucose-dependent manner. GLP-1 also inhibits α-cell secretion of glucagon. As few, if any, GLP-1r are expressed on α-cells, indirect regulation, via β- or δ-cell products has been thought to be the primary mechanism by which GLP-1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP-1r on α-cells for direct regulation as well. Although the predominant source of circulating GLP-1 is the intestine, the α-cell becomes a source of GLP-1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP-1 is also be important in regulating nutrient-induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg-derived protein produced by the α-cell, in stimulating insulin secretion by acting on GLP-1r. Altogether, these data clearly demonstrate the important role of Gcg-derived peptides in regulating insulin secretion. Because of GLP-1's important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus. © 2020 American Physiological Society. Compr Physiol 10:577-595, 2020.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Homeostasis; Humans; Pancreatic Hormones

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues.

Topics: Animals; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Oxidative Stress

Epidemiological evidence supports a reduced prevalence of Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA) in patients with Diabetes (DM). The mechanisms underlying this negative association are unknown. Some studies support that hyperglycemia has effects on the Extracellular Matrix (ECM), resulting in collagen cross-links and altered proteolytic activity, which ultimately counteracts aneurysm formation. However, recent experimental research indicates that incretin- based anti-diabetic therapy and Glucagon-Like Peptide-1 (GLP-1) may reduce the formation of TAA. GLP-1 is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signaling exerts numerous pleiotropic effects on various tissues, including protective effects on the myocardium and vascular endothelium. Recent studies also report protective effects of GLP-1 based therapy on the formation of aneurysms in animal models and direct effects of GLP-1 signaling on the molecular mechanisms suggested to influence TAA formation, including inflammation, proteolytic activity and collagen composition. In this narrative review, we present the available evidence for effects of GLP-1 on experimental aneurysm development and discuss the potential role of GLP-1 in aneurysm formation based on available data from pre-clinical and clinical studies.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Risk Factors; Signal Transduction; Treatment Outcome; Vascular Remodeling

Diabetes Mellitus (DM) is a leading cause of both Cardiovascular Disease (CVD) and End-stage Renal Disease (ESRD). After 2008, there has been much evidence presented, and recently the guidelines for sugar control have changed to focus on being more disease orientated. GLP-1 Receptor Agonists (GLP-1R) and sodium glucose cotransporter-2 inhibitors are suggested as the first line towards fighting all DM, CVD and ESRD. However, the benefits of GLP-1R in organ transplantation recipients remain very limited. No clinical trials have been designed for this particular population. GLP-1R, a gastrointestinal hormone of the incretin family, possesses antidiabetic, antihypertensive, anti-inflammatory, anti-apoptotic and immunomodulatory actions. There are few drug-drug interactions, with delayed gastric emptying being the major concern. The trough level of tacrolimus may not be significant but should still be closely monitored. There are some reasons which support GLP-1R in recipients seeking glycemic control. Post-transplant DM is due to an impaired β-cell function and glucose-induced glucagon suppression during hyperglycemia, which can be reversed by GLP-1R. GLP-1R infusion tends to relieve immunosuppressant related toxicity. Until now, in some cases, glycemic control and body weight reduction can be anticipated with GLP-1R. Additional renal benefits have also been reported. Side effects of hypoglycemia and gastrointestinal discomfort were rarely reported. In conclusion, GLP-1R could be implemented for recipients while closely monitoring their tacrolimus levels and any potential side effects. Any added benefits, in addition to sugar level control, still require more well-designed studies to prove their existence.

Topics: Diabetes Mellitus; Diabetic Nephropathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Transplantation; Metabolic Syndrome

To review the evolution and advancement of GLP-1 receptor agonist (GLP-1RA) therapy, through the lens of randomised controlled trials, from differentiating characteristics, efficacy, safety, tolerability, and cardiovascular outcomes, to evidence gaps and next steps.. Clinical review of published phase 3 or later RCT data studying efficacy, safety, and outcomes of approved GLP-1 RA therapies.. Through a wealth of studies, including both placebo-controlled and active-controlled studies, GLP-1 RAs have demonstrated high glycemic efficacy and ability to facilitate weight loss, with minimal risk of hypoglycemia, potential to restore beta cell function, and evidence for improved cardiovascular outcomes in those at risk.. Over a decade of clinical studies have established the unique contributions of GLP-1 RAs in the treatment of diabetes. Individual differences between the different GLP-1 RAs, in delivery, pharmacokinetic and clinical effects, exist, allowing for tailored approaches to clinical care. The strength of evidence generated through RCTs, both short-term and long-term studies, will continue to evolve and inform our current paradigms in diabetes care.

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome; Weight Loss

Identifying peptide hormones with multipotent actions on both weight and glycaemia can have a significant impact on therapeutic options in the treatment of obesity and diabetes. This has been exemplified by recent advances involving pharmacological exploitation of glucagon-like peptide 1 biology. Herein, we summarise evidence supporting the potential candidacy in this light of alpha-melanocyte stimulatory hormone, an endogenous peptide hormone and a breakdown product of the neuropeptide pro-opiomelanocortin. We reference its well described central actions in the control of food intake and moreover highlight new data pointing to an important role for this peptide hormone in the periphery, in relation to glycaemic control.

Topics: alpha-MSH; Body Weight; Diabetes Mellitus; Eating; Glucagon-Like Peptide 1; Humans; Obesity; Pro-Opiomelanocortin

Finding a radical cure for diabetes has reached paramount importance in medicine due to the widespread prevalence of the disease. A substantial reduction in insulin-secreting beta cells is evident in diabetes. The failure of cyclin-dependent kinases (CDKs) and cyclins to access the nucleus is responsible for quiescence or senescence in human and rodent beta cells. The augmentation of beta cell proliferation is supposed to reverse diabetes. This concept has inspired the discovery of newer drugs that encourage the proliferation of beta cells. Although it is a rational step towards a cure for diabetes, the differences in biochemical pathways in rodents and human beta cells pose difficulty in promoting the proliferation of human beta cells. Primarily, it is mandatory to clearly understand the intracellular pathways involved in the proliferation of beta cells so as to pave the way for therapeutic interventions. There are several intrinsic factors that trigger the proliferation of beta cells. Furthermore, it is also obvious that the early death of beta cells due to oxidative stress-related upregulation of pro-apoptotic genes also predisposes individuals to diabetes mellitus. Polyphenols, exendin 4, histone deacetylase inhibitors, glucagon-like peptide 1, phenyl pyruvic acid glucoside, and several flavonoids reduce the early apoptosis of beta cells partly through their role in the reduction of oxidative stress. A better understanding of intracellular pathways, the identification of specific mitogens, the induction of beta cell proliferation, and the inhibition of apoptosis may help us treat diabetes mellitus through an increase in beta cell mass.

Topics: Apoptosis; Cell Proliferation; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Insulin; Insulin-Secreting Cells

Technological Innovations in Diabetes Therapy Abstract. In the last few years a whole array of technical innovations has dramatically increased treatment options for patients with diabetes mellitus. Capillary blood glucose measurements are increasingly replaced by continuous glucose monitoring. More and more insulin pump systems are linked up to continuous glucose monitoring, which thereby become ever more self-regulating. Novel ultra-long and ultra-short acting insulins have become available. There will soon be oral alternatives for several anti-diabetic treatments, which hitherto needed to be injected.. Zusammenfassung. Über die vergangenen Jahre hat eine wahre Flut an technologischen Innovationen die Behandlungsmöglichkeiten für Menschen mit Diabetes mellitus drastisch erweitert. Die kapilläre Blutzuckermessung wird nach und nach durch die kontinuierliche Glukosemessung ersetzt. Immer mehr Insulinpumpen-Systeme werden an kontinuierliche Glukosemessung gekoppelt und dadurch zunehmend selbstregulierend. Neue ultra-lang und -kurz wirksame Insuline sind erhältlich. Für mehrere anti-diabetische Wirkstoffgruppen, die bisher injiziert werden mussten, gibt es bald orale Alternativen.

Topics: Administration, Oral; Blood Glucose Self-Monitoring; Clinical Trials, Phase III as Topic; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Infusion Systems; Inventions; Pancreas, Artificial

As well known to the scientific community, Alzheimer's disease (AD) is an irreversible neurodegenerative disease that ends up with impairment of memory and cognition due to neuronal and synapse loss. Patient's quality of life can be enhanced by targeting neurogenesis as a therapeutic paradigm. Moreover, several research evidences support the concept that AD is a type of metabolic disorder mediated by impairment in brain insulin responsiveness and energy metabolism. Growing evidence suggests that endogenous peptides such as glucagon-like peptide-1 (GLP-1) and stromal-derived factor-1α (SDF-1α) provide neuroprotection across a range of experimental models of AD. So, preserving functional activity of SDF-1α and GLP-1 by dipeptidyl peptidase-4 inhibition will enhance the homing/recruitment of brain resident and nonresident circulating stem cells/progenitor cells, a noninvasive approach for promoting neurogenesis. So, herewith we provide this in support of dipeptidyl peptidase-4 inhibitors as a new target of attention for treating AD.

Topics: Alzheimer Disease; Animals; Brain; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Memory; Neuronal Plasticity

Preclinical Research Mimetics of Glucagon-like peptide 1 (GLP-1) represent a useful alternative or complementary treatment choice to insulin in the treatment of diabetes mellitus. The lack of hypoglycemia as a side effect when GLP-1 receptor agonists are used along with the tendency of these therapeutic agents to prevent or even reduce weight gain makes them valuable targets in therapy development. However, native GLP-1 and many of its early analogues have very short half-lives, requiring repeated treatment to maintain therapeutic levels. As all current treatments are injected subcutaneously, a large focus has been made on trying to extend the half-lives of GLP-1 analogues while retaining bioactivity. Most success in this regard has been achieved with the use of peptide-protein fusions, which are not as well suited for oral administration. However, recent work focused on the development of non-fusion peptides with increased half-lives that may be more appropriate for oral administration. This minireview discusses the structural characteristics of past and present analogues as well as the recent work conducted toward developing novel GLP-1 receptor agonists. Drug Dev Res 78 : 292-299, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Administration, Oral; Animals; Clinical Trials as Topic; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Humans; Hypoglycemic Agents; Peptidomimetics; Structure-Activity Relationship

Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 (Keap1) signaling pathways play an important role in preventing stresses including oxidative and inflammatory stresses. Nrf2 is a master regulator of cellular stress responses, induces the expression of antioxidant and detoxification enzymes, and protects against oxidative stress-induced cell damage. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which was originally found to increase insulin synthesis and secretion. It is now widely accepted that GLP-1 has multiple functions beyond glucose control in various tissues and organs including brain, kidney, and heart. GLP-1 and GLP-1 receptor agonists are known to be effective in many chronic diseases, including diabetes, via antioxidative mechanisms. In this review, we summarize the current knowledge regarding the role of GLP-1 in the protection against oxidative damage and the activation of the Nrf2 signaling pathway.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Nervous System Diseases; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

Glucagon-like peptide-1 (GLP-1) is released in response to meals and exerts important roles in the maintenance of normal glucose homeostasis. GLP-1 is also important in the regulation of neurologic and cognitive functions. These actions are mediated via neurons in the nucleus of the solitary tract that project to multiple regions expressing GLP-1 receptors (GLP-1Rs). Treatment with GLP-1R agonists (GLP-1-RAs) reduces ischemia-induced hyperactivity, oxidative stress, neuronal damage and apoptosis, cerebral infarct volume, and neurologic damage, after cerebral ischemia, in experimental models. Ongoing human trials report a neuroprotective effect of GLP-1-RAs in Alzheimer's and Parkinson's disease. In this review, we discuss the role of GLP-1 and GLP-1-RAs in the nervous system with focus on GLP-1 actions on appetite regulation, glucose homeostasis, and neuroprotection.

Topics: Animals; Central Nervous System; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Neurodegenerative Diseases; Peripheral Nervous System

Treatments for diabetes and obesity based on enteroendocrine hormones are a focus of research interest, partly due to the successes of glucagon-like peptide-1 (GLP-1) mimetic peptides in the treatment of diabetes and the correlation of altered enteroendocrine profiles with the positive metabolic outcomes of gastric bypass surgery. It is thought that simultaneous stimulation of more than one receptor might mimic the superior efficacy of the latter and dual or triple-agonist peptides are under investigation. An important step in developing multiple agonists is to establish the relative pharmacological potency and efficacy of new molecules at its different target receptors, and to optimise the balance of activities to achieve the desired treatment outcome. In a recent issue of the Biochemical Journal, Naylor et al. described how they used CRISPR technology to modulate endogenous receptor density in insulinoma cells to get the balance right for a dual incretin peptide engaging both GLP-1- and glucose-dependent insulinotropic polypeptide-receptors.

Topics: Animals; Cell Line, Tumor; Clustered Regularly Interspaced Short Palindromic Repeats; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Obesity; Peptidomimetics

The global prevalence of "diabesity"-diabetes related to obesity-is increasing steadily over the past few decades because of the obesity epidemic. Although bariatric surgery is an effective treatment option for patients with diabesity, its limited availability, invasiveness, relatively high costs and the potential for surgical and postsurgical complications restrict its widespread use. Therefore, medical management is the only option for a majority of patients with diabesity. Diabetes control with several anti-diabetic agents, including insulin, causes weight gain with probability of worsening diabesity. Rational use of anti-diabetic medications with weight loss potential in varying combinations may help to address this key issue for long-term management of diabesity. There is no consensus on such an approach from different professional bodies like American Diabetes Association, European Association for Study of Diabetes, or International Diabetes Federation. We attempt to discuss the key issues and realistic targets for diabesity management in this paper.. Rational use of anti-diabetic combinations can mitigate worsening of diabesity to some extent while managing patients. Retrospective studies showed that combination therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose co-transporter 2 (SGLT-2) inhibitors, when administered along with other anti-diabetic medications, offer the best therapeutic benefit in the medical management of diabesity. Different combinations of other anti-diabetic drugs with minimum weight gain potential were also found useful. Because of insufficient evidence based on prospective randomised controlled trials (RCTs), future research should focus on evolving the appropriate rational drug combinations for the medical management of diabesity.

Topics: Diabetes Mellitus; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Sodium-Glucose Transporter 2 Inhibitors

Type 2 diabetes is associated with increased fracture risk and the mechanisms underlying the detrimental effects of diabetes on skeletal health are only partially understood. Antidiabetic drugs are indispensable for glycemic control in most type 2 diabetics, however, they may, at least in part, modulate fracture risk in exposed patients. Preclinical and clinical data clearly demonstrate an unfavorable effect of thiazolidinediones on the skeleton with impaired osteoblast function and activated osteoclastogenesis. The negative effect of thiazolidinediones on osteoblastogenesis includes decreased activity of osteoblast-specific transcription factors (e.g. Runx2, Dlx5, osterix) and decreased activity of osteoblast-specific signaling pathways (e.g. Wnt, TGF-β/BMP, IGF-1). In contrast, metformin has a positive effect on osteoblast differentiation due to increased activity of Runx2 via the AMPK/USF-1/SHP regulatory cascade resulting in a neutral or potentially protective effect on bone. Recently marketed antidiabetic drugs include incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2)-inhibitors. Preclinical studies indicate that incretins (GIP, GLP-1, and GLP-2) play an important role in the regulation of bone turnover. Clinical safety data are limited, however, meta-analyses of trials investigating the glycemic-lowering effect of both, GLP-1 receptor agonists and DPP4-inhibitors, suggest a neutral effect of incretin-based therapies on fracture risk. For SGLT2-inhibitors recent data indicate that due to their mode of action they may alter calcium and phosphate homeostasis (secondary hyperparathyroidism induced by increased phosphate reabsorption) and thereby potentially affect bone mass and fracture risk. Clinical studies are needed to elucidate the effect of SGLT2-inhibitors on bone metabolism. Meanwhile SGLT2-inhibitors should be used with caution in patients with high fracture risk, which is specifically true for the use of thiazolidinediones.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Fractures, Bone; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Like Growth Factor I; Metformin

Diabetes mellitus and obesity, which is a major risk factor in the development of type 2 diabetes mellitus, have reached epidemic proportions worldwide including the USA. The current statistics and forecasts, both short- and long-term, are alarming and predict severe problems in the near future. Therefore, there is a race for developing new compounds, discovering new receptors, or finding alternative solutions to prevent and/or treat the symptoms and complications related to obesity and diabetes mellitus. It is well demonstrated that members of the transient receptor potential (TRP) superfamily play a crucial role in a variety of biological functions both in health and disease. In the recent years, transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) were shown to have beneficial effects on whole body metabolism including glucose homeostasis. TRPV1 and TRPA1 have been associated with control of weight, pancreatic function, hormone secretion, thermogenesis, and neuronal function, which suggest a potential therapeutic value of these channels. This review summarizes recent findings regarding TRPV1 and TRPA1 in association with whole body metabolism with emphasis on obese and diabetic conditions.

Topics: Adipose Tissue; Animals; Autonomic Nervous System; Calcium Channels; Diabetes Mellitus; Diet Therapy; Dietary Supplements; Ghrelin; Glucagon-Like Peptide 1; Humans; Ligands; Nerve Tissue Proteins; Obesity; Pancreas; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

For decades, extensive research has aimed to clarify the role of pancreas and gut-derived peptide hormones in the regulation of glucose homeostasis and feeding behavior. Among these are the beta-cell hormone amylin and the intestinal L cell hormone glucagon-like peptide-1 (GLP-1). They exhibit distinct and yet several similar physiological actions including suppression of food intake, postprandial glucagon secretion, and gastric emptying-altogether lowering plasma glucose and body weight. These actions have been clinically exploited by the development of amylin and GLP-1 hormone analogs now used for treatment of diabetes and obesity. This review will outline the physiology and pharmacological potential of amylin and GLP-1, respectively, and focus on innovative peptide drug development leading to drugs acting on two or more distinct receptors, such as an amylin and GLP-1 peptide hybrid, potentially producing a more effective treatment strategy to combat the rapidly increasing global obesity.

Topics: Animals; Diabetes Mellitus; Eating; Glucagon-Like Peptide 1; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Obesity

This chapter deals with novel therapeutic approaches, predominantly for type 2 diabetes. Incretin-based therapies utilize the effects of glucagon-like peptide-1 (GLP-1), which stimulates insulin and inhibits glucagon secretion in a glucose-dependent manner. Incretin-based therapies comprise injectable GLP-1 receptor agonists and orally active dipeptidyl peptidase-IV inhibitors. Both have a low hypoglycaemia risk. GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide, albiglutide) reduce glycated haemoglobin levels more effectively than oral antidiabetic agents do and lead to weight loss as well as a slight decrease in systolic blood pressure. The most common side effects are nausea and fullness, especially during the start of therapy. Dipeptidyl peptidase-IV inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) are not inferior to sulfonylureas, causing significantly less hypoglycaemia and not inducing weight gain. Specific adverse effects have not been discovered yet, and cardiovascular safety has been demonstrated in respective studies. Sodium-glucose transporter-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin) were introduced recently. They block the tubular reabsorption of glucose in the kidney and represent an insulin-independent mode of action, with low hypoglycaemia risk and allowing weight loss. The most common side effects are genital and urinary tract infections. Other novel drugs in development (G-protein-coupled receptor agonists, interleukin-1 antagonists) are also described.

Topics: Animals; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium-glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential.. This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart.. SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins; Molecular Targeted Therapy; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors. In this review, we focus on the pancreatic effects exerted by current GLP-1 derivatives used to treat diabetes. Based on the results from in vitro and in vivo studies in humans and animal models, we describe the specific actions of GLP-1 analogs on the synthesis, processing, and secretion of insulin, islet morphology, and β cell proliferation and apoptosis.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Islets of Langerhans

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

Topics: Adrenal Cortex; Animals; Corticotropin-Releasing Hormone; Diabetes Mellitus; Female; Fetal Development; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucocorticoids; Humans; Hypothalamo-Hypophyseal System; Incretins; Insulin Resistance; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Stress, Physiological

Incretin-based therapies are revolutionizing the field of human diabetes mellitus (DM) by replacing insulin therapy with safer and more convenient long-acting drugs.. Incretin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) are secreted from the intestinal tract in response to the presence of food in the intestinal lumen. GLP-1 delays gastric emptying and increases satiety. In the pancreas, GLP-1 augments insulin secretion and suppresses glucagon secretion during hyperglycemia in a glucose-dependent manner. It also protects beta cells from oxidative and toxic injury and promotes expansion of beta cell mass.. Clinical data have revealed that GLP-1 analog drugs are as effective as insulin in improving glycemic control while reducing body weight in people suffering from type 2 DM. Furthermore, the incidence of hypoglycemia is low with these drugs because of their glucose-dependent mechanism of action. Another significant advantage of these drugs is their duration of action. While insulin injections are administered at least once daily, long-acting GLP-1 analogs have been developed as once-a-week injections and could potentially be administered even less frequently than that in diabetic cats.. This article reviews the physiology of incretin hormones, and the pharmacology and use of GLP-1 analogs, with emphasis on recent research in cats. Further therapies that are based on incretin hormones, such as DPP-4 inhibitors, are also briefly discussed, as are some other treatment modalities that are currently under investigation.

Topics: Animals; Cat Diseases; Cats; Diabetes Mellitus; Glucagon-Like Peptide 1; Incretins

The proglucagon-derived peptide hormone, glucagon, comprises 29 amino acids. Its secretion from the pancreatic α cells is regulated by several factors. Glucagon increases blood glucose levels through gluconeogenesis and glycogenolysis. Elevated plasma concentrations of glucagon, hyperglucagonemia, may contribute to diabetes. However, hyperglucagonemia is also observed in other clinical conditions than diabetes, including nonalcoholic fatty liver disease, glucagon-producing tumors and after gastric bypass surgery. Here, we review the current literature on hyperglucagonemia in disease with a particular focus on diabetes, and finally speculate that the primary physiological importance of glucagon may not reside in glucose homeostasis but in regulation of amino acid metabolism exerted via a hitherto unrecognized hepato-pancreatic feedback loop.

Topics: Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagonoma; Humans; Liver; Neoplasms; Non-alcoholic Fatty Liver Disease; Oxyntomodulin; Pancreas; Receptors, Glucagon

Diabetes is a global burden and the prevalence of the disease, in particular diabetes mellitus type 2 is rapidly increasing worldwide. After introduction of insulin into clinical therapy about 90 years ago a major number of pharmaceuticals has been developed for treatment of diabetes mellitus type 2. One of these, the incretin glucagon-like peptide 1 (GLP-1), like insulin, needs subcutaneous administration causing inconvenience to patients. However, administration of GLP-1 plays also a role for treatment of irritable bowel syndrome (IBS). To improve patient convenience inhaled insulin (Exubera(®)) was developed and approved but failed market acceptance some years ago. Recently, another inhalative insulin (Afrezza(®)) received market approval and GLP-1 may serve as another candidate drug for inhalative administration. This review analyzes the current literature investigating alternative administration of GLP-1 and GLP-1 analogs focusing on inhalation. Several formulations for inhalative administration of GLP-1 and analogs were investigated in animal studies, whereas there are only few clinical data. However, feasibility of GLP-1 inhalation has been shown and should be further investigated as such type of drug administration may serve for improvement of therapy in patients with diabetes mellitus or irritable bowel syndrome.

Topics: Administration, Inhalation; Aerosols; Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Irritable Bowel Syndrome

The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Energy Metabolism; Enteroendocrine Cells; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Homeostasis; Humans; Signal Transduction

Transplant physicians have tried to avoid graft rejection and early graft loss for many years. However, physicians are now aware about improving long-term kidney and patient survival, a challenge that needs to focus on cardiovascular risk management. One major contributor of this risk is the development of posttransplant diabetes mellitus (PTDM).. We performed a literature search based on PubMed, covering prevalence, risk factors, prevention and treatment of PTDM.. We need good quality clinical trials on PTDM prevention and management. In addition, basic and translational-targeted studies should be encouraged, as high-quality molecular and mechanistic analyses are not frequent in this area. Hard end points such as patient and graft survival, cardiovascular and other microvascular complications in patients with PTDM are very difficult to reach, so we need good surrogate end points. The currently used ones are extrapolations from the general population. The target glucose or HbA1c levels to achieve are largely unknown. We need strategies to delay or prevent PTDM, and tailoring immunosuppression and antidiabetic management including early insulin and oral agents from the early transplant surgery could be essential. Treatment of established PTDM with the new families of oral hypoglycemic agents--secretagogues and incretins--needs higher levels of evidence to prove their short- and long-term safety and efficacy, even at early PTDM stages.

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Graft Rejection; Graft Survival; Humans; Hypoglycemic Agents; Immunosuppression Therapy; Insulin; Kidney Transplantation; Risk Factors

CD26 is a widely expressed transmembrane glycoprotein with peptidase activity in its extracellular domain and which regulates multiple biological processes. It acts mainly as catabolic enzyme for a number of circulating proteins involved in common pathological conditions such as diabetes and cardiovascular disease and may represent a target to modulate bioavailability of crucial substrates. The aim of the present review is to summarize data regarding CD26-based pharmacological interventions. Four main subtopics were identified:1) CD26 as the target of pharmacological inhibitors to increase bioavailability of glucagon-like petide-1 (GLP-1) and hence to enhance GLP-1 glucose-lowering activity in diabetic patients; 2) role of CD26 in the physiology and pathology of the cardiovascular system; 3) the adverse prognostic value of CD26 expression on cancer cells; 4) CD26 down-regulation on lymphocytes as a mechanism of TGF-beta immunomodulation.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Molecular Targeted Therapy; Neoplasms

Insulin therapy remains the standard of care for achieving and maintaining adequate glycemic control, especially in hospitalized patients with critical and noncritical illnesses. Insulin therapy is more effective against elevated fasting glycaemia but less in the reduction of postprandial hyperglycaemia. It is associated with a high incidence of hypoglycemia and weight gain. Contrary, GLP-1 mimetic therapy improves postprandial glycaemia without the hypoglycaemia and weight gain associated with aggressive insulin therapy. Moreover, it has the potential to reduce cardiovascular related morbidity. However, its increased immunogenicity and severe gastrointestinal adverse effects present a huge burden on patients. Thus, a right combination of basal insulin which has lowering effect on fasting plasma glucose and GLP-1 mimetic with its lowering effect on postprandial plasma glucose with minimal gastrointestinal adverse effects, seems the right therapy choice from a clinical point of view for some diabetic patients. In this article, we discuss the pros and cons of the use of insulin analogues and GLP-1 mimetics that are associated with the treatment of type 2 diabetes.

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulins; Peptides

The number of young diabetics is increasing and therapeutic options for these patients are limited. Glucagon-like peptide-1 (GLP-1) is secreted from the gut after meals and enhances glucose-induced insulin secretion, inhibits glucagon secretion, suppresses appetite, and delays the gastric-emptying rate. GLP-1 analogs are already widely used in the adult population to improve glycemic control and induce weight loss in overweight subjects with type 2 diabetes. The glucose-lowering effects resulting from the inhibition of glucagon secretion and the gastric-emptying rate could be of clinical importance in type 1 diabetes. In this article we review clinical data regarding the use of GLP-1 receptor agonists in youth and address the potential benefits and safety aspects of these compounds. Large scale clinical trials are still needed in the pediatric population.

Topics: Adolescent; Adult; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Liraglutide; Male; Pediatric Obesity; Randomized Controlled Trials as Topic; Receptors, Glucagon

Glucagon-like peptide-1 (GLP-1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic β-cells. GLP-1 exerts its effects by binding to its G-protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic β-cells. In addition to its insulinotropic effects, GLP-1 also preserves pancreatic β-cell mass by stimulating β-cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP-1 is affected by and interplays with glucose levels. Due to such advantages, GLP-1-based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP-1 potentiates diminished glucose-stimulated insulin secretion and β-cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP-1 in regulation of insulin secretion and pancreatic β-cell proliferation.

Topics: Animals; Blood Glucose; Cell Proliferation; Cyclic AMP; Diabetes Mellitus; Gene Expression Regulation; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Signal Transduction; Transcription, Genetic

Glucagon-like peptide 1 (GLP1) is a major incretin hormone. This means that it is secreted by the gut in response to food and helps in reducing post-prandial glucose exertion. It achieves this through a number of mechanisms, including stimulating insulin release by pancreatic β-cells in a glucose-dependent manner; inhibition of glucagon release by pancreatic α-cells (also in a glucose-dependent manner); induction of central appetite suppression and by delaying gastric empting thereby inducing satiety and also reducing the rate of absorption of nutrients. However, GLP1 receptors have been described in a number of extra-pancreatic tissues, including the endothelium and the myocardium. This suggests that the physiological effects of GLP1 extend beyond post-prandial glucose control and raises the possibility that GLP1 might have cardiovascular effects. This is of importance in our understanding of incretin hormone physiology and especially because of the possible implications that it might have with regard to cardiovascular effects of incretin-based therapies, namely DPP-IV inhibitors (gliptins) and GLP1 analogues. This review analyzes the animal and human data on the effects of GLP1 on the cardiovascular system in health and in disease and the currently available data on cardiovascular effects of incretin-based therapies. It is the author's view that the physiological role of GLP1 is not only to minimize postprandial hypoglycaemia, but also protect against it.

Topics: Animals; Blood Glucose; Cardiovascular System; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Inflammation; Insulin-Secreting Cells; Oxidative Stress; Triglycerides

Topics: Diabetes Mellitus; Education, Medical, Continuing; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Practice Guidelines as Topic

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, and somatostatin to facilitate glucose disposal. The actions of incretin hormones are terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) and through renal clearance. GLP-1 and GIP promote β-cell proliferation and survival in rodents. DPP-4 inhibitors expand β-cell mass, reduce α-cell mass, and inhibit glucagon secretion in preclinical studies; however, whether incretin-based therapies sustain functional β-cell mass in human diabetic subjects remains unclear. GLP-1 and GIP exert their actions predominantly through unique G protein-coupled receptors expressed on β-cells and other pancreatic cell types. Accurate localization of incretin receptor expression in pancreatic ductal or acinar cells in normal or diabetic human pancreas is challenging because antisera used for detection of the GLP-1 receptor often are neither sufficiently sensitive nor specific to yield reliable data. This article reviews recent advances and controversies in incretin hormone action in the pancreas and contrasts established mechanisms with areas of uncertainty. Furthermore, methodological challenges and pitfalls are highlighted and key areas requiring additional scientific investigation are outlined.

Topics: Acinar Cells; Animals; Atherosclerosis; Blotting, Western; Cell Proliferation; Cricetinae; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Inflammation; Insulin-Secreting Cells; Male; Mice; Pancreas; Rats; Real-Time Polymerase Chain Reaction; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

Cardiovascular diseases are major killers in all developed societies and rapidly becoming the leading cause of morbidity and mortality in the developing world. Patients with diabetes mellitus are at particular risk of developing cardiovascular diseases. The present treatment options for management of diabetes have expanded since the development of glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. There is a growing body of evidence that these agents may have cardioprotective effects even in patients who do not have diabetes. Here, we discuss this evidence as well as pathways that DPP-4 inhibitors target in the cardiovascular system. These agents over time will find an appropriate place in the management of cardiovascular diseases.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Complications; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents

Glucagon-like peptide-1 (GLP-1) is one of the hormones responsible for the incretin effect, a term that refers to the observation that orally administered glucose results in a larger increase in plasma insulin levels and insulin-dependent decrease in blood glucose concentration when compared to the same amount of glucose given intravenously. GLP-1 is secreted mainly by gut endocrine L-cells and is released under the control of carbohydrates, proteins and lipids. Upon secretion, GLP-1 targets different cell types and exerts a wide variety of actions such as potentiation of glucose-stimulated insulin secretion, reduction of appetite, delay of gastric emptying and increase in β-cell mass. These beneficial effects have resulted in the application of GLP-1-based therapies in patients with type 2 diabetes, but also exploitation of its effects in type 1 diabetes is being envisaged. In this review, we focus on the different, short- and long-term action mechanisms of GLP-1 with specific emphasis on its role as a modulator of β-cell function and survival.

Topics: Animals; Cell Death; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Insulin-Secreting Cells

The glucagon-like peptide-1 receptors agonists (GLP1RA) are a relatively new class of drugs, used for management of type 2 diabetes. This review studies the characteristics of these drugs, focusing upon their mechanism of action, intra-class differences, and utility in clinical practice. It compares them with other incretin based therapies, the dipeptidyl peptidase-IV inhibitors, and predicts future developments in the use of these molecules, while highlighting the robust indications for the use of these drugs.

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Receptors, Glucagon

It has been established that diabetes is an independent risk factor for microvascular and macrovascular complications, and many studies indicate that diabetic subjects are at greater risk of dementia, depression and fracture. Risk reductions for microvascular, macrovascular and death were observed by intensive therapy using insulin or oral diabetic agents. But a history of hypoglycemia was increased myocardial infarction, mortality, dementia and fracture. So it is important that optimum glycemic control has to be achieved without hypoglycemia. Treatment with a long-acting basal insulin analogue or glucagon-like peptide-1(GLP-1) receptor agonist, provide effective glycemic control without serious hypoglycemia in elderly patients. Self-monitoring of blood glucose might be effective in improving glycemic control in elderly patients, and it is useful for the diagnosis of hypoglycemia.

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood Glucose Self-Monitoring; Diabetes Mellitus; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Liraglutide; Receptors, Glucagon

Heart failure (HF) and diabetes mellitus (DM) commonly co-exist, with a prevalence of DM of up to 40 % in HF patients. Treatment of DM in patients with HF is challenging since many of the contemporary therapies used for the treatment of DM are either contraindicated in HF or are limited in their use due to the high prevalence of co-morbidities such as significant renal dysfunction. This article presents an overview of the physiology of the incretin system and how it can be targeted therapeutically, highlighting implications for the management of patients with DM and HF. Receptors for the incretin glucagon-like peptide-1 (GLP-1) are expressed throughout the cardiovascular system and the myocardium and are up-regulated in HF. GLP-1 therapy improves cardiac function in animal models of HF through augmented glucose uptake in the myocardium mediated through a p38 MAP kinase pathway. Small clinical studies have shown that GLP-1 improves ejection fraction, reduces BNP levels and enhances functional capacity in patients with chronic HF. A number of randomized controlled trials are currently underway to define the utility of targeting the incretin system in HF patients with DM. Incretin-based therapy may represent a novel therapeutic strategy in the treatment of HF patients with diabetes, in particular for their cardioprotective effects independent of those attributable to tight glycemic control.

Topics: Comorbidity; Diabetes Mellitus; Glucagon-Like Peptide 1; Heart Failure; Humans; Incretins; Treatment Outcome

The increasing epidemic of diabetes mellitus around the globe is increasing the risk of various other chronic diseases i.e. coronary artery diseases, myocardial infarction, hypertension, dyslipidemia and number of other complicated disorders. Diabetes mellitus is clinically characterized by a marked increase in blood glucose levels and is associated with mild hyperlipidemia. Although the prevalence of this health ailment is increasing dramatically, various therapeutic compounds have been developed to treat this disease that is available in the market as synthetic, formulated and combined forms. Recently, various compounds have come through preclinical studies and shown the therapeutic efficacy of using multiple/ specific drug targets. Recent research approaches have been based on receptors targeting, islet cell transplantation, gene expression profiling, glucagon-like peptide-1, dipeptidyl peptidase IV inhibitors, insulin therapy, modulators of peroxisome proliferator-activated receptors (PPAR), glucagon receptor antagonists, insulin analogues, sensitizers and combination therapies. Furthermore various, latest findings claimed to identifying new anti-diabetic regimens with novel mechanism of action are being developed. This review provides an update on the use of approaches to the development of preventive and therapeutic strategies against diabetes and recent patents that could develop into novel therapeutics available to the clinical success for the management of the disease.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans Transplantation; Molecular Targeted Therapy; Patents as Topic; Peroxisome Proliferator-Activated Receptors

Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obesity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3 Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral β-amyloidogenesis in murine model of AD, accompanied by a significant elevation in APP (Amyloid Precursor Protein) and BACE1 (β-site APP Cleaving Enzime 1). Similarly, deposits of Aβ produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway. Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat together AD and DM. The aim of the present review is to better understand the strengths and drawbacks of these therapies.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypoglycemic Agents; Incidence; Liraglutide; Male; Metformin; Receptor, Insulin; Risk Factors; tau Proteins

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus; Drug Discovery; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Models, Molecular; Molecular Sequence Data; Receptors, Glucagon

The discoveries of the incretin hormone glucagon-like peptide-1 (GLP-1) and the β-cell hormone amylin have translated into hormone-based therapies for diabetes. Both classes of molecules also exhibit weight-lowering effects and have been investigated for their anti-obesity potential. In the present review, we explore the mechanisms underlying the physiological and pharmacological actions of GLP-1 and amylin agonism. Despite their similarities (e.g. both molecular classes slow gastric emptying, decrease glucagon and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on glycaemia and energy balance. We suggest that understanding the similarities and differences between these molecules holds important implications for the development of novel, combination-based therapies, which are increasingly the norm for diabetes/metabolic disease. Finally, the future of GLP-1- and amylin agonist-based therapeutics is discussed.

Topics: Animals; Diabetes Mellitus; Eating; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Islet Amyloid Polypeptide; Metabolic Diseases; Obesity; Receptors, Glucagon

Recently incretin-based therapies have been developed in the clinical practice, this class includes both the dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin), and the glucagon-like peptide- 1 (GLP-1) receptor agonists [exenatide, exenatide long acting release (LAR) and liraglutide]. In particular exenatide and liraglutide have structural similarity and bind to the GLP-1 receptor, displaying a similar broad range of activities relevant to improving glycemic control, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety, reducing the food intake; it also promotes β-cell proliferation and probably neogenesis, while reducing apoptosis in animal models. We conducted a review analyzing clinical efficacy and safety of GLP-1 receptor agonists exenatide and liraglutide, both alone and in combination with other anti-diabetic drugs, including the most important studies about them in the latest ten years. We concluded that GLP-1 receptor agonists appear to be a good choice to decrease HbA1c levels and to lower postprandial blood glucose levels. They also suppress glucagon secretion and slow gastric motility. They also have positive effects on β-cell function and they gave a significant decrease of body weight. They are not associated with hypoglycemia, but cause a relatively high frequency of gastrointestinal disturbances, with some patients experiencing one or more episodes of nausea, vomiting, or diarrhea. However, after an evaluation of the advantages and the disadvantages, we concluded that, once metformin fails to reach an adequate glycemic control, GLP-1 receptor agonists can be a valid alternative, especially in obese type 2 diabetic patients. GLP-1 receptor agonists should be considered also in patients in therapy with metformin and another agent, such as a sulfonylurea, because of the minor risk of developing hypoglycemia and the positive effect on body weight.

Topics: Animals; Diabetes Mellitus; Exenatide; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Liraglutide; Peptides; Treatment Outcome; Venoms

Recent findings in animal models suggest that resistant starch is beneficial for both body weight regulation and glycaemic control. The purpose of this review is to summarize the current evidence and recommendations in humans.. When resistant starch replaces available carbohydrate in a meal, postprandial glycaemia is reduced. There are some data to suggest that resistant starch may affect glycaemia even when the available carbohydrate portion remains constant; however, there is inconsistency in the literature. Recent animal data suggest that chronic resistant starch feeding upregulates glucagon-like peptide 1 expression in the large bowel with concomitant increases in neuropeptide expression in the hypothalamus, combining to result in weight loss and improvements in glycaemic control. However, to date there is no evidence for this in humans.. Resistant starch may have a role in glycaemic control in healthy individuals and those with type 2 diabetes; however, there are limited interventional trials in humans to support this. There are no data concerning resistant starch feeding in human diabetes and as such no health recommendation can be made.

Topics: Animals; Blood Glucose; Colon; Diabetes Mellitus; Diet; Dietary Carbohydrates; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypothalamus; Neuropeptides; Starch; Up-Regulation; Weight Loss

There is a concern on the risk of thyroid cancer associated with glucagon-like peptide-1 (GLP-1) analogs including liraglutide and exenatide. In this article, we review related experimental studies, clinical trials and observational human studies currently available. In rodents, liraglutide activated the GLP-1 receptors on C-cells, causing an increased incidence of C-cell neoplasia. Animal experiments with monkeys demonstrated no increase in calcitonin release and no C-cell proliferation after long-term liraglutide administration. Longitudinal 2-year data from clinical trials do not support any significant risk for the activation or growth of C-cell cancer in humans in response to liraglutide. However, an analysis of the FDA adverse event reporting system database suggested an increased risk for thyroid cancer associated with exenatide after its marketing. Noticeably, a recent study discovered that GLP-1 receptor could also be expressed in human papillary thyroid carcinomas (PTC), but the impact of GLP-1 analogs on PTC is not known. Therefore, GLP-1 analogs might increase the risk of thyroid C-cell pathology in rodents, but its risk in humans awaits confirmation. Since GLP-1 receptor is also expressed in PTC besides C-cells, it is important to investigate the actions of GLP-1 on different subtypes of thyroid cancer in the future.

Topics: Animals; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Disease Models, Animal; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Liraglutide; Macaca fascicularis; Mice; Peptides; Rats; Receptors, Glucagon; Thyroid Neoplasms; Venoms

The mechanisms for hyperglycemia-mediated harm in the hospitalized cardiac patient are poorly understood. Potential obstacles in the inpatient management of hyperglycemia in cardiac patients include rapidly changing clinical status, frequent procedures and interruptions in carbohydrate exposure, and short hospital length of stay. A patient's preadmission regimen is rarely suitable for inpatient glycemic control. Instead, an approach to a flexible, physiologic insulin regimen is described, which is intended to minimize glycemic excursions. When diabetes or hyperglycemia is addressed early and consistently, the hospital stay can serve as a potential window of opportunity for reinforcing self-care behaviors that reduce long-term complications.

Topics: Acute Disease; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Risk

Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Oxyntomodulin; Receptors, Glucagon

Diabetic nephropathy has become a worldwide epidemic accounting for approximately one-third of all cases of end-stage renal disease. The problem is expected to grow, as the prevalence of diabetes is expected to increase from 285 million patients at present to 438 million patients in the year 2030, with increasing prevalence of diabetes particularly in Asia, and a global prevalence of microalbuminuria of ∼ 40%. This will have a major societal impact because of the enormous financial burden of renal replacement therapy and the invalidating character of this disease. Improved management of diabetes is clearly required, including improved glycemic control to avoid initiation of diabetic nephropathy, particularly in high-risk patients. Recently, the benefits of strict glycemic control on micro- and macrovascular complications have been questioned despite the clear association in observational studies between hyperglycemia and complications. It has been suggested that the benefit of lowering glucose is partly offset by side effects to the glucose-lowering medications, such as hypoglycemia, weight gain, and fluid retention. New treatment strategies with fewer side effects are necessary. Such a treatment could be an incretin-based treatment with glucagon-like peptide 1 analogs, with dipeptidyl peptidase-4 inhibitors that have recently been marketed, or with sodium-glucose transporter 2 inhibitors that are being developed in phase III studies. However, studies with renal end points using these agents are lacking.

Topics: Diabetes Mellitus; Diabetic Nephropathies; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Kidney Failure, Chronic; Sodium-Glucose Transporter 2 Inhibitors

The traditional renin-angiotensin system (RAS) components have been studied extensively since the rate-limiting component of RAS, renin, was first characterized. The ongoing identification of various novel RAS components and signaling pathways continues to elaborate the complexity of this system. Regulation of RAS according to the conventional and contemporary views of its functions in various tissues under pathophysiological conditions is a main treatment strategy for many metabolic diseases. The local pancreatic RAS, first proposed to exist in pancreatic islets two decades ago, could regulate islet function and glycemic control via influences on islet cell mass, inflammation, and ion channels. Insulin secretion, the major function of pancreatic islets, is controlled by numerous factors. Among these factors and of particular interest are glucagon-like peptide-1 (GLP-1) and vitamin D, which may regulate islet function by directly binding receptors on islet beta cells. These factors may work with local RAS signaling in islets to protect and maintain islet function under diabetic and hyperglycemic conditions. In this concise review, the local islet RAS will be discussed with particular attention being paid to recent notable findings.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Islets of Langerhans; Renin-Angiotensin System

Both diabetes mellitus and thyroid disorders are common diseases. According to epidemiologic studies the prevalence of specific thyroid disorders in diabetic subjects is two times higher. Risk factors are age, female gender and autoimmune diabetes mellitus. However, thyroid disorders are diagnosed only half of the cases in diabetic population. The review briefly summarizes the association of autoimmune diabetes mellitus and thyreoiditis, the risk of thyroid disorders in type 1 diabetic pregnant women. Furthermore, the influence of obesity in the risk on thyroid cancer and the effect of glucagon-like peptide 1 analogue on thyroid medullary C-cells are discussed.

Topics: Age Factors; Autoimmunity; Carbohydrate Metabolism; Comorbidity; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Humans; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Obesity; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Risk Factors; Sex Factors; Thyroid Diseases; Thyroid Hormones; Thyroid Neoplasms; Thyroiditis, Autoimmune

The prevalence of diabetes mellitus (DM) is increasing rapidly in the 21st century as a result of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. This costly and chronic disease has been likened recently to the 'Black Death' of the 14th century. Type 2 DM is the more common form and the primary aim of management is to delay the micro- and macrovascular complications by achieving good glycaemic control. This involves changes in lifestyle, such as weight loss and exercise, and drug therapy. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues. GLP-1 agonists mimic the effect of this incretin, whereas DPP-4 inhibitors prevent the inactivation of the endogenously released hormone. Both agents offer an effective alternative to the currently available hypoglycaemic drugs but further evaluation is needed to confirm their safety and clinical role. The past decade has seen the rise and fall in the use of the TZDs (glitazones), such that the only glitazone recommended is pioglitazone as a third-line treatment. The association between the use of rosiglitazone and adverse cardiac outcomes is still disputed by some authorities. The advent of new insulin analogues, fast-acting, and basal release formulations, has enabled the adoption of a basal-bolus regimen for the management of blood glucose. This regimen aims to provide a continuous, low basal insulin release between meals with bolus fast-acting insulin to limit hyperglycaemia after meals. Insulin therapy is increasingly used in type 2 DM to enhance glycaemic control. Recently, it has been suggested that the use of the basal-release insulins, particularly insulin glargine may be associated with an increased risk of cancer. Although attention is focused increasingly on newer agents in the treatment of diabetes, metformin and the sulphonylureas are still used in many patients. Metformin, in particular, remains of great value and may have novel anti-cancer properties.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Thiazolidinediones

Glucagon-like peptide 1 (GLP-1) is a small peptide component of the prohormone, proglucagon, that is produced in the gut. Exendin-4, a GLP-1 receptor agonist originally isolated from the saliva of H. suspectum or Gila monster, is a peptide that shares sequence and functional homology with GLP-1. Both peptides have been demonstrated to stimulate insulin secretion, inhibit glucagon secretion, promote satiety and slow gastric emptying. As such, GLP-1 and Exendin-4 have become attractive pharmaceutical targets as an adjunctive therapy for individuals with type II diabetes mellitus, with several products currently available clinically. Herein we summarize the cell biology leading to GLP-1 production and secretion from intestinal L-cells and the endocrine functions of this peptide and Exendin-4 in humans. Additionally, gene therapeutic applications of GLP-1 and Exendin-4 are discussed with a focus on recent work using the salivary gland as a gene therapy target organ for the treatment of diabetes mellitus.

Topics: Animals; Diabetes Mellitus; Exenatide; Gene Transfer Techniques; Genetic Therapy; Glucagon-Like Peptide 1; Humans; Organ Specificity; Peptides; Salivary Glands; Venoms

Topics: Cardiovascular System; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Liraglutide; Treatment Outcome

Type 2 diabetes mellitus (DM) affects an estimated 25.8 million people in the United States and is the 7th leading cause of death. While effective therapy can prevent or delay the complications that are associated with diabetes, according to the Center for Disease Control, 35% of Americans with DM are undiagnosed, and another 79 million Americans have blood glucose levels that greatly increase their risk of developing DM in the next several years. One of the Healthy People 2020 goals is to reduce the disease and economic burden of DM and improve the quality of life for all persons who have, or are at risk for, DM. Achieving this goal requires a concentrated focus on improving the management of diabetes and in targeting prevention of macrovascular complications. This article reviews established and emerging therapeutic approaches for managing DM and prevention of macrovascular complications.

Topics: Algorithms; Cardiomyopathy, Hypertrophic; Cerebrovascular Disorders; Diabetes Mellitus; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Glucagon-Like Peptide 1; Glycated Hemoglobin; Healthy People Programs; Humans; Hyperglycemia; Hypertension; Life Style; Myocardial Infarction; Risk Factors

Research has substantiated that patients with type 2 diabetes mellitus are at increased risk for cardiovascular (CV) disease. It is well established that aggressive management of metabolic risk factors is critical to reducing morbidity and mortality in patients with diabetes. A number of clinical trials are currently focusing on evaluating the safety and efficacy of therapeutic approaches to diabetes. These trials will provide additional information on the role of aggressive management of glucose in patients with diabetes and CV risk. This article provides a summary of these ongoing trials, and discusses the impact of glycemic control and strategies to promote CV risk reduction in patients with diabetes.

Topics: Adamantane; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drugs, Investigational; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Risk Assessment; Risk Reduction Behavior

The prevalence of obesity and diabetes is epidemic. Severe insulin resistance (defined as the need for > or = 200 units of insulin per day to achieve glycemic control) is commonly seen with obesity and can complicate diabetes management. The management of patients with diabetes who have severe insulin resistance is difficult, and at times frustrating, and requires a multifaceted approach. Weight loss is the best treatment option, which can be a challenging task for patients to achieve and maintain. Medications that decrease insulin needs like metformin, thiazolidinediones, or pramlintide may help, but some patients also need high doses of insulin. This article reviews these different treatment options and provides practical advice on weight loss, use of insulin sensitizers, and use of U-500 insulin.

Topics: Amyloid; Bariatric Surgery; Diabetes Mellitus; Diet, Reducing; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Exercise; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Liraglutide; Metformin; Obesity; Peptides; Thiazolidinediones; Treatment Failure; Venoms; Weight Loss

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Incretins

Topics: Blood Pressure; Body Weight; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Lipid Metabolism; Receptors, Glucagon; Regeneration

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Patients; Pharmaceutical Services

In type 2 diabetes (DM2) there is progressive deterioration in beta-cell function and mass. It was found that islet function was about 50% of normal at the time of diagnosis and reduction in beta-cell mass of about 60% at necropsy (accelerated apoptosis). Among the interventions to preserve the beta-cells, those to lead to short-term improvement of beta-cell secretion are weight loss, metformin, sulfonylureas, and insulin. The long-term improvement was demonstrated with short-term intensive insulin therapy of newly diagnosed DM2, the use of antiapoptotic drugs such as glitazones, and the use of glucagon-like peptide-1 receptor agonists (GLP-1 mimetics), not inactivated by the enzyme dipeptidyl peptidase 4 and/or to inhibit that enzyme (GLP-1 enhancers). The incretin hormones are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas and overall maintenance of glucose homeostasis. From the two major incretins, GLP-1 and GIP (glucose-dependent insulinotropic polypeptide), only the first one or its mimetics or enhancers can be used for treatment. The GLP-1 mimetics exenatide and liraglutide as well as the DPP 4 inhibitors (sitagliptin and vildagliptin) were approved for treatment of DM2.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Insulin; Insulin-Secreting Cells; Liraglutide; Models, Biological; PPAR gamma; Thiazolidinediones

Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients.. This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient-stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin-treated type 2 diabetic patients, co-ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying.

Topics: Adipose Tissue; Blood Glucose; Cholecystokinin; Critical Illness; Diabetes Mellitus; Dyspepsia; Gastric Emptying; Gastroparesis; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Peptide YY; Postprandial Period

Multiple hormones and transmitter systems contribute to glucose homeostasis and the control of metabolism. Recently, the gastrointestinal peptide hormones glucagon-like peptide 1 and amylin have been shown to significantly contribute to this complex physiology. These advances provide the foundation for new treatments for diabetes mellitus. Therapies based on glucagon-like peptide 1 and amylin have now been introduced into clinical practice. Rimonabant, the selective endocannabinoid receptor antagonist, had been used in European countries for the treatment of obesity; it has recently been withdrawn for this indication. This drug exhibited therapeutic benefits for metabolic variables and for type 2 diabetes mellitus. Anesthesia providers caring for patients with diabetes mellitus will need to understand the implications of these new therapies in perioperative settings, particularly with respect to side effects and interactions.

Topics: Amyloid; Anesthesia; Animals; Cannabinoid Receptor Modulators; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Islet Amyloid Polypeptide

Topics: Adamantane; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Standard therapies for type 2 diabetes often fail to maintain glycemic control over the long term, in part because they do not target the underlying cause. Current treatments may also be associated with weight gain, hypoglycemia, and other adverse effects, and can be difficult to use. Disease progression is accompanied by a progressive decline in beta-cell function, which begins early in the disease course, and an impaired incretin response. The recently developed glucagon-like peptide-1 (GLP-1) receptor agonists overcome some of the limitations of conventional treatments. This article summarizes the key results of the new GLP-1 receptor agonist (liraglutide) phase 3 Liraglutide Effect and Action in Diabetes (LEAD) studies. This series of 6 randomized controlled studies involved > 4400 patients with type 2 diabetes who were unable to maintain glycemic control with diet and exercise alone or with oral treatment, approximately 2700 of whom received liraglutide. The studies demonstrated the efficacy and safety of liraglutide both as monotherapy and as combination therapy with 1 or 2 oral agents. In addition to providing robust glycemic control in these studies, liraglutide reduced weight in most patients, improved beta-cell function, lowered blood pressure and triglycerides, and was well tolerated with minimal risk of hypoglycemia.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Liraglutide; Program Evaluation; Treatment Outcome

The prevalence of diabetes is expected to rise together with an increase in morbidity and a reduction in life expectancy. A leading cause of death is cardiovascular disease, and hypertension and diabetes are additive risk factors for this complication. Selected treatment options should neither increase cardiovascular risk in patients with diabetes, nor increase risk of hyperglycaemia in patients with hypertension. The efficacy of present antihyperglycaemic agents is limited and new therapies, such as incretin-targeted agents, are under development. Even though most patients do not achieve glycated haemoglobin targets, trial data show that such interventions reduce the incidence of macrovascular events; however, intensive lowering may be detrimental in patients with existing cardiovascular disease. Currently available oral drugs do not address the key driver of type 2 diabetes--loss of functional beta-cell mass. In the future, new oral treatments must improve this, whilst providing durable blood glucose control and long-term tolerability.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Outbreaks; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Incretins; Male

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are produced predominantly by enteroendocrine cells and have multiple blood glucose-lowering effects. Recent years have seen a surge of interest in understanding the basic physiology and pathophysiology of incretins and in applying this knowledge to the treatment of diabetes and obesity. Considerable gains have been made in elucidating the mechanisms controlling incretin secretion, and there is growing evidence to suggest that incretins might be involved in the rapid reversal of diabetes observed in gastric bypass patients. Here, we review these recent advances and outline the multiple strategies being pursued to exploit the potential therapeutic benefits of GIP and GLP-1.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Eating; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Islets of Langerhans; Molecular Mimicry; Obesity

The incretin effect, that is, the postprandial augmentation of insulin secretion by gastrointestinal hormones, mediates approximately 50-70% of the overall insulin responses after a mixed meal or glucose ingestion in healthy subjects. In patients with type 2 diabetes, the incretin effect is markedly reduced, and this has been attributed to defects in the secretion and insulinotropic action of the two main incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). It has been speculated that a reduced incretin effect might precede the onset of hyperglycaemia in patients with type 2 diabetes. However, the secretion and action of GIP and GLP-1 is relatively unaltered in normal glucose-tolerant individuals at high risk for type 2 diabetes (e.g., first-degree relatives) and a diminished incretin effect is also detectable in other types of diabetes, thereby arguing against such reasoning. This article will describe the defects in the incretin system in patients with type 2 diabetes, summarise their relevance in the development of hyperglycaemia and discuss the potential individual roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Postprandial Period; Prediabetic State

Topics: Animals; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Receptors, Glucagon

The WNT signalling pathway is involved in many physiological and pathophysiological activities. WNT ligands bind to Frizzled receptors and co-receptors (LDL receptor-related protein 5/6), triggering a cascade of signalling events. The major effector of the canonical WNT signalling pathway is the bipartite transcription factor beta-catenin/T cell transcription factor (beta-cat/TCF), formed by free beta-cat and one of the four TCFs. The WNT pathway is involved in lipid metabolism and glucose homeostasis, and mutations in LRP5 may lead to the development of diabetes and obesity. beta-Cat/TCF is also involved in the production of the incretin hormone glucagon-like peptide-1 in the intestinal endocrine L cells. More recently, genome-wide association studies have identified TCF7L2 as a diabetes susceptibility gene, and individuals carrying certain TCF7L2 single nucleotide polymorphisms could be more susceptible to the development of type 2 diabetes. Furthermore, beta-cat is able to interact with forkhead box transcription factor subgroup O (FOXO) proteins. Since FOXO and TCF proteins compete for a limited pool of beta-cat, enhanced FOXO activity during ageing and oxidative stress may attenuate WNT-mediated activities. These observations shed new light on the pathogenesis of type 2 diabetes as an age-dependent disease.

Topics: Animals; beta Catenin; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Models, Biological; Signal Transduction; Wnt Proteins

The gastrointestinal tract is increasingly viewed as a critical organ in glucose metabolism because of its role in delivering glucose to the circulation and in secreting multiple glucoregulatory hormones that, in concert with insulin and glucagon, regulate glucose homeostasis. Under normal conditions, a complex interplay of these hormones acts to maintain plasma glucose within a narrow range despite large variations in the availability of glucose, particularly during transition from the fasting to fed state. In the fed state, the rate at which nutrients are passed from the stomach to the duodenum, termed gastric emptying rate, is a key determinant of postprandial glucose flux. In patients with diabetes, the regulation of glucose metabolism is disrupted resulting in fasting and postprandial hyperglycaemia. Elucidation of the role of the gastrointestinal tract, gut-derived glucoregulatory peptides and gastric emptying rate offers a new perspective on glucose homeostasis and the respective importance of these factors in the diabetes state. This review will highlight the importance of the gastrointestinal tract in playing a key role in glucose homeostasis, particularly in the postprandial period, and the role of established or new therapies that either leverage or modify gastrointestinal function to improve glycaemic state.

Topics: Blood Glucose; Diabetes Mellitus; Energy Metabolism; Female; Gastric Emptying; Gastrointestinal Tract; Glucagon-Like Peptide 1; Homeostasis; Hormones; Humans; Male

Topics: Animals; Blood Glucose; Diabetes Mellitus; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Lizards; Obesity; Peptides; Venoms

This is the second of a 2-part series focusing on newer therapies for type 2 diabetes and their cardiovascular implications. In the first segment, we reviewed the thiazolidinediones, highlighting emerging data concerning their cardiovascular effects, both positive and negative. Here, we present a corresponding discussion of the newest antihyperglycemic category, modulators of the incretin system, which include the glucagon-like peptide-1 mimetics and the dipeptidyl peptidase-4 inhibitors. In addition, we briefly survey several novel drug classes in development, provide summary recommendations for glucose-lowering regimens in specific patient types, underscore the importance of nonglucose cardiovascular risk reduction strategies, and comment on present and future considerations for the regulatory review of diabetes drugs.

Topics: Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Protease Inhibitors

Under normal conditions, insulin and glucagon are counter-regulatory hormones whose balanced action exhibits a relationship that ensures normoglycaemia. Elevated glucose levels following a meal stimulate pancreatic islet beta cells to secrete insulin and islet alpha cells to downregulate production of glucagon. With declining glucose and insulin levels, alpha-cell production of glucagon is increased to stimulate hepatic glucose production, preventing fasting hypoglycaemia. In type 2 diabetes mellitus (T2DM), beta-cell insulin response to glucose is blunted, including absence of early acute response, and alpha-cell response to glucose is impaired, resulting in absolute or relative hyperglucagonaemia and inappropriate hepatic glucose output that contributes to fasting hyperglycaemia. These changes are associated with structural and functional changes in pancreatic islets, including reduced beta-cell mass and reduced beta-cell:alpha-cell ratio. The role of the incretin hormone glucagon-like peptide-1 (GLP-1) in regulating glucose-dependent beta-cell insulin production and glucose-dependent alpha-cell glucagon production has been used to develop GLP-1-based therapies. These therapies may reduce the imbalances among insulin and glucagon that characterise T2DM, resulting in improved glycaemic control.

Topics: Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Postprandial Period

Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor beta-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and incretin enhancers, which inhibit the incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here.

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Secreting Cells

The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K(+) selective pores, either K(IR)6.1/KCNJ8 or K(IR)6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K(+) channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K(+) (K(ATP)) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic beta cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K(ATP) channel activity by a K(IR)6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K(ATP) channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.

Topics: Amino Acids; Animals; ATP-Binding Cassette Transporters; Calcium; Catecholamines; Congenital Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Infant; Infant, Newborn; Insulin; Insulin Secretion; Liver; Mice; Mice, Transgenic; Models, Molecular; Potassium Channels; Potassium Channels, Inwardly Rectifying; Protein Structure, Tertiary; Receptors, Drug; Sulfonylurea Receptors

Drug delivery strategies for diabetes have included a wide range of scientific and engineering approaches, including molecular design, formulation and device design. Molecular engineering has resulted in modified pharmacokinetics, such as rapid-acting or slow-release analogs of insulin. Long-acting insulin formulations are designed to meet the body's basal needs, whereas rapid-acting insulin formulations are designed to cover mealtime glucose spikes. Furthermore, the discovery of new therapeutic biomolecules, which like insulin need to be injected, will drive the need for more flexible and universally applicable delivery systems. Formulation design, such as particle engineering, can be used to modify pharmacokinetic profiles. In general, suspension formulations of insulin commonly demonstrate reduced solubility and result in sustained release. Similarly, depot injections can result in precipitation of insulin at the site of injection, again resulting in lower solubility and sustained release. Particle engineering also has been applied to pulmonary formulations for delivery to the deep lung. The creation of novel drug delivery methods for the treatment of diabetes should remove barriers to insulin therapy and increase patient acceptance and compliance. Eliminating routine injections with needle-free injectors, insulin pumps, inhalation, buccal sprays, intra-nasal delivery, and transdermal patches may offer increasingly attractive alternatives.

Topics: Amino Acid Sequence; Diabetes Mellitus; Dimerization; Disulfides; Drug Delivery Systems; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Models, Chemical; Molecular Sequence Data; Peptides; Protein Conformation; Protein Engineering; Protein Structure, Secondary; Zinc

Although the insulinotropic role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes mellitus has been substantiated, its role in cardioprotection remains largely unknown. To ascertain the role of the cardiovascular actions of GLP-1 in health and disease states necessitates a review of the current evidence as well as ongoing investigation. Of cardiovascular significance, both positive inotropic and chronotropic effects, unmodifiable by beta-adrenergic blockers, have been reportedly attributed to GLP-1 actions on the myocardium. However, the potent role of GLP-1 and its analogues in eliciting tachycardic and pressor effects should be of some concern. Aside from its reported insulinotropic activity, GLP-1 impacts the myocardium directly. Highly specific GLP-1 receptors have been identified in the heart and within the central nervous system, particularly in the nucleus tractus solitarius, a neuromodulatory centre of cardiovascular control. The occurrence of GLP-1 receptors in cardiac tissue and autonomic regions of cardiovascular control has stimulated investigation, particularly as these sites may be suitable targets for the pharmacological action of GLP-1 and long-acting analogues. Discordance on the haemodynamic consequences of GLP-1 pharmacotherapy in experimental animals and human patients has been reported in the literature. However, long-term pharmacological doses of GLP-1 have shown prolonged and beneficial actions on cardiovascular homeostasis in the adjuvant treatment of metabolic disease.

Topics: Animals; Autonomic Nervous System; Brain; Cardiovascular Physiological Phenomena; Diabetes Mellitus; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Myocardium; Receptors, Glucagon

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

Topics: Animals; Diabetes Mellitus; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Obesity; Proglucagon; Receptors, Glucagon

Exenatide is the first in a new class of compounds, which possess similar activity to the naturally-occurring hormone glucagon-like peptide-1 (GLP-1). It mirrors many of the effects of GLP-1, improving glycaemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduced appetite. Phase III clinical trials showed exenatide therapy for 30 weeks significantly reduced glycated haemoglobin, and fasting and postprandial plasma glucose compared with baseline when added to metformin and sulfonylureas or a combination of the two, with an average weight loss of approximately 2 kg. Exenatide can also be used in combination with thiazolidinediones and may be an alternative to insulin in patients requiring additional therapy. In patients with established Type 2 diabetes, control of both glycaemia and body weight are important to minimise the risk of future diabetes complications. Open-label extensions from these pivotal trials demonstrate that patients treated with exenatide for < or = 3 years sustained the reductions in glycaemic control achieved at 30 weeks and had a progressive reduction in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Hypoglycaemia has been encountered in clinical trials of exenatide, especially on initiation of therapy with sulfonylureas (not with metformin). Exenatide may enable patients with Type 2 diabetes to improve glycaemic control and reduce or eliminate the risk of hypoglycaemia and weight gain.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Venoms

This article discusses glucagon-like peptide 1 physiology and its various sites of action beyond the incretin effect and highlights recent findings (2005 and 2006).. Glucagon-like peptide 1 is a physiological incretin in humans and promotes insulin secretion after nutrient ingestion. It is secreted from intestinal L cells after meals and may be partially responsible for the improved glycemic control and weight loss after bariatric surgery. In vivo, glucagon-like peptide 1 is quickly degraded by dipetidyl peptidase IV to glucagon-like peptide 1(9-36), which has unclear physiologic activity. Glucagon-like peptide 1 and its specific receptor are also expressed in the brain, and central nervous system. Glucagon-like peptide 1 can reduce food intake, mediate toxic illness responses and control muscle and liver glucose disposal. In the heart, glucagon-like peptide 1 receptor activation improves cardiac hemodynamics in patients following angioplasty and has a beneficial effect on myocardial function in heart failure and postischemic animal models. Finally, glucagon-like peptide 1 augments islet mass and recent studies have identified cellular mechanisms by which glucagon-like peptide 1 receptor signaling affects this process.. Glucagon-like peptide 1 is emerging as a regulatory factor with a broad range of actions related to substrate and energy metabolism. With the recent development of medications based on glucagon-like peptide 1 receptor signaling for diabetes treatment, these new findings suggest the promise of further application of this system for the treatment of other conditions such as obesity and cardiovascular disease.

Topics: Animals; Central Nervous System; Diabetes Mellitus; Energy Metabolism; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Insulin Secretion; Intestinal Mucosa; Nutritional Physiological Phenomena; Receptors, Glucagon; Signal Transduction

Topics: Diabetes Mellitus; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Venoms

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from enteroendocrine L cells in response to ingested nutrients. The first recognized and most important action of GLP-1 is the potentiation of glucose-stimulated insulin secretion in beta-cells, mediated by activation of its seven transmembrane domain G-protein-coupled receptor. In addition to its insulinotropic actions, GLP-1 exerts islet-trophic effects by stimulating replication and differentiation and by decreasing apoptosis of beta-cells. The GLP-1 receptor is expressed in a variety of other tissues important for carbohydrate metabolism, including pancreatic alpha-cells, hypothalamus and brainstem, and proximal intestinal tract. GLP-1 also appears to exert important actions in liver, muscle and fat. Thus, GLP-1 suppresses glucagon secretion, promotes satiety, delays gastric emptying and stimulates peripheral glucose uptake. The impaired GLP-1 secretion observed in type 2 diabetes suggests that GLP-1 plays a role in the pathogenesis of this disorder. Thus, because of its multiple actions, GLP-1 is an attractive therapeutic target for the treatment of type 2 diabetes, and major interest has resulted in the development of a variety of GLP-1 receptor agonists for this purpose. Ongoing clinical trials have shown promising results and the first analogs of GLP-1 are expected to be available in the near future.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Liraglutide; Maleimides; Molecular Sequence Data; Nitriles; Peptides; Protease Inhibitors; Pyrrolidines; Receptors, Glucagon; Venoms

A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic beta-cell. One such approach is based on the inhibition of dipeptidyl peptidase IV (DP IV), the major enzyme responsible for degrading the incretins in vivo. DP IV exhibits characteristics that have allowed the development of specific inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 human diabetics. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion and important effects on beta-cell differentiation, mitogenesis and survival, by the incretins and other DP IV-sensitive peptides, can potentially preserve beta-cell mass, and improve insulin secretory function and glucose handling in diabetics.

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Tolerance Test; Humans; Molecular Sequence Data; Peptide Fragments; Protease Inhibitors

Type 2 diabetes mellitus is a major and growing health problem throughout the world. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve beta-cell mass and to prevent loss of beta-cell function. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to meal ingestion is a novel pharmacological target with multiple antihyperglycemic actions. GLP-1 glucoregulatory actions include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, dipeptidyl peptidase IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential therapy for type 2 diabetes. However, both the strategies are having their own advantages and limitations. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 mimetics and DPP-IV inhibitors. Further, the potential advantages and the limitations of both the strategies are discussed.

Topics: Animals; Diabetes Mellitus; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Protease Inhibitors; Receptors, Glucagon

Scientists and science in the pharmaceutical industry rely heavily on the more academically orientated basic research carried out at Universities, for first of all training, but also as a source of new ideas and approaches to drug discovery. Progress in the discovery and development of novel therapeutics benefits from a healthy alliance with, and the output from, more basic research institutions, and the reverse is also true, with many advances in understanding of physiological and pathological processes being as the result of the application of novel targeted molecules. To illustrate this, some examples related to the themes of this meeting from my experiences in three different companies will be described. The first involves a metabolic angle in the unravelling of the mechanism of the novel anti-anginal agent ranolazine. The second describes the application of detailed knowledge of insulin structure and action to then use recombinant approaches to design novel molecules to be able to offer the Type I (insulin-dependent) diabetic patient therapies allowing a more physiological treatment regime, and also the further application of learned technology to then discover a means of harnessing the potential of GLP-1 (glucagon-like polypeptide 1) for treating Type II (non-insulin-dependent) diabetes. The last illustrates how findings of novel binding sites on glycogen phosphorylase and glucokinase as the result of drug discovery programmes have led to increased understanding of these key metabolic enzymes and also potential new therapies for Type II diabetes.

Topics: Acetanilides; Animals; Diabetes Mellitus; Drug Design; Glucagon-Like Peptide 1; Glucokinase; Humans; Insulin; Piperazines; Ranolazine

Diabetes Mellitus (DM) is a highly prevalent chronic disease. Recent years have witnessed development of many new oral drugs; novel insulin analogs and their delivery systems for the treatment of patients with either type-1 or type-2 DM. The impetus for developing new antidiabetic drugs comes from the unmet need of pharmacological tools that allow diabetic patients to achieve recommended glucose control targets by precise, safe and effective ways. The number of people afflicted with DM worldwide has increased considerably in recent years and is projected to increase dramatically over the next decades. In the recent times, design and synthesis of bioactive peptides and peptidomimetics has undergone a paradigm shift. Non-proteinogenic amino acids, peptides and peptidomimetics are emerging as novel drug candidates for the treatment of various diseases and/or disorders. This review mainly discusses the advancements in the usage of unnatural amino acids, peptides and peptidomimetics as potential therapeutic agents for the treatment of DM.

Topics: Amino Acids; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Molecular Mimicry; Peptide Fragments; Peptides; Protein Precursors

Topics: Adiponectin; Animals; Diabetes Mellitus; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glycogen Phosphorylase; Humans; Hypoglycemic Agents; Imidazoles; Insulin; Intercellular Signaling Peptides and Proteins; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon; Venoms

Two major initiatives are under way to correct the beta-cell deficit of diabetes: one would generate beta-cells ex vivo that are suitable for transplantation, and the second would stimulate regeneration of beta-cells in the pancreas. Studies of ex vivo expansion suggest that beta-cells have a potential for dedifferentiation, expansion, and redifferentiation. Work with mouse and human embryonic stem (ES) cells has not yet produced cells with the phenotype of true beta-cells, but there has been recent progress in directing ES cells to endoderm. Putative islet stem/progenitor cells have been identified in mouse pancreas, and formation of new beta-cells from duct, acinar and liver cells is an active area of investigation. Peptides, including glucagon-like peptide-1/exendin-4 and the combination of epidermal growth factor and gastrin, can stimulate regeneration of beta-cells in vivo. Recent progress in the search for new sources of beta-cells has opened promising new opportunities and spawned clinical trials.

Topics: Cell Differentiation; Diabetes Mellitus; Embryo, Mammalian; Embryo, Nonmammalian; Epidermal Growth Factor; Exenatide; Gastrins; Glucagon; Glucagon-Like Peptide 1; Islets of Langerhans; Pancreas; Peptide Fragments; Peptides; Protein Precursors; Regeneration; Stem Cells; Venoms

Glucagon-like peptide-1 (GLP-1) is produced both in the human and rat intestine and brain. The release of GLP-1 into the blood is mediated by factors of neural and hormonal origin and is stimulated by the presence of nutrients in the digestive tract, while the enzyme dipeptidyl peptidase IV and the kidneys are responsible for, respectively, the rapid degradation and excretion of the hormone. Peripherally secreted GLP-1 enhances insulin synthesis and release and maintains the normal anatomical status of pancreatic islets. Diminished GLP-1 response to ingested food, associated with attenuated insulin release and glucose intolerance, was found in non-insulin-dependent diabetes mellitus. GLP-1 replacement in diabetic subjects normalized these parameters, thus indicating a role for this peptide in the pathogenesis of type 2 diabetes. GLP-1 might also be involved in the pathophysiology of obesity and stress to some extent. Both peripheral and central GLP-1 are probably involved in the control of feeding centers as an anorexic agent. GLP-1 affects the activity of the hypothalamo-pituitary-adrenal axis both under basal and stress conditions, including taste aversion learning. Hence, GLP-1-dependent pathophysiological mechanisms may participate in the pathogenesis of the most common metabolic and behavioral disorders.

Topics: Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Humans; Obesity; Pancreas; Peptide Fragments; Protein Precursors; Stress, Physiological

Topics: Biomarkers; Diabetes Mellitus; Diagnostic Techniques, Endocrine; Enzyme-Linked Immunosorbent Assay; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Postprandial Period; Radioimmunoassay; Reference Values; Specimen Handling

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that promotes glucose homeostasis through the regulation of insulin and glucagon secretion, gastric emptying, and food intake. This spectrum of effects makes GLP-1 an attractive candidate for drug development. However, because GLP-1 is a small peptide with rapid metabolism in the circulation, its usefulness to treat patients is limited. However, GLP-1 mimetics that are resistant to degradation have been developed and are effective in lowering blood glucose in diabetic patients. A second strategy for harnessing GLP-1 therapeutically is to inhibit the metabolism of endogenous GLP-1; several orally available compounds are in clinical trials. These two new classes of drugs both enhance GLP-1 signaling but differ in several key characteristics that may lead to distinct roles in the treatment of diabetic patients.

Topics: Adenosine Deaminase Inhibitors; Diabetes Mellitus; Dipeptidyl Peptidase 4; Drug Design; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycoproteins; Peptides; Protease Inhibitors; Receptors, Glucagon; Signal Transduction; Venoms

Rapid-acting genetically engineered insulin analogues emerging in the last 10 years are now established as more effective prandial insulins than traditional short-acting human insulin. The development of analogues for use as basal insulin, however, has been much slower. Methods of pro-tracting the time-action curve of injected insulin include complexing with proteins, insulin crystal formation, shifting the iso-electric point of the amino acid sequence or attaching a fatty-acid side chain to the molecule. The latter two methods have been more successful in producing physiologic insulin profiles when compared with the former methods. The principle of acylation has also been applied to prolong the action of other hormones, such as glucagon-like peptide 1 (GLP-1), as the native peptide has a very short half-life. Preliminary results with this compound and other GLP-1 analogues show promise in treating patients with type 2 diabetes. In summary, the development of new insulin and other hormone preparations by the manipulation of native peptide structure has recently improved our antidiabetic armamentarium, and further research will continue this fruitful approach.

Topics: Acylation; Diabetes Mellitus; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin

It has been known for at least one century that agents secreted from the intestine during meal absorption regulates glucose assimilation. Extensive research during the past three decades has identified two gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory polypeptide) that are important in postprandial glucose metabolism. Both peptides are incretins; they are secreted during carbohydrate absorption and increase insulin secretion. Since they are potent insulin secretagogues, GIP and GLP-1 have received considerable attention as potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to the need to develop compounds that overcome this rapid inactivation. Two approaches have been taken to utilise the insulinotropic and glucose-lowering actions of GLP-1 as an antidiabetic agent: the development of DPP-IV-resistant analogues and the inhibition of DPP-IV. This review focuses on the physiology of GLP-1 and GIP and the advances that have been made thus far in developing treatments based on these physiological incretins for Type 2 diabetes.

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peptide Fragments; Peptide Hormones; Protease Inhibitors; Protein Precursors; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

Topics: Animals; Diabetes Mellitus; Digestive System Physiological Phenomena; Dipeptidyl Peptidase 4; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Insulin; Insulin Secretion; Peptide Fragments; Protein Precursors

The development of incretin hormones and incretin analogues for the therapy of diabetes highlights the importance of the gastrointestinal tract in the maintenance of glucose tolerance.. The review focuses on recent information on the role of incretins and their breakdown products on insulin secretion, gastric emptying, and satiety. The importance of gastric emptying and its absorptive potential as well as of dietary composition on gastric emptying and glucose tolerance is highlighted. The concept of a portal glucose sensor in humans has been the subject of some controversy but has been recently revisited.. The gastrointestinal tract plays an important part in glucose tolerance. In this review we have examined how factors altering gastric emptying, insulin secretion in response to meal ingestion, and gastric emptying contribute to the maintenance and deterioration of glucose tolerance.

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Energy Metabolism; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Secretion; Peptide Fragments; Protein Precursors

Recent progress in islet transplantation coupled with the extremely limited supply of primary human islets has spurred the search for alternative sources of beta-cells for transplantation therapy in treating diabetes. Many potential sources of cells are being explored, including embryonic and adult stem cells, identification of intrapancreatic precursor cells, and human beta-cell lines. Here, we review the promise and problems with those cell sources, focusing on our studies in developing functional human beta-cell lines. Those efforts involve a two-step process in which the first is to introduce growth stimulatory genes that induce human beta-cells to enter the cell cycle. Immortalization can then be achieved by expressing the hTERT telomerase subunit. The second step is to induce differentiation. This involves a complex set of manipulations, including the expression of the important beta-cell transcription factor PDX-1. Although PDX-1 is critical for promoting beta-cell differentiation, we do not find increased expression of the glucagon-like peptide-1 receptor, a gene that has been reported to be induced by PDX-1. Further understanding of the factors governing beta-cell development are likely to be required before a robust cell-based therapy is available for the treatment of diabetes.

Topics: Animals; Cell Culture Techniques; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus; Embryonic Stem Cells; Gene Expression Profiling; Glucagon-Like Peptide 1; Humans; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Models, Biological; Reverse Transcriptase Polymerase Chain Reaction

Topics: Animals; Cytokines; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Peptide Fragments

Two landmark intervention studies, the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes mellitus and the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes mellitus, have unequivocally demonstrated that intensive diabetes therapy reduces the risk of long-term diabetic complications. As a result, the commonly accepted treatment goal for most patients with diabetes is the achievement and maintenance of glycemic control that is as close to the normal range as safely possible. Important adverse effects of intensive diabetes therapy, particularly when the treatment includes insulin or several of the oral antihyperglycemic agents, are an increased risk of hypoglycemia and undesired weight gain. Improvement of glycemic control with insulin, insulin secretagogues (sulfonylureas, meglitinides), and insulin sensitizers (thiazolidinediones) is often accompanied by weight gain. The etiology of this weight gain is likely multifaceted, including a reduction of glucosuria, increased caloric intake to prevent hypoglycemia, and anabolic effects on adipose tissue. Biguanides and alpha-glucosidase inhibitors have a neutral or even positive effect (decrease) on weight, which may partly be attributable to their non-insulinotropic mechanism of action, a modest effect on satiety, and to their gastrointestinal adverse effect profile. Several antihyperglycemic agents that are currently in clinical development may improve glycemic control in conjunction with weight reduction. These include an analog of the pancreatic beta-cell hormone amylin (pramlintide), as well as glucagon-like peptide-1 (GLP-1) and exendin, and their analogs. Pharmacological agents with antihyperglycemic and positive weight effects have the potential to become important additions to our therapeutic armamentarium, in that they may help to achieve glycemic targets while addressing the long-standing clinical problem of weight gain as an adverse effect of intensive diabetes therapy.

Topics: Amyloid; Benzamides; Biguanides; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Obesity; Peptide Fragments; Protein Precursors; Sulfonylurea Compounds; Thiazolidinediones; Weight Gain

Topics: Animals; Blood Glucose; Diabetes Mellitus; Fasting; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucokinase; Glucose; Glucose Transporter Type 2; Glycogen; Humans; Insulin; Insulin Secretion; Intestinal Absorption; Liver; Monosaccharide Transport Proteins; Peptide Fragments; Protein Precursors

Topics: Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hyperglycemia; Peptide Fragments; Peptides; Protein Precursors

The glucagon-like peptides GLP-1 and GLP-2 are produced in enteroendocrine L cells of the small and large intestine and secreted in a nutrient-dependent manner. GLP-1 regulates nutrient assimilation via inhibition of gastric emptying and food intake. GLP-1 controls blood glucose following nutrient absorption via stimulation of glucose-dependent insulin secretion, insulin biosynthesis, islet proliferation, and neogenesis and inhibition of glucagon secretion. Experiments using GLP-1 antagonists and GLP-1 receptor-/- mice indicate that the glucoregulatory actions of GLP-1 are essential for glucose homeostasis. In the central nervous system, GLP-1 regulates hypothalamic-pituitary function and GLP-1-activated circuits mediate the CNS response to aversive stimulation. GLP-2 maintains the integrity of the intestinal mucosal epithelium via effects on gastric motility and nutrient absorption, crypt cell proliferation and apoptosis, and intestinal permeability. Both GLP-1 and GLP-2 are rapidly inactivated in the circulation as a consequence of amino-terminal cleavage by the enzyme dipeptidyl peptidase IV (DP IV). The actions of these peptides on nutrient absorption and energy homeostasis and the efficacy of GLP-1 and GLP-2 in animal models of diabetes and intestinal diseases, respectively, suggest that analogs of these peptides may be clinically useful for the treatment of human disease.

Topics: Animals; Central Nervous System; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestines; Pancreas; Peptide Fragments; Peptides; Protein Precursors

Topics: Diabetes Mellitus; Digestive System; Glucagon; Glucagon-Like Peptide 1; Humans; Peptide Fragments; Protein Precursors

Glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) are coencoded within a single mammalian proglucagon precursor, and are liberated in the intestine and brain. GLP-1 exerts well known actions on islet hormone secretion, gastric emptying, and food intake. Recent studies suggest GLP-1 plays a central role in the development and organization of islet cells. GLP-1 receptor signaling appears essential for beta cell signal transduction as exemplified by studies of GLP-1R-/- mice. GLP-2 promotes energy assimilation via trophic effects on the intestinal mucosa of the small and large bowel epithelium via a recently cloned GLP-2 receptor. The actions of GLP-2 are preserved in the setting of small and large bowel injury and inflammation. The biological actions of the glucagon-like peptides suggest they may have therapeutic efficacy in diabetes (GLP-1) or intestinal disorders (GLP-2).

Topics: Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; In Vitro Techniques; Intestinal Diseases; Intestinal Mucosa; Islets of Langerhans; Mice; Mice, Knockout; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon; Signal Transduction

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Liver Diseases; Peptide Fragments; Receptor, Insulin

Topics: Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Humans; Peptide Fragments; Protein Precursors

GLP-1 (glucagon-like peptide-1) is a gut hormone which is released into the blood stream after feeding. Its main action is to stimulate insulin secretion through potentiating the insulinotropic action of glucose. The peptide is encoded in the glucagon gene and expressed mainly in the gut L cells. It exerts its actions through activating specific receptors of the seven transmembraneous domain-G-protein-coupled type with 463 amino acids. Its main signalling mechanism is activation of adenylate cyclase and formation of cyclic AMP. The peptide also increases the cytoplasmic concentration of Ca2 which is thought to be executed both through a Na(+)-dependent uptake of extracellular Ca2+ and through release of Ca2+ from intracellular Ca2+ stores. GLP-1 also inhibits glucagon secretion and inhibits gastric emptying and gastric acid and pancreatic exocrine secretion. Its integrated action on carbohydrate metabolism results in reduction of circulating glucose, and GLP-1 has therefore been suggested as a therapeutic alternative in diabetes. Finally, GLP-1 is also expressed in neurons in the hypothalamus, and may be involved in the regulation of feeding behaviour, since it inhibits food intake.

Topics: Adenylyl Cyclases; Amino Acid Sequence; Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Molecular Sequence Data; Peptide Fragments; Proglucagon; Protein Precursors; Signal Transduction

A functional connection between the small intestine and endocrine pancreas was proved in the sixties, after it became possible to determine the exact amount of insulin in plasma. The insulin response after oral doses of glucose is substantially stronger than after intravenous doses of sugar, even when identical glucose plasma levels are attained. This incretin effect is explained by the connection of the entero-insular axis. The intestinal hormones, that are released by the small intestine after meals, circulate measurably in plasma, and strengthen the glucose-induced insulin secretion, are responsible for this effect. In addition to the classical incretin hormone "Gastric inhibitory polypeptide-1" (GIP), "Glucagon-like peptide-1" (GLP-1) is very interesting to investigators today. In a relatively short amount of time, GLP-1 has matured from a physiologically interesting incretin hormone candidate to a potentially therapeutical alternative for the treatment of diabetes mellitus. GLP-1 stimulates glucose-dependent insulin secretion, decreases plasma glucagon levels, delays gastric emptying, and putatively exerts an additional effect on peripheral glucose utilization. On top of that, GLP-1 has effects on the central nervous system thereby impacting on feeding behavior.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Peptides; Postprandial Period

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 1; Digestive System; Digestive System Physiological Phenomena; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Islets of Langerhans; Peptide Fragments; Proglucagon; Protein Precursors; Protein Processing, Post-Translational; Reference Values

Topics: Diabetes Mellitus; Diet Therapy; Dietary Fiber; Dietetics; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Peptide Fragments

Topics: Amino Acid Sequence; Blood Glucose; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Molecular Sequence Data; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus; Gene Expression Regulation; Glicentin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Homeostasis; Humans; Hypoglycemia; Islets of Langerhans; Molecular Sequence Data; Peptide Fragments; Protein Precursors

Glucagonlike peptide (GLP) 1, a peptide of 30 amino acids with 50% sequence homology to glucagon, results from expression of the glucagon gene in the L cells of the distal intestinal mucosa. It is secreted early in response to mixed meals by mechanisms involving the presence of unabsorbed nutrients in the gut lumen or the absorptive process itself, but other mechanisms may also be involved. GLP-1 has two important actions. First, it stimulates insulin secretion and inhibits glucagon secretion and thereby inhibits hepatic glucose production and lowers blood glucose levels. It may have effects on glucose clearance independent of its pancreatic effects. It acts on recently cloned G protein-coupled specific receptors and seems to increase insulin secretion via cyclic adenosine monophosphate-dependent increases in intracellular calcium. It has been suggested that activation of the beta cells by GLP-1 is a prerequisite for glucose-induced insulin secretion. Second, it also potently inhibits gastrointestinal secretion and motility and is likely to act as an "ileal brake," possibly after activation of cerebral receptors. Therefore, GLP-1 physiologically seems to signal nutritional abundancy and enhance deposition of nutrients. Because of these effects, however, the peptide can completely normalize blood glucose levels in type 2 diabetics and is therefore of considerable pharmaceutical interest.

Topics: Blood Glucose; Diabetes Mellitus; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Liver; Peptides

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Diabetes Mellitus; Gastric Acid; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Insulin; Pancreatitis; Pepsin A; Peptide Fragments; Peptides; Proinsulin; Radioimmunoassay; Salivation; Splanchnic Circulation

Epidemiologic studies have revealed that consuming green tea or coffee reduces diabetes risk. We evaluated the effects of the combined consumption of green tea catechins and coffee chlorogenic acids (GTC+CCA) on postprandial glucose, the insulin incretin response, and insulin sensitivity. Eleven healthy men were recruited for this randomized, double-blinded, placebo-controlled crossover trial. The participants consumed a GTC+CCA-enriched beverage (620 mg GTC, 373 mg CCA, and 119 mg caffeine/day) for three weeks; the placebo beverages (PLA) contained no GTC or CCA (PLA: 0 mg GTC, 0 mg CCA, and 119 mg caffeine/day). Postprandial glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) responses were measured at baseline and after treatments. GTC+CCA consumption for three weeks showed a significant treatment-by-time interaction on glucose changes after the ingestion of high-fat and high-carbohydrate meals, however, it did not affect fasting glucose levels. Insulin sensitivity was enhanced by GCT+CCA compared with PLA. GTC+CCA consumption resulted in a significant increase in postprandial GLP-1 and a decrease in GIP compared to PLA. Consuming a combination of GTC and CCA for three weeks significantly improved postprandial glycemic control, GLP-1 response, and postprandial insulin sensitivity in healthy individuals and may be effective in preventing diabetes.

Topics: Blood Glucose; Catechin; Chlorogenic Acid; Cross-Over Studies; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Postprandial Period; Tea

Granular study of metabolic responses to alterations in the ratio of dietary macro-nutrients can enhance our understanding of how dietary modifications influence patients with impaired glycemic control. In order to study the effect of diets enriched in fat or carbohydrates, fifteen healthy, normal-weight volunteers received, in a cross-over design, and in a randomized unblinded order, two weeks of an iso-caloric high-fat diet (HFD: 60E% from fat) and a high-carbohydrate diet (HCD: 60E% from carbohydrates). A mixed meal test (MMT) was performed at the end of each dietary period to examine glucose clearance kinetics and insulin and incretin hormone levels, as well as plasma metabolomic profiles. The MMT induced almost identical glycemia and insulinemia following the HFD or HCD. GLP-1 levels were higher after the HFD vs. HCD, whereas GIP did not differ. The HFD, compared to the HCD, increased the levels of several metabolomic markers of risk for the development of insulin resistance, e.g., branched-chain amino acid (valine and leucine), creatine and α-hydroxybutyric acid levels. In normal-weight, healthy volunteers, two weeks of the HFD vs. HCD showed similar profiles of meal-induced glycemia and insulinemia. Despite this, the HFD showed a metabolomic pattern implying a risk for a metabolic shift towards impaired insulin sensitivity in the long run.

Topics: Adaptation, Physiological; Adult; Appetite; Blood Glucose; Cross-Over Studies; Diabetes Mellitus; Diet, High-Fat; Dietary Carbohydrates; Discriminant Analysis; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycemic Control; Healthy Volunteers; Humans; Incretins; Insulin; Insulin Resistance; Least-Squares Analysis; Male; Metabolome; Risk Factors

Oleuropein, a component of extra virgin olive oil (EVOO), reduces post-prandial glycemia with a mechanism counteracting oxidative stress-mediated incretin down-regulation. In this study we evaluated if the intake of an oleuropein-enriched chocolate could have positive effects on glycaemia and insulin levels in patients with type 2 diabetes mellitus (T2DM) and healthy subjects (HS).. Twenty-five consecutive T2DM patients and 20 HS were recruited. Participants were randomized to receive 40 g oleuropein-enriched chocolate by EVOO or 40 g control chocolate spread in a cross-over design. Serum glucose, insulin, glucagon-like peptide-1 (GLP1), and dipeptidyl-peptidase-4 (DPP4) were measured before and 2 h after chocolate intake.. In T2DM, the pairwise comparisons showed that intake of oleuropein-enriched chocolate was associated with a significantly less increase of blood glucose compared to control; GLM analysis showed a significant difference for treatments with respect to glucose (p = 0.04), GLP1 (p < 0.001) and DPP-4 activity (p = 0.01). In HS, the pairwise comparisons showed that, after oleuropein-enriched chocolate intake, blood glucose concentration and DPP4 activity did not change; conversely a significant increase was observed for insulin and GLP1. After control chocolate intake, a significant increase for blood glucose, insulin levels and DPP4 activity were observed while GLP1 did not change.. The study shows that using EVOO as source of oleuropein administration of 40 g oleuropein-enriched chocolate is associated with a modest increase or no change of glycemia in T2DM and HS respectively, via an incretin-mediated mechanism.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Chocolate; Cross-Over Studies; Diabetes Mellitus; Diet, Diabetic; Dipeptidyl Peptidase 4; Female; Food, Fortified; Glucagon-Like Peptide 1; Glycemic Control; Humans; Hyperglycemia; Insulin; Iridoid Glucosides; Male; Middle Aged; Olive Oil; Postprandial Period; Rome; Single-Blind Method; Time Factors; Treatment Outcome

Pasireotide (PAS) is an effective treatment for Cushing's disease (CD) but its use is burdened by an associated high incidence of diabetes mellitus (DM). The aim of this study was to examine the effect of a single subcutaneous injection of PAS on glucose metabolism in CD, and to identify predictors of DM onset.. Fifteen patients with CD (13 females, 2 males; median age 43 years [IQR 34-50]) were submitted to an acute PAS test (600 µg s.c.), measuring glucose, insulin, C-peptide, GIP, glucagon, GLP-1, ACTH, and cortisol at the baseline and every 30 min for 2 h. Then they were treated twice daily with PAS 600 µg, and followed up with clinical and hormone assessments for a median of 6 months [2-13].. PAS prompted a significant decrease in all hormonal parameters considered except for glycemia, which increased (as expected), reaching the highest value at 120' (p < 0.0001). Overall, 9/15 patients developed DM within 2 months of starting PAS therapy. There were no differences in age, weight, visceral adiposity, HOMA index, fasting glucose or severity of CD between patients who developed DM and those who did not. Baseline fasting glucagon levels were higher in the DM patients (17.95 [12.45-20.54] vs. 10.53 [8.11-12.33] pmol/L, p = 0.0256), and so were GIP and HbA1c levels (37 [5.5-39.5] vs. 29 [27-31.8] mmol/mol, p = 0.0008). Glucose at 120' was also significantly higher in the DM patients (9.5 [8.65-11.95] vs. 6.85 [4.48-9] mmol/L, p = 0.012).. PAS was rapidly able to suppress insulin and incretin secretion, with a subsequent rise in glucose levels into the diabetic range. It also induced a significant inhibition of glucagon production. The patients at higher risk of DM during PAS therapy were those with higher glucagon levels, HbA1c > 34.5 mmol/mol, and a glucose peak after PAS administration > 9 mmol/L. CD patients with these features given PAS therapy should therefore be monitored more carefully.

Topics: Adult; Blood Glucose; Diabetes Mellitus; Female; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Male; Middle Aged; Pilot Projects; Somatostatin

Glycemic variability (GV) is an indicator of glycemic control and can be evaluated by calculating the SD of blood glucose measurements. In humans with diabetes mellitus (DM), adding a glucagon-like peptide-1 (GLP-1) analogue to conventional therapy reduces GV. In diabetic cats, the influence of GLP-1 analogues on GV is unknown.. To evaluate GV in diabetic cats receiving the GLP-1 analogue exenatide extended release (EER) and insulin.. Thirty client-owned cats with newly diagnosed spontaneous DM.. Retrospective study. Blood glucose curves from a recent prospective placebo-controlled clinical trial generated 1, 3, 6, 10, and 16 weeks after starting therapy were retrospectively evaluated for GV. Cats received either EER (200 μg/kg) or 0.9% saline SC once weekly, insulin glargine and a low-carbohydrate diet. Mean blood glucose concentrations were calculated and GV was assessed by SD. Data were analyzed using nonparametric tests.. In the EER group, GV (mean SD [95% confidence interval]) was lower at weeks 6 (1.69 mmol/L [0.9-2.48]; P = .02), 10 (1.14 mmol/L [0.66-1.62]; P = .002) and 16 (1.66 mmol/L [1.09-2.23]; P = .02) compared to week 1 (4.21 mmol/L [2.48-5.93]) and lower compared to placebo at week 6 (3.29 mmol/L [1.95-4.63]; P = .04) and week 10 (4.34 mmol/L [2.43-6.24]; P < .000). Cats achieving remission (1.21 mmol/L [0.23-2.19]) had lower GV compared to those without remission (2.96 mmol/L [1.97-3.96]; P = .01) at week 6.. The combination of EER, insulin, and a low-carbohydrate diet might be advantageous in the treatment of newly diagnosed diabetic cats.

Topics: Animals; Blood Glucose; Cat Diseases; Cats; Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Prospective Studies; Retrospective Studies

A commonly used therapeutic strategy for type 2 diabetes mellitus (DM) in humans involves the use of synthetic incretin hormone-based therapies including exenatide, a glucagon-like pepetide-1 hormone agonist. Glucagon-like pepetide-1 agonists can be used alone or as an ancillary therapy with other agents, including insulin and oral antihyperglycemics. Little is known about the role of these therapies for DM in cats. Therefore, the primary objective of this study was to evaluate the safety and efficacy of short-acting exenatide combined with insulin, as compared to placebo and insulin for the treatment of DM in cats. Treatment with exenatide was well tolerated; only 2 cats developed side effects requiring dose reduction. Two cats (25%) went into diabetic remission while receiving exenatide and insulin, whereas remission was not reported during placebo treatment. The average change in the daily exogenous insulin dose was significant (β = -0.56 U/kg, 95% confidence interval, -0.96 to -0.15, P = 0.007), and the dose of insulin administered was lower during exenatide treatment. The average weight loss experienced on exenatide was significantly higher than on placebo (β = 0.65 kg, 95% confidence interval, 0.09-1.21, P = 0.02). There was no significant difference in any of the hormone concentrations evaluated for cats on exenatide vs placebo treatments. Overall, the treatment of diabetic cats with insulin and a fixed dose of exenatide was found to be safe. The weight loss and decreased exogenous insulin requirement experienced with exenatide treatment could be a significant benefit for overweight diabetic cats and warrants further evaluation.

Topics: Animals; Blood Glucose; Cat Diseases; Cats; Cross-Over Studies; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Glargine; Male; Placebos; Random Allocation; Weight Loss

The relationship between plasma glucagon-like peptide-1 (GLP-1) and coronary plaque characteristics in humans remains unclear.. A total of 85 culprit coronary vessels excluding the 10-mm culprit segments in non-diabetic patients with acute coronary syndrome (ACS) were examined using integrated backscatter intravascular ultrasound, performed using a 40-MHz intravascular catheter before PCI. All patients underwent 75-g oral glucose tolerance test (OGTT), and the plasma GLP-1 response was evaluated on the basis of the area under the GLP-1 concentration-time curve (GLP-1 AUC) from 0 to 120 min. Patients in the low GLP-1 AUC tertile had a significantly greater percentage lipid area than did patients in the intermediate and high tertiles (low tertile vs. intermediate tertile vs. high tertile: 57.3 ± 12.1% vs. 47.2 ± 15.4% vs. 46.3 ± 12.7%, P<0.01, ANOVA) and a smaller percentage fibrosis area (38.1 ± 9.4% vs. 44.6 ± 11.5% vs. 45.7 ± 9.0%; P=0.01, ANOVA). On multiple regression analysis, low GLP-1 AUC tertile was independently associated with percentage lipid area.. Low plasma GLP-1 during 75-g OGTT is associated with increased lipid content in non-diabetic patients with ACS, suggesting that plaque vulnerability is increased in this subgroup of patients.

Topics: Acute Coronary Syndrome; Aged; Coronary Artery Disease; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Ultrasonography, Interventional

The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads.. The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water.. Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects.. It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance.. ClinicalTrials.gov NCT01875575.

Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus; Double-Blind Method; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Young Adult

New-onset diabetes after transplantation (NODAT) is a common complication after renal transplantation. There are limited available oral drugs to treat hyperglycaemia in this population owing to reduced renal function, potential interactions with immunosuppressive drugs and adverse effects such as hypoglycaemic events that may increase the cardiovascular risk. This study was initiated to investigate efficacy and safety of sitagliptin treatment that may represent a novel alternative in renal transplant recipients.. Nineteen long-term stable renal transplant recipients with NODAT were included in a controlled, cross-over study and randomized to first receive either sitagliptin 50-100 mg/day or a sitagliptin-free period of 4 weeks. Median age (interquartile range, IQR) was 67 (62-72) years (12 males/7 females), all studied 1 (1-3) year after transplantation. The immunosuppressive regimen was a triple calcineurin inhibitor-based therapy. Oral glucose tolerance test (OGTT) with insulin and C-peptide responses and laser Doppler (LD) flowmetry assessment of endothelial function were performed at baseline and after each treatment period. Home measurements of plasma glucose were performed daily during the study.. The median (IQR) first- and second-phase insulin secretion responses increased significantly by 56.3% (45.2-112.6%, P = 0.005) and 39.3% (26.5-81.0%, P = 0.006), respectively, following sitagliptin treatment as compared with no sitagliptin treatment. Fasting and 2-h plasma glucose concentrations fell significantly {0.9 mmol/L [0.5-1.7 mmol/L (16.2 mg/dL), P = 0.003] and 2.9 mmol/L [0.5-6.4 mmol/L (52.3 mg/dL), P = 0.004], respectively}, as did also home measurements of plasma glucose. Endothelial function and plasma markers of cardiovascular risk were unaffected. No serious adverse events were observed. Two mild and asymptomatic hypoglycaemic episodes were observed in combination with glipizide.. Sitagliptin increases insulin secretion and reduces fasting and postprandial plasma glucose in renal transplant recipients with NODAT. The short-term treatment was well tolerated, and sitagliptin seems safe in this population.

Topics: Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postprandial Period; Prospective Studies; Pyrazines; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles

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.

Topics: Adult; Aged; Chymotrypsin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Genotype; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Receptors, Glucagon; Signal Transduction

In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes.. Subjects aged 12-25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects.. GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group.. Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Carbonated Beverages; Child; Cross-Over Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose; Humans; Male; Peptide YY; Young Adult

Topics: Adult; ATP-Binding Cassette Transporters; Diabetes Mellitus; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Incretins; Insulin-Secreting Cells; Male; Middle Aged; Mutation; Peptides; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Receptors, Glucagon; Sulfonylurea Receptors; Venoms

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion. However, GLP-1 also improves endothelial function in diabetes.. Sixteen type 2 diabetic patients and 12 control subjects received a meal, an oral glucose tolerance test (OGTT), and two hyperglycemic clamps, with or without GLP-1. The clamps were repeated in diabetic patients after 2 months of strict glycemic control.. During the meal, glycemia, nitrotyrosine, and plasma 8-iso prostaglandin F2α (8-iso-PGF2a) remained unchanged in the control subjects, whereas they increased in diabetic patients. Flow-mediated vasodilation (FMD) decreased in diabetes, whereas GLP-1 increased in both groups. During the OGTT, an increase in glycemia, nitrotyrosine, and 8-iso-PGF2a and a decrease in FMD were observed at 1 h in the control subjects and at 1 and 2 h in the diabetic patients. In the same way, GLP-1 increased in both groups at the same levels of the meal. During the clamps, in both the control subjects and the diabetic patients, a significant increase in nitrotyrosine and 8-iso-PGF2a and a decrease in FMD were observed, effects that were significantly reduced by GLP-1. After improved glycemic control, hyperglycemia during the clamps was less effective in producing oxidative stress and endothelial dysfunction and the GLP-1 administration was most effective in reducing these effects.. Our data suggest that during the meal GLP-1 can simultaneously exert an incretin effect on insulin secretion and a protective effect on endothelial function, reasonably controlling oxidative stress generation. The ability of GLP-1 in protecting endothelial function seems to depend on the level of glycemia, a phenomenon already described for insulin secretion.

Topics: Diabetes Mellitus; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Male; Middle Aged; Tyrosine; Vasodilation

Glucagon-like peptide-1 is an insulin secretion-stimulating gut hormone that is produced in response to food intake. Orlistat (Xenical, F. Hoffman-La Roche, Basel, Switzerland), which decreases fat absorption and increases intestinal fat content, may therefore affect the secretion of glucagon-like peptide-1. In this study we examined the immediate effects of orlistat on postprandial serum glucose, insulin and glucagon-like peptide-1 levels prior to a change in body weight.. Randomized, clinical study.. Sixteen nondiabetic obese patients (body mass index 35.7 +/- 3.8 kg/m(2), range 32.5-43.1) were enrolled in this study. The patients were randomly assigned to either the group treated with orlistat (120 mg, single dose) or the control group. There were eight patients in each of the two groups. Orlistat was given before a standard 600-kcal mixed meal containing 60% carbohydrates, 25% lipids and 15% protein. Blood samples were collected at baseline and at 30-min intervals for 180 min after the test meal. Graphical tendencies, peak value, time to reach the peak value, and area under the curve in the two groups were compared.. Blood samples were obtained for the measurement of GLP-1, glucose, insulin, high density lipoprotein, total cholesterol and triglycerides.. We found no difference in sex distribution, mean age, anthropometric measurements, or baseline glucose, insulin and glucagon-like peptide-1 levels between the orlistat and placebo groups. The peak insulin and glucagon-like peptide-1 levels were determined at 60 min in the control group. Hourly changes in serum glucose and insulin levels were similar between the groups, although the peak insulin and glucagon-like peptide-1 levels were reached at 120 min in the orlistat group. There were no statistically significant differences between the groups.. A single dose of 120-mg orlistat caused no change in postprandial serum glucose, insulin or glucagon-like peptide-1 levels in nondiabetic obese patients. Although glucagon-like peptide-1 increases were delayed in the orlistat group, these changes were nonsignificant.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Lactones; Male; Middle Aged; Obesity; Orlistat

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

Topics: Animals; Behavior, Animal; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Synergism; Eating; Energy Intake; Feeding Behavior; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Immunohistochemistry; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Peptide Fragments; Peptide YY; Rats

Orlistat leads to improved glycemic control in obese type 2 diabetic patients, which is attributed to decreased insulin resistance associated with weight loss. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are gut hormones that are secreted in response to food intake, and they both stimulate insulin secretion. Orlistat decreases fat absorption and increases intestinal fat content, which may lead to increased secretion of these peptides. In this pilot study, we tested the hypothesis that increased levels of these intestinal hormones may be involved in the improvement of postprandial hyperglycemia observed previously with orlistat in type 2 diabetic patients.. A total of 29 type 2 diabetic patients, who were not taking insulin or alpha-glucosidase inhibitors, were enrolled in the study. On a crossover and single-blind design, after an overnight fasting, the patients received 120-mg orlistat or placebo capsules, followed by a standard 600-kcal mixed meal that contained 38% fat. At baseline and 60 min after the meal, blood samples were obtained for the measurement of GLP-1, GIP, insulin, C-peptide, triglycerides, free fatty acids, and glucose.. All measured parameters increased significantly in response to the mixed meal compared with baseline, both with orlistat or placebo. When compared with the placebo, the orlistat administration resulted in a significantly enhanced postprandial increase in GLP-1 and C-peptide levels and attenuated the postprandial rise in glucose and triglycerides.. The results of this study suggest that apart from decreasing insulin resistance as a result of weight loss, orlistat may increase postprandial GLP-1 levels, thereby enhancing the insulin secretory response to the meal and blunting the postprandial rise in glucose in type 2 diabetic patients. Increased GLP-1 levels, which lead to decreased food intake, may also contribute to the weight loss that is associated with the use of this drug.

Topics: Adult; Aged; Anti-Obesity Agents; Cross-Over Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Lactones; Male; Middle Aged; Obesity; Orlistat; Peptide Fragments; Protein Precursors; Single-Blind Method; Weight Loss

Postprandial lipemia is important in the development of coronary artery disease because of elevated postprandial triacylglycerol-rich plasma lipoproteins and suppressed HDL-cholesterol concentrations. We showed in healthy subjects a possible association between postprandial lipid metabolism and the responses of the duodenal incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide after meals rich in saturated and monounsaturated fatty acids (oleic acid), respectively.. The objective was to compare the postprandial responses (8 h) of glucose, insulin, fatty acids, triacylglycerol, gastric inhibitory polypeptide, and GLP-1 to saturated- and monounsaturated-rich test meals.. Twelve overweight patients with type 2 diabetes ingested 3 meals randomly: an energy-free soup with 50 g carbohydrate (control meal), the control meal plus 100 g butter, and the control meal plus 80 g olive oil. Triacylglycerol responses were measured in total plasma and in a chylomicron-rich and a chylomicron-poor fraction.. No significant differences in the glucose, insulin, or fatty acid responses to the 2 fat-rich meals were seen. The plasma triacylglycerol and chylomicron triacylglycerol responses were highest after the butter meal. HDL-cholesterol concentrations decreased significantly after the butter meal but did not change significantly after the olive oil meal. GLP-1 responses were highest after the olive oil meal.. Olive oil induced lower triacylglycerol concentrations and higher HDL-cholesterol concentrations than did butter, without eliciting significant changes in glucose, insulin, or fatty acids. Furthermore, olive oil induced higher concentrations of GLP-1, which may indicate a relation between fatty acid composition, incretin responses, and triacylglycerol metabolism postprandially in patients with type 2 diabetes.

Topics: Area Under Curve; Blood Glucose; Butter; Cholesterol, HDL; Chylomicrons; Coronary Artery Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Acids; Fatty Acids, Monounsaturated; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Obesity; Olive Oil; Peptide Fragments; Plant Oils; Postprandial Period; Protein Precursors; Triglycerides

Glucagon-like peptide 1 (GLP-1) is a proglucagon derivative secreted primarily from the L-cells of the small intestinal mucosa in response to the ingestion of meals. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. It has previously been shown that intravenous or subcutaneous administration of GLP-1 concomitant with intravenous glucose results in hypoglycemia in healthy subjects. Because GLP-1 is also effective in type 2 diabetic patients and is currently being evaluated as a therapeutic agent, it is important to investigate whether GLP-1 may cause hypoglycemia in such patients. We have previously shown that GLP-1 does not cause hypoglycemia in obese type 2 diabetic patients with insulin resistance amounting to 5.4 +/- 1.1 according to homeostasis model assessment (HOMA). In this study, we investigated diabetic patients with normal or close to normal insulin sensitivity.. Eight lean type 2 diabetic patients (group 1) aged 60 years (range 50-72) with BMI 23.1 kg/m(2) (20.3-25.5) and HbA(1c) 8.0% (6.9-11.4) and eight patients with type 2 diabetes secondary to chronic pancreatitis (group 2) aged 52 years (41-62) with BMI 21.9 kg/m(2) (17.6-27.3) and HbA(1c) 7.8% (6.2-12.4) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body wt. Then, 15 min later, at the time of peak GLP-1 concentration, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus. HOMA (mean +/- SEM) showed insulin resistance amounting to 1.9 +/- 0.3 and 1.7 +/- 0.5 in the two groups, respectively.. In both groups, PG decreased rapidly and stabilized at 7.5 mmol/l (range 3.9-10.1) and 7.2 mmol/l (3.1-10.9) in groups 1 and 2, respectively, after 90 min. Neither symptoms of hypoglycemia nor biochemical hypoglycemia were observed in any patient.. We conclude that a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycemia in insulin-sensitive type 2 diabetic patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Kinetics; Middle Aged; Pancreatitis; Peptide Fragments; Protein Precursors

Previous studies reported that administration of first generation alpha-glucosidase inhibitors (AGIs), such as voglibose or acarbose, produced exaggerated and sustained postprandial responses of glucagon-like peptide-1 (GLP-1), an incretin hormone from the enteroinsular axis, in healthy humans. Little is known about the postprandial release of GLP-1 after AGI therapy in diabetics. GLP-1 plays a role to mediate satiety. Any agent that substantially elevates GLP-1 levels may theoretically reduce hunger, increase satiation and limit food intake.. This study was performed to analyse the effect of miglitol, a more potent second generation AGI with fewer gastrointestinal side-effects, on the regulation of meal-related GLP-1 secretion and on the change of insulin-glucose dynamics as well as the release of gastric inhibitory polypeptide (GIP), another incretin hormone, after stimulation by an ordinary meal in obese type-2-diabetic subjects. Miglitol's subsequent influences on appetite sensations and food intake were also measured.. In total, 8 obese type-2-diabetic women were randomized to receive treatment with 100 mg of miglitol or placebo three times a day for 2 days (six doses total) in a double-blind fashion. On day 3 of each treatment period (miglitol or placebo), measurements of GLP-1, GIP, insulin and glucose were taken periodically during 3 h after eating a 720 kcal breakfast. Appetite ratings with visual analogue scales (VASs) were used to assess ingestive behaviour hourly just before breakfast and hourly after for 6 h until immediately before lunch. The number of tuna sandwiches eaten at lunch was used to measure food consumption.. The plasma GLP-1, glucose, insulin and GIP levels in response to the mixed meal were compared after the miglitol and placebo treatment. Miglitol effectively enhanced postprandial GLP-1 release and suppressed plasma GIP secretion. The ingestion of a mixed meal induced a remarkable rise in GLP-1 after miglitol as compared with placebo in overweight diabetic subjects. The meal-related rise in GLP-1 after miglitol was significantly greater at all time-points between 30 and 180 min than after the placebo. The postprandial incremental area under the curve for GLP-1 with miglitol treatment was about twofold that with the placebo. The GLP-1 level reached a maximum at 120 min after the mixed meal and steadily rose throughout the rest of the 3-h study period. In the miglitol-treated condition, the average caloric intake at lunch during a 30-min eating period was 12% lower (p < 0.05) as compared with that after the placebo in six out of the eight subjects who exhibited a GLP-1 rise after the breakfast meal by greater than 30% from the placebo-treated condition. Correspondingly, the average rating scores were significantly lower for hunger feelings and markedly greater for sensations of satiety under the miglitol treatment; beginning 2 and 3 h, respectively, before the lunch test.. Miglitol induced an enhanced and prolonged GLP-1 release at high physiological concentrations after ingesting an ordinary meal in glycaemic-controlled diabetics. The excessive postprandial GLP-1 elevation after miglitol therapy modified feeding behaviour and food intake, and thereby has potential value in regulating appetite and stabilizing body weight in obese type-2-diabetic patients.

Topics: 1-Deoxynojirimycin; Adult; Aged; Appetite; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucosamine; Humans; Hypoglycemic Agents; Imino Pyranoses; Middle Aged; Obesity; Peptide Fragments; Postprandial Period; Protein Precursors

An important cause of elevated glucose levels in elderly patients with diabetes is an alteration in non-insulin-mediated glucose uptake (NIMGU). Glucagon-like peptide 1 (GLP-1) is an intestinal insulinotropic hormone. It has been proposed that this hormone also lowers glucose levels by enhancing NIMGU. This study was conducted to determine whether GLP-1 augments NIMGU in elderly patients with diabetes, a group in which NIMGU is known to be impaired. Studies were conducted on 10 elderly patients with type 2 diabetes (aged 75 +/- 2 years, BMI 27 +/- 1 kg/m(2)) who underwent paired 240-min glucose clamp studies. In each study, octreotide was infused to suppress endogenous insulin release, and tritiated glucose methodology was used to measure glucose production and disposal rates. For the first 180 min, no glucose was infused. From 180 to 240 min, glucose was increased to 11 mmol/l using the glucose clamp protocol. In the GLP-1 study, GLP-1 was infused from 30 to 240 min. In a subsequent control study, insulin was infused using the glucose clamp protocol from 30 to 240 min to match the insulin levels that occurred during the GLP-1 infusion study. During hyperglycemia, GLP-1 enhanced glucose disposal (control study: 2.52 +/- 0.19 mg x kg(-1) x min(-1); GLP-1 study: 2.90 +/- 0.17 mg x kg(-1) x min(-1); P < 0.0001). Hepatic glucose output was not different between studies. We conclude that GLP-1 may partially reverse the defect in NIMGU that occurs in elderly patients with diabetes.

Topics: Administration, Oral; Aged; Analysis of Variance; Blood Glucose; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Patient Selection; Peptide Fragments; Peptides

Diabetes mellitus secondary to chronic pancreatitis is characterized by a progressive destruction of the pancreas, including loss of the islet cells, leading to a form of diabetes that can mimic both type 1 and type 2 diabetes. Glucagon-like peptide 1(7-36)amide (GLP-1), an intestinally derived insulinotropic hormone, represents a potential therapeutic agent for type 2 diabetes, because exogenous GLP-1 has been shown to increase the insulin and reduce the glucagon concentrations in these patients, and thus induce lower blood glucose, but without causing hypoglycemia. Ten patients with diabetes mellitus secondary to chronic pancreatitis and five normal subjects were studied. Nine patients were treated with insulin and one patient with sulfonylurea. In the fasting state, saline or GLP-1 in doses of 0.4 or 1.2 pmol/min/kg body weight were infused intravenously for 4 hours. Blood glucose was reduced in all patients with both doses of GLP-1; plasma C-peptide increased (p<0.02), and plasma glucagon decreased (p<0.02) compared with basal levels, also in three patients with normoglycemia and high levels of presumably exogenous insulin. Similar results were obtained in the normal subjects. In conclusion, GLP-1 treatment may be considered in patients with diabetes mellitus secondary to chronic pancreatitis, provided that a certain amount of alpha- and beta-cell secretory capacity is still present.

Topics: Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Middle Aged; Pancreatitis; Peptide Fragments

Natural products have contributed immensely towards the treatment of various diseases including diabetes. Here, a database of small molecules from nature possessing antidiabetic properties was analysed and shortlisted according to their structural diversity. Later, those structures were screened by

Topics: Computational Biology; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Receptors, Glucagon

Glucagon-like peptide-1 (GLP-1) can improve cardiac function and cardiovascular outcomes in diabetic cardiomyopathy; however, the beneficial effect of GLP-1 on human diabetic cardiomyocytes (DCMs) and its mechanism have not been fully elucidated. Here, the DCMs model by human-induced pluripotent stem cells-derived cardiomyocytes is developed. Two subtypes of GLP-1, GLP-1

Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Glucagon-Like Peptide 1; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac

Public safety (prevention of accidents) is the primary objective in assessing fitness to drive a motor vehicle. However, general access to mobility should not be restricted if there is no particular risk to public safety. For people with diabetes mellitus, the Führerscheingesetz (Driving Licence Legislation) and the Führerscheingesetz-Gesundheitsverordnung (Driving Licence Legislation Health enactment) regulate important aspects of driving safety in connection with acute and chronic complications of the disease. Critical complications that may be relevant to road safety include severe hypoglycemia, pronounced hyperglycemia and hypoglycemia perception disorder as well as severe retinopathy and neuropathy, endstage renal disease and certain cardiovascular manifestations. If there is a suspicion of the presence of one of these complications, a detailed evaluation is required.In addition, the individual antihyperglycemic medication should be checked for existing potential for hypoglycemia. Sulfonylureas, glinides and insulin belong to this group and are therefore associated with the requirement of a 5-year limitation of the driver's license. Other antihyperglycemic drugs without potential for hypoglycemia such as Metformin, SGLT‑2 inhibitors (Sodium-dependent-glucose-transporter‑2 inhibitors, gliflozins), DPP-4-inhibitors (Dipeptidyl-Peptidase inhibitors, gliptins), and GLP‑1 analogues (GLP‑1 rezeptor agonists) are not associated with such a time limitation.The relevant laws which regulate driving safety give room for interpretation, so that specific topics on driving safety for people with diabetes mellitus are elaborated from a medical and traffic-relevant point of view. This position paper is intended to support people involved in this challenging matter.. Bei der Beurteilung der gesundheitlichen Eignung zum Lenken eines Kraftfahrzeuges ist die öffentliche Sicherheit (Unfallprävention) das vorrangige Ziel. Der generelle Zugang zu Mobilität sollte jedoch nicht eingeschränkt werden, wenn kein besonderes Risiko für die öffentliche Sicherheit besteht. Für Menschen mit Diabetes mellitus sind im Führerscheingesetz (FSG) und in der Führerscheingesetz-Gesundheitsversorgung (FSG-GV) wichtige Aspekte zur Fahrsicherheit in Zusammenhang mit akuten und chronischen Komplikationen der Erkrankung geregelt. Zu den kritischen Komplikationen, die für die Verkehrssicherheit relevant sind, gehören schwere Hypoglykämie, ausgeprägte Hyperglykämie und Hypoglykämiewahrnehmungsstörung, sowie schwere Retinopathie und Neuropathie, weiters fortgeschrittene Nierenerkrankung und bestimmte kardiovaskuläre Manifestationen. Bei Verdacht auf Präsenz einer dieser Akutkomplikationen oder Folgeschäden ist eine genaue Evaluierung erforderlich.Darüber hinaus ist die individuelle antihyperglykämische Medikation auf vorhandenes Potenzial für Hypoglykämien zu überprüfen. Sulfonylharnstoffe, Glinide und Insulin gehören in diese Gruppe und sind daher automatisch mit der Auflage einer 5‑jährigen Befristung des Führerscheines assoziiert. Metformin, DPP-4-Hemmer (Dipeptidyl-Peptidase-4-Hemmer, Gliptine), SGLT2-Hemmer (Sodium-dependent-glucose-transporter‑2 inhibitors, Gliflozine), Glitazone und die zu injizierenden GLP-1 Analoga (GLP‑1 Rezeptor Agonisten) weisen kein Hypoglykämiepotential auf und sind daher nicht mit einer Befristung verbunden.Die FSG-GV gibt Spielraum für Interpretation, sodass im Folgenden spezifische Themen zur Fahrsicherheit für Menschen mit Diabetes mellitus aus fachärztlicher und verkehrsrelevanter Sicht aufgearbeitet wurden. Dieses Positionspapier dient zur Unterstützung von Personen, die mit dieser herausfordernden Materie befasst sind.

Topics: Accidents, Traffic; Austria; Automobile Driving; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents

Diabetes mellitus (DM) is one of the most common diseases worldwide. DM may disrupt hormone regulation. Metabolic hormones, leptin, ghrelin, glucagon, and glucagon-like peptide 1, are produced by the salivary glands and taste cells. These salivary hormones are expressed at different levels in diabetic patients compared to control group and may cause differences in the perception of sweetness. This study is aimed at assessing the concentrations of salivary hormones leptin, ghrelin, glucagon, and GLP-1 and their correlations with sweet taste perception (including thresholds and preferences) in patients with DM. A total of 155 participants were divided into three groups: controlled DM, uncontrolled DM, and control groups. Saliva samples were collected to determine salivary hormone concentrations by ELISA kits. Varying sucrose concentrations (0.015, 0.03, 0.06, 0.12, 0.25, 0.5, and 1 mol/l) were used to assess sweetness thresholds and preferences. Results showed a significant increase in salivary leptin concentrations in the controlled DM and uncontrolled DM compared to the control group. In contrast, salivary ghrelin and GLP-1 concentrations were significantly lower in the uncontrolled DM group than in the control group. In general, HbA1c was positively correlated with salivary leptin concentrations and negatively correlated with salivary ghrelin concentrations. Additionally, in both the controlled and uncontrolled DM groups, salivary leptin was negatively correlated with the perception of sweetness. Salivary glucagon concentrations were negatively correlated with sweet taste preferences in both controlled and uncontrolled DM. In conclusion, the salivary hormones leptin, ghrelin, and GLP-1 are produced either higher or lower in patients with diabetes compared to the control group. In addition, salivary leptin and glucagon are inversely associated with sweet taste preference in diabetic patients.

Topics: Diabetes Mellitus; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Leptin; Taste; Taste Perception; Transcription Factors

Peptides are sustainable alternatives to conventional therapeutics for G protein-coupled receptor (GPCR) linked disorders, promising biocompatible and tailorable next-generation therapeutics for metabolic disorders including type-2 diabetes, as agonists of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However, single agonist peptides activating GLP-1R to stimulate insulin secretion also suppress obesity-linked glucagon release. Hence, bioactive peptides cotargeting GCGR and GLP-1R may remediate the blood glucose and fatty acid metabolism imbalance, tackling both diabetes and obesity to supersede current monoagonist therapy. Here, we design and model optimized peptide sequences starting from peptide sequences derived from earlier phage-displayed library screening, identifying those with predicted molecular binding profiles for dual agonism of GCGR and GLP-1R. We derive design rules from extensive molecular dynamics simulations based on peptide-receptor binding. Our newly designed coagonist peptide exhibits improved predicted coupled binding affinity for GCGR and GLP-1R relative to endogenous ligands and could in the future be tested experimentally, which may provide superior glycemic and weight loss control.

Topics: Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Peptides; Receptors, Glucagon

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0-240 minutes) for total GLP-1 and GIP were compared between groups, using non-parametric statistical methods. Post-meal GLP-1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate-sensitive potassium channel-independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone.

Topics: Adult; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Infant, Newborn; Insulin

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Physicians

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Pakistan

G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.

Topics: Animals; Blood Glucose; Calcium; Cell Line; Cyclic AMP; Diabetes Mellitus; Enteroendocrine Cells; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; HEK293 Cells; HeLa Cells; Humans; Incretins; Insulin; Insulin Secretion; Intestinal Mucosa; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Obesity; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone

Single anastomosis duodeno-ileostomy with sleeve gastrectomy (SADI-S) is a powerful form of bariatric surgery; however, it has a high risk of malnutrition. Single anastomosis sleeve ileal (SASI) bypass with sleeve gastrectomy may be used as an alternative procedure to avoid malnutrition associated with SADI-S; however, no comparison between the two procedures has been performed.. Sprague-Dawley rats with diabetes (n = 32) were divided into four groups: SADI-S (n = 8), SASI (n = 8), SG (n = 8), and SHAM (n = 8). Body weight, food intake, and fasting blood glucose were measured, and the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed before and after surgery. Blood samples were collected before and after the surgery to assess the levels of glucagon-like peptide-1 (GLP-1), hemoglobin, albumin, vitamin B12, calcium, and iron.. The SADI-S and SASI groups showed significantly greater weight loss and better glucose control than the SG group postoperatively. The SADI-S and SASI groups showed similar improvements in glucose control throughout the study. The SADI-S and SASI groups had significantly higher GLP-1 levels than the SG group at 6 months. The SADI-S and SASI groups presented with various degrees of deficiencies, with the SADI-S group showing a higher risk for hypoalbuminemia and iron deficiency than the SASI group.. The SASI procedure may be a better alternative as it has excellent bariatric and metabolic results with lower risk for hypoalbuminemia and can be easily converted into either SADI-S or SG procedures. Nevertheless, further clinical results are needed.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; Diabetes Mellitus; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoalbuminemia; Malnutrition; Obesity, Morbid; Rats; Rats, Sprague-Dawley; Retrospective Studies; Rodentia

This study aimed to determine the change of gastrointestinal (GI) emptying time after ileal interposition (IT) and elucidate the role of altered GI peristalsis in diabetic control.. Twelve male Goto-Kakizaki rats were randomly divided into IT and sham groups. Body weight and food intake were recorded. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), plasma glucagon-like peptide-1 (GLP-1), and gastric emptying were measured at baseline and 4 and 8 weeks after operation. At 9 weeks postoperatively, the rats in the IT group were given atropine which can suppress the emptying of stomach and upper intestine, while sham rats were given metoclopramide (to expedite gastric emptying) for 1 week. At week 10 postoperatively, OGTT and GLP-1 were detected. The intestinal transit was tested at postoperative 12 weeks.. No differences were found between groups at baseline. After operation, the IT rats had lower body weight than sham rats. At 4 and 8 weeks postoperatively, the IT group showed better OGTT and ITT, with significantly elevated GLP-1 relative to sham. After administration of the GI motility drugs, however, the effect of diabetic control for the two groups became similar. The GI transit after IT was significantly slower than sham at all tested time points.. Although IT inhibits the GI transit time, the earlier interaction between undigested nutrients and interpositioned ileum promotes gut hormone secretion and thus reduces body weight and alleviates hyperglycemia. A decrease of GI transit of IT rats exacerbates the antidiabetic effects.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Gastric Emptying; Gastrointestinal Transit; Glucagon-Like Peptide 1; Ileum; Male; Rats

With the rapid development of IoT technology, it is a new trend to combine edge computing with smart medicine in order to better develop modern medicine, avoid the crisis of information "sibling," and meet the requirements of timeliness and computational performance of the massive data generated by edge devices. However, edge computing is somewhat open and prone to security risks, so the security and privacy protection of edge computing systems for smart healthcare is receiving increasing attention. The two groups were compared before and after treatment for blood glucose, blood lipids, blood pressure, renal function, serum advanced glycosylation end products (AGEs) and cyclic adenosine monophosphate (cAMP), serum oxidative stress indicators, and levels of cAMP/PKA signalling pathway-related proteins in peripheral blood mononuclear cells. The results of this study show that the reduction of AGEs, the improvement of oxidative stress, and the regulation of the cAMP/PKA signalling pathway may be associated with a protective effect against early DKD. By introducing the edge computing system and its architecture for smart healthcare, we describe the security risks encountered by smart healthcare in edge computing, introduce the solutions proposed by some scholars to address the security risks, and finally summarize the security protection framework and discuss the specific solutions for security and privacy protection under this framework, which will provide some help for the credible research of smart healthcare edge computing.

Topics: Delivery of Health Care; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Kidney; Leukocytes, Mononuclear

Ablation of glucagon receptor (GCGR) signalling is a potential treatment option for diabetes, whilst glucagon-like peptide-1 (GLP-1) receptor agonists are clinically approved for both obesity and diabetes. There is a suggestion that GCGR blockade enhances GLP-1 secretion and action, whilst GLP-1 receptor activation is known to inhibit glucagon release, implying potential for positive interactions between both therapeutic avenues. The present study has examined the ability of sustained GCGR antagonism, using desHis

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diet, High-Fat; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Insulin; Mice; Receptors, Glucagon

We study the efficacy of a glucagon-like peptide-1 (GLP-1) and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. GLP1-E2 provides superior protection from insulin-deficient diabetes induced by multiple low-dose streptozotocin (MLD-STZ-diabetes) and by the Akita mutation in mice than a GLP-1 monoagonist. GLP1-E2 does not protect from MLD-STZ-diabetes in estrogen receptor-α (ERα)-deficient mice and fails to prevent diabetes in Akita mice following GLP-1 receptor (GLP-1R) antagonism, demonstrating the requirement of GLP-1R and ERα for GLP1-E2 antidiabetic actions. In the MIN6 β cell model, GLP1-E2 activates estrogen action following clathrin-dependent, GLP-1R-mediated internalization and lysosomal acidification. In cultured human islet, proteomic bioinformatic analysis reveals that GLP1-E2 amplifies the antiapoptotic pathways activated by monoagonists. However, in cultured mouse islets, GLP1-E2 provides antiapoptotic protection similar to monoagonists. Thus, GLP1-E2 promotes GLP-1 and E2 antiapoptotic signals in cultured islets, but

Topics: Animals; Diabetes Mellitus; Estrogen Receptor alpha; Estrogens; Glucagon-Like Peptide 1; Insulin; Insulin, Regular, Human; Islets of Langerhans; Mice; Proteomics; Streptozocin

Cushing’s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM−) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin; Insulin Resistance; Meals; Pituitary ACTH Hypersecretion; Somatostatin

Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1)-based diabetes drugs. Semaglutide possesses a longer half-life. Utilizing relatively lower doses, we compared the beneficial metabolic effects of these 2 drugs in mice fed a high-fat diet (HFD), aiming to deepen our mechanistic understanding on their energy homeostatic functions.. Male C57BL/6J mice were fed an HFD for 10 weeks, followed by daily phosphate-buffered saline (PBS, as control); liraglutide (150 μg/kg body weight); or semaglutide (12 μg/kg body weight, low dose [LD]; or 60 μg/kg body weight, high dose [HD]) injection for 4 weeks. Metabolic tolerance and other tests were conducted within the 4-week period. Expression of metabolism-related genes, including Fgf21 in the liver and adipose tissues, was assessed after mice were euthanized.. HFD-induced body weight gain, increasing inguinal fat tissue mass, glucose defects and insulin intolerance were effectively and comparably attenuated in the 3 experimental groups. HD semaglutide showed an even better effect on attenuating hyperleptinemia. Liraglutide but not semaglutide treatment enhanced hepatic fibroblast growth factor 21 (FGF21) protein level. All 3 experimental groups showed elevated expression of genes that encode pyruvate dehydrogenase kinase 4 and enoyl-CoA hydratase and 3-hydroxyacyl-coenzyme A dehydrogenase, associated with reduced plasma triglyceride levels. Finally, the plasma "GLP-1" level in HD semaglutide-treated mice was 14-fold higher than in HFD-fed control mice.. Liraglutide, but not semaglutide, increased hepatic FGF21 protein level, whereas semaglutide had a greater effect on attenuating hyperleptinemia. Thus, these 2 GLP-1-based diabetes drugs may target metabolic organs, including liver and adipose tissue, with differing levels of efficacy.

Topics: Animals; Body Weight; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Mice; Mice, Inbred C57BL

Extra virgin olive oil (EVOO) improves post-prandial glycemia, but the underlying mechanism has not been fully elucidated. We tested the hypothesis that EVOO improves post-prandial glycemia by reducing gut permeability-derived low-grade endotoxemia.. Serum levels of lipopolysaccharides (LPS), zonulin, a marker of gut permeability, glucose, insulin and glucagon-like peptide 1 (GLP1) were measured in 20 patients with impaired fasting glucose (IFG) and 20 healthy subjects (HS) matched for sex and age. The same variables were measured in IFG patients (. Compared to HS, IFG had higher levels of LPS and zonulin. In HS, meal intake was associated with a significant increase of blood glucose, insulin, and GLP1 with no changes of blood LPS and zonulin. Two hours after a meal intake containing EVOO, IFG patients showed a less significant increase of blood glucose, a more marked increase of blood insulin and GLP1 and a significant reduction of LPS and zonulin compared to IFG patients not given EVOO. Correlation analysis showed that LPS directly correlated with blood glucose and zonulin and inversely with blood insulin. Similar findings were detected in IFG patients given a chocolate added or without EVOO.. Addition of EVOO to a Mediterranean diet or chocolate improves gut permeability and low-grade endotoxemia.

Topics: Blood Glucose; Diabetes Mellitus; Endotoxemia; Glucagon-Like Peptide 1; Humans; Insulin; Lipopolysaccharides; Olive Oil; Permeability; Prediabetic State

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

Topics: Animals; Diabetes Mellitus; Diet, High-Fat; Fatty Acids; Glucagon-Like Peptide 1; Insulin Resistance; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Rats

Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Fenofibrate; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Insulin; Liraglutide; Male; Metformin; Obesity; Ramipril; Rats; Rats, Sprague-Dawley; Rats, Zucker; Rosuvastatin Calcium; Somatostatin

Topics: Cardiovascular Diseases; Diabetes Mellitus; Expert Testimony; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Poland

Mitchell-Riley syndrome due to RFX6 gene mutations is characterized by neonatal diabetes and protracted diarrhea. The RFX6 gene encodes a transcription factor involved in enteroendocrine cell differentiation required for beta-cell maturation. In contrast to the pathway by which RFX6 mutations leads to diabetes, the mechanisms underlying protracted diarrhea are unknown.. To assess whether glucagon-like peptide-1 (GLP-1) was involved in the pathogenesis of Mitchell-Riley syndrome protracted diarrhea.. Two case report descriptions. in a tertiary pediatric hospital. "Off-label" treatment with liraglutide. We describe 2 children diagnosed with Mitchell-Riley syndrome, presenting neonatal diabetes and protracted diarrhea. Both patients had nearly undetectable GLP-1 plasma levels and absence of GLP-1 immunostaining in distal intestine and rectum. The main outcome was to evaluate whether GLP-1 analogue therapy could improve Mitchell-Riley syndrome protracted diarrhea.. "Off-label" liraglutide treatment, licensed for type 2 diabetes treatment in children, was started as rescue therapy for protracted intractable diarrhea resulting in rapid improvement during the course of 12 months.. Congenital GLP-1 deficiency was identified in patients with Mitchell-Riley syndrome. The favorable response to liraglutide further supports GLP-1 involvement in the pathogenesis of protracted diarrhea and its potential therapeutic use.

Topics: Child; Consanguinity; Diabetes Mellitus; Diarrhea; Fatal Outcome; Female; Gallbladder Diseases; Glucagon-Like Peptide 1; Hepatic Encephalopathy; Humans; Infant; Intestinal Atresia; Mutation, Missense; Portugal; Regulatory Factor X Transcription Factors

Beinaglutide has been approved for glucose lowering in type 2 diabetes mellitus (T2DM) in China. In addition to glycemic control, significant weight loss is observed from real world data. This study is designed to investigate the pharmacological and pharmacokinetic profiles of beinaglutide in different models.. The pharmacological efficacy of beinaglutide was evaluated in C57BL/6 and ob/ob mice after single administration. Pharmacokinetic profiles in mice were investigated after single or multiple administration. Sub-chronic pharmacological efficacy was investigated in ob/ob mice for two weeks treatment and diet-induced ob/ob mice model of nonalcoholic steatohepatitis (NASH) for four weeks treatment.. Beinaglutide could dose-dependently reduce the glucose levels and improve insulin secretion in glucose tolerance tests, inhibit food intake and gastric emptying after single administration. At higher doses, beinaglutide could inhibit food intake over 4 h, which results in weight loss in ob/ob mice after about two weeks treatment. No tachyphylaxis is observed for beinaglutide in food intake with repeated administration. In NASH model, beinaglutide could reduce liver weight and hepatic steatosis and improve insulin sensitivity. Signiant changes of gene levels were observed in fatty acid β-oxidation (Ppara, Acadl, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), Sirt1, and et al. SIGNIFICANCE: Our results characterize the pharmacological and pharmacokinetic profiles of beinaglutide in mice and supported that chronic use of beinaglutde could lead to weight loss and reduce hepatic steatosis, which suggest beinaglutide may be effective therapy for the treatment of obesity and NASH.

Topics: Animals; Antioxidants; Diabetes Complications; Diabetes Mellitus; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liraglutide; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; Peptide Fragments; PPAR alpha; Weight Loss

To elucidate the pathogenesis of postpancreatectomy diabetes mellitus (PPDM).. Forty-eight patients without diabetes undergoing either pancreatoduodenectomy (PD) (. During follow-up (median 3.19 years), 2 of 20 PD patients and 16 of 28 DP patients developed PPDM. Proteobacteria relative abundance, plasma glucagon-like peptide 1 (GLP-1), and fecal butyrate levels increased only after PD. Postsurgical butyrate levels were correlated with postsurgical GLP-1 levels. With no significant difference in the volume of the resected pancreas between the surgical procedures, both β-cell and α-cell areas in the resected pancreas were significantly higher in DP patients than in PD patients. In DP patients, the progressors to diabetes showed preexisting insulin resistance compared with nonprogressors, and both increased α- and β-cell areas were predictors of PPDM. Furthermore, in DP patients, α-cell and β-cell areas were associated with ALDH1A3 expression in islets.. We postulate that a greater removal of β-cells contributes to the development of PPDM after DP. Islet expansion along with preexisting insulin resistance is associated with high cellular plasticity, which may predict the development of PPDM after DP. In contrast, PD is associated with alterations of gut microbiome and increases in SCFA production and GLP-1 secretion, possibly protecting against PPDM development.

Topics: Cell Plasticity; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Insulin; Islets of Langerhans; Pancreatectomy

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; History, 20th Century; History, 21st Century; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans Transplantation

A glucagon knock-out mouse with preserved GLP-1 and GLP-2 secretion allows for the improved study of transplanted human islets and glucagon responses- providing an unprecedented resource in human α-cell and diabetes research.

Topics: Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Islets of Langerhans; Mice

To engineer and screen a novel GLP-1/anti-apolipoprotein B (apoB) bifunctional fusion protein with therapeutic potential on alleviating diabetes and diabetic complication in combination with low-intensity ultrasound.. Anti-apoB antibodies were screened by phage display technology and further fused to mutated GLP-1 (7-37) via light or heavy fusion to generate bifunctional fusion protein (termed aBG). The optimal design of aBG fusion protein was further confirmed by in vitro epitope competition assay and cAMP accumulation assay. Subsequently, chronic study in DIO mice were subjected to assess the long-term efficacy of screened fusion protein.. The selected GLP-1/anti-apoB fusion protein, aBG-8, exerted either the highest binding affinities for GLP-1R and apoB, or the greatest LDL-C uptake capacity and GLP-1R activation activity. After 60-day treatment in DIO mice, aBG-8 was proved to exert the promising improvement on hyperglycemia, hyperlipidemia, and obesity in DIO mice. Furthermore, combined therapy of aBG-8 and low-intensity ultrasound could accelerate skin wound closure in diabetic mice.. A novel long-lasting bifunctional fusion molecule, aBG-8, was designed with the enormous potential on alleviating diabetes and diabetic complications in combination with low-intensity ultrasound.

Topics: Animals; Antibodies; Apolipoproteins B; CHO Cells; Cricetulus; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Hep G2 Cells; Humans; Male; Mice, Inbred C57BL; Recombinant Fusion Proteins; Ultrasonic Therapy

The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function

Topics: Amides; Animals; beta-Arrestins; Calcium; CHO Cells; Cricetulus; Diabetes Mellitus; Dipeptidyl Peptidase 4; Eating; G-Protein-Coupled Receptor Kinase 1; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Insulin; Islets of Langerhans; Mice; Obesity; Phosphorylation; Receptors, Glucagon; Renal Insufficiency, Chronic; Signal Transduction

Diabetes is a metabolic disorder described as insufficient secretion of insulin in the pancreas or the inability of the existing insulin to function properly. It poses a greater risk on human health as it is considered the base of several diseases. Thus, this study was designed to evaluate two novel strains of Lactobacillus in handling pancreas disorders. 50 BALB/c male mice were divided into five groups; (a) feeding on normal diet only as control group, (b) given 21% fructose in drinking water as diabetes group, (c) feeding on Lactobacillus rhamnosus strain Pro2 (MT505335.1) plus 21% fructose as LR group, (d) feeding on Lactobacillus plantarum strain Pro1 (MT505334.1) plus 21% fructose as LP group and (e) mixture of two strains plus 21% fructose as Mix group. The serum content of glucose, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) was determined. Pancreases histopathology was examined. Expression of GH, IGF1, and GLP-1 genes was measured in the liver and pancreas by RT-qPCR. Serum content of glucose, ALT, and AST significantly increased in diabetes group, and significantly reduced in (LP) and (Mix) groups compared with control. Pathological changes occurred in the exocrine and endocrine components of the diabetes group pancreas. Besides, islet cells are almost entirely disturbed and acinar cells degenerated. However, in (LP) and (Mix) groups, the pathological changes significantly decreased and became related to the control group. Expression of GH, IGF1, and GLP-1 genes was significantly downregulated in the liver and pancreas of mice given fructose compared with control. Expression of these genes was either significantly upregulated in groups (LP and Mix) or identical to the control group. This study shows that the strain Pro1 (MT505334.1) or a combination of two strains is useful in reducing diabetic risk.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Diabetes Mellitus; Diet, Carbohydrate Loading; Fructose; Gene Expression; Glucagon-Like Peptide 1; Growth Hormone; Insulin-Like Growth Factor I; Lacticaseibacillus rhamnosus; Lactobacillus plantarum; Liver; Male; Mice; Mice, Inbred BALB C; Pancreas; Probiotics; Protective Agents; Treatment Outcome

Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology.. We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues.. GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070).. These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM patients.

Topics: Breast Neoplasms; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

It has been reported that hepatitis B virus (HBV) infection has an impact on intestinal microbiota imbalance to induce diabetes mellitus (DM), but the underlying mechanisms still remain to be explored. The present study aimed to investigate the regulatory role of microRNA‑192 (miR‑192‑5p) and glucagon‑like peptide‑1 (GLP‑1) in intestinal microbiota imbalance by recruiting patients with DM infected with HBV. In the present study, patients with HBV infection and different levels of alanine transaminase (ALT) were recruited and divided into three groups. Intestinal microbiota analysis was performed to evaluate the fecal bacterial composition of patients in various groups. Quantitative PCR was performed to explore the differential expression of miR‑192‑5p and GLP‑1 in the feces, peripheral blood and intestinal mucosal tissue samples of each patient. Immunohistochemistry was used to assess the expression of GLP‑1 protein in the intestinal mucosal tissue samples. Luciferase assays were performed by cell transfection of miR‑192‑5p mimics/precursors/inhibitors to study the inhibitory effect of miR‑192‑5p on GLP‑1 expression. Intestinal microbiota imbalance was observed in hepatitis B surface antigen (HBsAg)‑positive patients with high ALT. The expression of miR‑192‑5p was significantly elevated in the feces, peripheral blood and intestinal mucosal tissue samples of HBsAg‑positive patients with high ALT along with decreased GLP‑1 mRNA and protein expression. Luciferase activity of GLP‑1 vector was inhibited by miR‑192‑5p mimics and promoted by miR‑192‑5p inhibitors. Transfection of miR‑192‑5p precursors resulted in upregulation of miR‑192‑5p and downregulation of GLP‑1, while miR‑192‑5p inhibitors remarkably suppressed the expression of miR‑192‑5p and notably induced the expression of GLP‑1. These results showed a regulatory network involving HBV infection, intestinal microbiota imbalance, and miR‑192‑5p and GLP‑1 expression.

Topics: Adult; Alanine Transaminase; Cell Line, Tumor; Diabetes Mellitus; Feces; Female; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Intestinal Mucosa; Male; MicroRNAs; Middle Aged

Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on β cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on β cell function in vivo by imaging Ca

Topics: Animals; Bariatric Surgery; Blood Glucose; Calcium; Diabetes Mellitus; Female; Gastrectomy; Glucagon-Like Peptide 1; Humans; Insulin; Insulin-Secreting Cells; Intravital Microscopy; Male; Mice; Mice, Inbred C57BL; Stomach

The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting.. Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses.. Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found.. Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.

Topics: Aged; Blood Glucose; Case-Control Studies; Cognition; Cross-Sectional Studies; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycation End Products, Advanced; Humans; Insulin; Insulin Resistance; Male; Mental Status and Dementia Tests; Optical Imaging; Sweden

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Liraglutide

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose Transporter Type 2; Humans; Insulin Resistance; Mice; Mitochondria; Renal Insufficiency; Shift Work Schedule

Immunosuppressive drugs used in transplantation patients, may contribute to the development of post-transplant diabetes mellitus through their possible adverse effects on incretins. We aimed to compare the effects of different immunosuppressive drugs used in renal transplantation patients on glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels.. Forty five subjects were enrolled in the study (cyclosporine-treated 15 and tacrolimus-treated renal transplant patients 15, and healthy volunteers as a control group 15). Oral glucose tolerance test with 75 gr glucose was performed. GLP-1 and GIP levels were measured at 0 (baseline), 30, 60, 90, 120 min using ELISA method.. A statistically significant level of difference was detected in GLP-1 levels at the baseline, 30th and 120th minutes among all three groups (p < 0,001, p = 0,026 and p = 0,022, respectively). Baseline GLP-1 levels in cyclosporine-treated renal transplant patients were higher than in both tacrolimus-treated renal transplant patients (p = 0,016) and control groups (p < 0,001). GLP-1 levels at the 30th minute were higher in tacrolimus-treated renal transplant patients when compared to the cyclosporine-treated renal transplant patients (p = 0,024). GLP-1 levels at the 120th minute were higher in tacrolimus-treated renal transplant patients than the control group (p = 0,024). The areas under the curve of GLP-1 was higher in tacrolimus-treated renal transplant patients when compared to the control group (p = 0,018). GIP levels at 120th was lower in cyclosporine-treated renal transplant patients when compared to control group (p = 0,003).. These findings showed a temporally affected incretin hormones in renal transplant patients, a preserved GLP-1 response to an oral glucose load in renal transplant patients on cyclosporine and increased GLP -1 response to an oral glucose load in those on tacrolimus.

Topics: Adult; Blood Glucose; Case-Control Studies; Cyclosporine; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Incretins; Insulin; Kidney Transplantation; Tacrolimus

Topics: Betacoronavirus; Coronavirus Infections; COVID-19; Diabetes Mellitus; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2

Objectives Prader-Willi Syndrome (PWS) is characterised by hyperphagia often leading to obesity; a known risk factor for insulin resistance and type 2 (T2) diabetes. We present a prepubertal girl with PWS who developed diabetes. Case presentation Our case was diagnosed with PWS in infancy following investigation for profound central hypotonia and feeding difficulties. She commenced growth hormone (GH) aged 8 years for short stature and treatment improved linear growth. At age 12 years, she presented with polydipsia, polyuria and vulvovaginitis. She was overweight (BMI SDS +1.43). Diabetes was diagnosed (Blood glucose = 24.2 mmol/L, HbA1c = 121 mmol/mol or 13.2%). She was not acidotic and had negative blood ketones. Autoantibodies typical of type 1 diabetes were negative. She was initially treated with basal bolus insulin regime. GH was discontinued 3 months later due to concerns regarding GH-induced insulin resistance. Off GH, insulin requirements reduced to zero, allowing Metformin monotherapy. However off GH, she reported significant lethargy with static growth and increased weight. Combinations of Metformin with differing insulin regimes did not improve glucose levels. Liraglutide (GLP-1 agonist) and Metformin did not improve glucose levels nor her weight. Liraglutide and Empaglifozin (SGLT-2 inhibitor) therapy used in combination were well tolerated and demonstrated rapid normalisation of blood glucose and improvement in her HbA1c to within target (48 mmol/mol) which was sustained after 6 months of treatment. Conclusions Newer treatments for type 2 diabetes (e. g. GLP-1 agonists or SGLT-2 inhibitors) offer potential treatment options for those with diabetes and PWS when conventional treatments are ineffective.

Topics: Adolescent; Benzhydryl Compounds; Blood Glucose; Child; Diabetes Mellitus; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glucosides; Humans; Liraglutide; Prader-Willi Syndrome; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Endocannabinoids; Female; Glucagon; Glucagon-Like Peptide 1; Halogenated Diphenyl Ethers; Hormones; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Pregnancy; Prenatal Exposure Delayed Effects

Background and aims Advanced glycation end products (AGEs) and receptor of advanced glycation end products (RAGE), are associated with cognition decline. We aim to investigate the effect of liraglutide on cognitive function in diabetic mice. Results Diabetic mice showed decreased cognitive function. Moreover, lower glucagon like peptide-1 (GLP-1) levels in plasma were detected in db/db mice. Additionally, up-regulated RAGE and down-regulated glucagon like peptide-1 (GLP-1R) levels were observed in db/db mice. However, decreased GLP-1R and increased RAGE were reversed by liraglutide. We also found decreased cellular activity in cells with AGEs. Moreover, AGEs up-regulated RAGE in PC12 and HT22 cells. However, liraglutide improved the cell activity damaged by AGEs. Although we did not discover the direct-interaction between RAGE and GLP-1R, elevated RAGE levels induced by AGEs were restored by liraglutide. Conclusion We demonstrated that the cognitive function of diabetic mice was improved by liraglutide via the down-regulation of RAGE. Methods db/db mice and db/m mice were used in this study. Liraglutide was used to remedy diabetic mice. Neurons and RAGE in hippocampus were shown by immunofluorescence. And then, PC12 cells or HT22 cells with AGEs were treated with liraglutide. GLP-1R and RAGE were measured by western blotting.

Topics: Animals; Cell Survival; Cognition; Cognitive Dysfunction; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycation End Products, Advanced; Hippocampus; Hypoglycemic Agents; Liraglutide; Mice; Mice, Obese; Neurons; PC12 Cells; Rats; Receptor for Advanced Glycation End Products

To investigate the incretin axis in people with cystic fibrosis.. Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min.. Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

Topics: Adult; C-Peptide; Cystic Fibrosis; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Incretins; Infusions, Intravenous; Insulin; Male

Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD.. This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m. A greater GLP-1 response was associated with lower central systolic and diastolic BP of - 1.17 mmHg (95% confidence interval (CI) - 2.07 to - 0.27 mmHg, P = 0.011) and - 0.74 mmHg (95% CI - 1.29 to - 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of - 1.27 mmHg (95% CI - 2.20 to - 0.33 mmHg, P = 0.008) and - 1.00 (95% CI - 1.56 to - 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: - 4.94 (95% CI - 8.56 to - 1.31) mmHg, central diastolic BP: - 3.05 (95% CI - 5.29 to - 0.80) mmHg, brachial systolic BP: - 5.18 (95% CI - 8.94 to - 1.42) mmHg, and brachial diastolic BP: - 2.96 (95% CI - 5.26 to - 0.67) mmHg).. Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005.

Topics: Aged; Biomarkers; Blood Pressure; Brachial Artery; Cardiovascular Diseases; Cross-Sectional Studies; Denmark; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Male; Middle Aged; Pulse Wave Analysis; Risk Assessment; Risk Factors; Vascular Stiffness

Topics: Case-Control Studies; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Islets of Langerhans Transplantation; Pancreatectomy; Pancreatic Diseases; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Transplantation, Autologous; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Middle Aged; Obesity; Schizophrenia

Prolonged exposure to high levels of glucose and fatty acid (FFA) can induce tissue damage commonly referred to as glucolipotoxicity and is particularly harmful to pancreatic β-cells. Glucolipotoxicity-mediated β-cell failure is a critical causal factor in the late stages of diabetes, which suggests that mechanisms that prevent or reverse β-cell death may play a critical role in the treatment of the disease. Transcription factor PDX1 was recently reported to play a key role in maintaining β-cell function and survival, and glucolipotoxicity can activate mammalian sterile 20-like kinase 1 (Mst1), which, in turn, stimulates PDX1 degradation and causes dysfunction and apoptosis of β-cells. Interestingly, previous research has demonstrated that increased glucagon-like peptide-1 (GLP-1) signalling effectively protects β cells from glucolipotoxicity-induced apoptosis. Unfortunately, few studies have examined the related mechanism in detail, especially the role in Mst1 and PDX1 regulation. In the present study, we investigate the toxic effect of high glucose and FFA levels on rat pancreatic RINm5F β-cells and demonstrate that the GLP-1 analogue liraglutide restores the expression of PDX1 by inactivating Mst1, thus ameliorating β-cell impairments. In addition, liraglutide also upregulates mitophagy, which may help restore mitochondrial function and protect β-cells from oxidative stress damage. Our study suggests that liraglutide may serve as a potential agent for developing new therapies to reduce glucolipotoxicity.

Topics: Animals; Apoptosis; Cell Line; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Homeodomain Proteins; Insulin-Secreting Cells; Liraglutide; Mitochondria; Oxidative Stress; Protective Agents; Rats; Signal Transduction; Trans-Activators; Transcription Factors; Up-Regulation

It is controversial whether sodium glucose transporter (SGLT) 2 inhibitors increase glucagon secretion via direct inhibition of SGLT2 in pancreatic α cells. The role of SGLT1 in α cells is also unclear. We aimed to elucidate these points that are important not only for basic research but also for clinical insight.. Plasma glucagon levels were assessed in the high-fat, high-sucrose diet (HFHSD) fed C57BL/6J mice treated with dapagliflozin or canagliflozin. RT-PCR, RNA sequence, and immunohistochemistry were conducted to test the expression of SGLT1 and SGLT2 in α cells. We also used αTC1 cells and mouse islets to investigate the molecular mechanism by which SGLT1 modulates glucagon secretion.. Dapagliflozin, but not canagliflozin, increased plasma glucagon levels in HFHSD fed mice. SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in αTC1 cells, mouse islets and human islets. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. Canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in α cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. SGLT1 effect on glucagon secretion depended on glucose transport, but not glucose metabolism. Islets from HFHSD and db/db mice displayed higher SGLT1 mRNA levels and lower GLUT1 mRNA levels than the islets from control mice. These expression levels were associated with higher glucagon secretion. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets.. These data suggested that a novel mechanism regulated glucagon secretion through SGLT1 in α cells. This finding possibly explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice.

Topics: Animals; Benzhydryl Compounds; Blood Glucose; Canagliflozin; Diabetes Mellitus; Diet, High-Fat; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Glucosides; Glycosuria; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Fibroblast Activation Protein (FAP), an enzyme structurally related to dipeptidyl peptidase-4 (DPP-4), has garnered interest as a potential metabolic drug target due to its ability to cleave and inactivate FGF-21 as well as other peptide substrates. Here we investigated the metabolic importance of FAP for control of body weight and glucose homeostasis in regular chow-fed and high fat diet-fed mice.. FAP enzyme activity was transiently attenuated using a highly-specific inhibitor CPD60 and permanently ablated by genetic inactivation of the mouse Fap gene. We also assessed the FAP-dependence of CPD60 and talabostat (Val-boroPro), a chemical inhibitor reportedly targeting both FAP and dipeptidyl peptidase-4 RESULTS: CPD60 robustly inhibited plasma FAP activity with no effect on DPP-4 activity. Fap gene disruption was confirmed by assessment of genomic DNA, and loss of FAP enzyme activity in plasma and tissues. CPD60 did not improve lipid tolerance but modestly improved acute oral and intraperitoneal glucose tolerance in a FAP-dependent manner. Genetic inactivation of Fap did not improve glucose or lipid tolerance nor confer resistance to weight gain in male or female Fap. Although pharmacological FAP inhibition improves glucose tolerance, the absence of a metabolic phenotype in Fap

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endopeptidases; Female; Fibroblast Growth Factors; Gelatinases; Glucagon-Like Peptide 1; Glucose; Homeostasis; Insulin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Serine Endopeptidases; Weight Gain

Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. Despite substantial progress, the successful development of peptides as drugs still requires a number of limitations to be addressed, including short in vivo half-lives and poor membrane permeability. Here, we describe the use of oligourea foldamers as tool to improve the pharmaceutical properties of GLP-1, a 31 amino acid peptide hormone involved in metabolism and glycemic control. Our strategy consists in replacing four consecutive amino acids of GLP-1 by three consecutive ureido residues by capitalizing on the structural resemblance of oligourea and α-peptide helices. The efficacy of the approach is demonstrated with three GLP-1-oligourea hybrids showing prolonged activity in vivo. Our findings should enable the use of oligoureas in other peptides to improve their pharmaceutical properties and may provide new therapeutic applications.

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Kinetics; Male; Mice, Inbred C57BL; Models, Molecular; Molecular Sequence Data; Peptides

Growing evidence indicates links between type 2 diabetes and Parkinson's disease. The glucagon-like peptide 1 analogue, liraglutide, a commonly used anti-diabetic drug, has protective effects on neurons. The goal of this study was to determine whether long-term liraglutide treatment could reduce the risk of adult type 2 diabetic mice developing Parkinson's disease. Male diabetic db/db mice (12 weeks old) were injected daily with liraglutide (n = 8), or saline (n = 8), and non-diabetic m/m littermates (n = 6) were included as controls. Motor function was assessed every 4 weeks and all mice were sacrificed after 8 weeks of drug intervention for further analysis. The results revealed that long-term treatment of liraglutide protected the db/db mice against the motor function decay and the dopaminergic neuron loss. Liraglutide also restored the impaired AMP kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1a (PGC-1a) signaling in the striatum of db/db mice. Further experiments in SH-SY5Y cells supported that AMPK is involved in the neuroprotective effect of liraglutide. In summary, long-term liraglutide ameliorated motor dysfunction and dopaminergic neuron impairment in type 2 diabetic mice, probably via enhancing AMPK/PGC-1a signaling.

Topics: Adenylate Kinase; AMP-Activated Protein Kinases; Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucagon-Like Peptide 1; Hypoglycemic Agents; Liraglutide; Male; Mice; Mice, Inbred C57BL; Motor Disorders; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction

We here reported 2 novel

Topics: Animals; Area Under Curve; Blood Glucose; Cell Survival; Cisplatin; Cross-Linking Reagents; Diabetes Mellitus; Dipeptides; Drug Administration Schedule; Energy Metabolism; Gastric Emptying; Glucagon-Like Peptide 1; Half-Life; Insulin; Kaolin; Male; Mice; Mice, Inbred ICR; Mice, Inbred NOD; Molecular Structure; Obesity; Rats; Rats, Sprague-Dawley; Xenopus

Glucagon-like peptide-1 (GLP-1) is a potent therapeutic agent for the treatment of diabetes and has been proven to protect pancreatic β-cells from glucotoxicity; however, its mechanisms of action are not entirely understood. Autophagy is a dynamic lysosomal degradation process that can protect organisms against metabolic stress. Studies have shown that autophagy plays a protective role in the survival of pancreatic β-cells under high glucose conditions. In the present study, we explored the role of autophagy in GLP-1-induced protection of pancreatic β-cells exposed to high glucose. We demonstrated that the GLP-1 analogue liraglutide increased autophagy in rat INS-1 β-cells, and inhibition of autophagy abated the anti-apoptosis effect of liraglutide under high glucose conditions. Our results also showed that activation of 5'-AMP-activated protein kinase (AMPK) reduced liraglutide-induced autophagy enhancement and inhibited liraglutide-induced protection of INS-1 β-cells from high glucose. These data suggest that GLP-1 may protect β-cells from glucotoxicity through promoting autophagy by the modulation of AMPK. Deeper insight into the molecular mechanisms linking autophagy and GLP-1-induced β-cell protection may reveal novel therapeutic targets to preserve β-cell mass.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Cell Proliferation; Diabetes Mellitus; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose; Humans; Insulin-Secreting Cells; Liraglutide; Rats; Stress, Physiological

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Goals; Humans; Hypoglycemic Agents; Liraglutide; Peptides

The long-acting glucagon-like peptide-1 analogue liraglutide has proven efficiency in the management of type 2 diabetes and also has beneficial effects on cardiovascular diseases. Liraglutide's protracted action highly depends on its capacity to bind to albumin via its palmitic acid part. However, in diabetes, albumin can undergo glycation, resulting in impaired drug binding. Our objective in this study was to assess the impact of human serum albumin (HSA) glycation on liraglutide affinity. Using fluorine labeling of the drug and

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Glycosylation; Humans; Liraglutide; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Serum Albumin, Human

Topics: Anti-Inflammatory Agents; Cardiovascular Diseases; Diabetes Mellitus; Fibrinolytic Agents; Glucagon-Like Peptide 1; Humans; Hyperlipidemias; Inflammation; PCSK9 Inhibitors; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Thrombosis

Topics: Animals; Blood Glucose; Cell Movement; Diabetes Mellitus; Diabetic Nephropathies; Glucagon-Like Peptide 1; Kidney; Mice

The objective of this study was to identify the therapeutic effect and the underlying mechanism of glucagon-like peptide 1 (GLP-1) in the treatment of STZ-induced diabetes mellitus (DM).. Mice were treated with STZ to establish an animal model of DM, which was further treated with a GLP-1 receptor agonist. Subsequently, the status of glucose, insulin, nitric oxide, inflammatory and oxidative factors was evaluated and compared among Sham, STZ, and STZ + GLP-1 groups. In addition, the intestinal flora spectrum in each group was also evaluated.. In this study, it was found that the administration of STZ increased the level of glucose and glycosylated hemoglobin but reduced the level of insulin. It was also found that the levels of inflammation and oxidative stress in STZ-induced DM were both enhanced, as evidenced by a decreased level of catalase, superoxide dismutase, glutathione peroxidase, as well as increased levels of malonyldialdehyde, interleukin-1β (IL-1β), and IL-6. Meanwhile, the expression of nitric oxide, a factor associated with both oxidative stress and inflammation, was also suppressed in STZ-induced DM. More importantly, the imbalance of intestinal flora was observed in STZ-induced DM, as shown by a decreased level of both total bacteria and that of some strains including Clostridium, Bacteroides, Lactobacilli, and Bifidobacteria.. In summary, the findings of this study confirmed the antihyperglycemic effect of GLP-1 and demonstrated that the therapeutic effect of GLP-1 in the treatment of STZ-induced DM was mediated, at least partially, by its ability to restore the balance of intestinal flora.

Topics: Animals; Antioxidants; Blood Glucose; Catalase; Diabetes Mellitus; Diabetes Mellitus, Experimental; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose; Humans; Inflammation; Insulin; Malondialdehyde; Mice; Nitric Oxide; Oxidative Stress; Rats

Preclinical Research & Development The purpose of the present study is to evaluate the neuroprotective effect of recombinant human glucagon-like peptide-1 (rhGLP-1) as well as to explore corresponding mechanisms in diabetic rats with cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion (MCAO). Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. The rats were pretreated with rhGLP-1 (20 μg/kg intraperitoneally, thrice a day) for 14 days. Thereafter, the rats were subjected to MCAO 90 min/reperfusion 24 hr. At 2 and 24 hr of reperfusion, the rats were assessed for neurological deficits and subsequently executed for the evaluation of cerebral infarct volume, oxidative stress parameters, and the expression of excitatory amino acid transporter 2 (EAAT2) and apoptotic markers. Results indicate that rhGLP-1 significantly ameliorated neurological deficits and reduced cerebral infarct volume in diabetic MCAO rats. In addition, oxidative stress parameters in ischemic penumbra were significantly alleviated in rhGLP-1-pretreated diabetic MCAO rats. rhGLP-1 significantly upregulated the ratio of Bcl-2/Bax and EAAT2 expression and downregulated cleaved caspase-3 expression in ischemic penumbra of diabetic MCAO rats. Our results suggest that rhGLP-1 could significantly ameliorate neurological deficits and reduce cerebral infarct volume in diabetic MCAO rats, which may be due to the inhibition of oxidative stress and apoptosis and the promotion of EAAT2 expression.

Topics: Animals; Apoptosis; Brain Ischemia; Diabetes Complications; Diabetes Mellitus; Excitatory Amino Acid Transporter 2; Glucagon-Like Peptide 1; Humans; Incretins; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Oxidative Stress; Rats; Recombinant Proteins; Reperfusion Injury

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (K

Topics: Animals; Blood Glucose; Cytokines; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glyburide; Inflammation; Insulin; Insulin Resistance; Leptin; Mice; Mice, Transgenic; Mutation; Potassium Channels, Inwardly Rectifying

BACKGROUND The aim of this study was to investigate the efficacy and clinical value of liraglutide for the treatment of patients with diabetes mellitus (DM) complicated by non-alcoholic fatty liver disease (NAFLD). MATERIAL AND METHODS Patients with DM complicated by NAFLD (n=835) were enrolled. Patients were divided into 2 groups: 424 patients were included in the liraglutide group and 411 patients were included in the conventional drug group. Venous blood was collected to test blood glucose levels, blood lipid levels, and liver function. After discharge, patients were followed up for between 6 months and 1 year and assigned a quality-of-life score. RESULTS The blood glucose levels of patients in both groups were improved after treatment (P<0.05). The blood lipid levels of patients in both groups improved after treatment (P<0.05). Various blood lipid parameters of patients in the liraglutide group were significantly better than in the conventional drug group (P<0.05). The liver function of patients in the conventional drug group was not significantly different before or after treatment (P>0.05), while in the liraglutide group it improved significantly after treatment (P<0.05). The average quality-of-life score at follow-up in the liraglutide group was 81.00±9.33 points, which was significantly higher than the 68.53±8.44 points in the conventional drug group (P<0.05). CONCLUSIONS Liraglutide for the treatment of DM complicated by NAFLD can effectively improve the blood glucose and lipid levels as well as liver function of patients.

Topics: Aged; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Liraglutide; Liver; Liver Function Tests; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome

With the increasingly dominant role of smartphones in our lives, mobile health care systems integrating advanced point-of-care technologies to manage chronic diseases are gaining attention. Using a multidisciplinary design principle coupling electrical engineering, software development, and synthetic biology, we have engineered a technological infrastructure enabling the smartphone-assisted semiautomatic treatment of diabetes in mice. A custom-designed home server SmartController was programmed to process wireless signals, enabling a smartphone to regulate hormone production by optically engineered cells implanted in diabetic mice via a far-red light (FRL)-responsive optogenetic interface. To develop this wireless controller network, we designed and implanted hydrogel capsules carrying both engineered cells and wirelessly powered FRL LEDs (light-emitting diodes). In vivo production of a short variant of human glucagon-like peptide 1 (shGLP-1) or mouse insulin by the engineered cells in the hydrogel could be remotely controlled by smartphone programs or a custom-engineered Bluetooth-active glucometer in a semiautomatic, glucose-dependent manner. By combining electronic device-generated digital signals with optogenetically engineered cells, this study provides a step toward translating cell-based therapies into the clinic.

Topics: Animals; Cell Engineering; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose; Humans; Mice; Smartphone

Topics: Brain; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Obesity; Precision Medicine

Now, the quantification of proinsulin/insulin contents within organisms tends to be evaluated only by enzyme-linked immunosorbent assay (ELISA), although assessing the adequacy of results by some quantification method is important. Remarkably, few scientific papers use detection by Western blotting (WB), another immunological assay, of proinsulin/insulin. We found two problems with quantification of insulin and proinsulin by general WB: the shape of an insulin band in gel electrophoresis is distorted, and the retention potency to a blotting membrane of the peptide hormones (mainly insulin) is low. We solved the first problem by optimizing the sodium dodecyl sulfate concentration in the sample buffer and the second problem by glutaraldehyde fixation following treatment with a blocking solution for a short time. The improvements were confirmed by quantification of proinsulin/insulin in standards, MIN6c4 cell lysates, and MIN6c4 culture supernatants. Furthermore, we showed that the modified WB is applicable to other diabetes-associated peptide hormones: insulin analogs, glucagon, GLP-1s, somatostatins, ghrelins, and pancreatic polypeptide. Our data showed that the modified WB can contribute to qualitative or quantitative analyses of diabetes-associated peptides by providing analytical information based on electrophoresis, although ELISA, which is an almost exclusive method in the quantification of peptide hormones, supplies only numerical data.

Topics: Blotting, Western; Cell Line; Diabetes Mellitus; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Pancreatic Polypeptide; Peptide Hormones; Proinsulin; Protein Precursors; Sodium Dodecyl Sulfate; Somatostatin

Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic β-cell function, but its effect against restenosis is unknown.. We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted β-galactosidase cDNA in the same vector (rAd-βGAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-βGAL delivery (NS + rAd-βGAL), (2) exenatide plus rAd-βGAL delivery (Exenatide + rAd-βGAL), and (3) normal saline plus rAd-GLP-1 delivery (NS + rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS + rAd-βGAL group showed the highest intima-media ratio (IMR; 3.73 ± 0.90), the exenatide + rAd-βGAL treatment was the next highest (2.80 ± 0.51), and NS + rAd-GLP-1 treatment showed the lowest IMR (1.58 ± 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS + rAd-GLP-1 than in the exenatide or rAd-βGAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS + rAd-GLP-1 group than in the other two groups (all P < 0.05).. Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes.

Topics: Adenoviridae; Animals; Apoptosis; Carotid Artery Injuries; Carotid Artery, External; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Stenosis; Diabetes Mellitus; Disease Models, Animal; Exenatide; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glucagon-Like Peptide 1; Human Umbilical Vein Endothelial Cells; Hypoglycemic Agents; Incretins; Male; Matrix Metalloproteinase 2; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Peptides; Rats, Inbred OLETF; Transcription Factor RelA; Transfection; Venoms

Aim to confirm whether the treatment of GLP-1 can modulated body weight, lipid metabolism, insulin content, pancreas oxidative stress, improved T-AOC, MDA levels related to FFA-Induced oxidative stress in C57BL/6 mice and INS-1 cells. In this study, GLP-1 makes the expression of AMPK, PPARα, CPT1A and SIRT1 increased, and the expression of SREBP1c, miR-33 and miR-370 decreased. Interestingly, the effects of GLP-1 were less dose dependent as GLP-1 regulated the FFA, which related to gene expression at much lower doses (3 μg/kg, 10 mM, mice and INS-1 respectively) and effects were relatively maintained at higher dose (30 μg/kg, 100 mM, mice and INS-1 respectively) as well. Subsequently, the analysis showed that inhibited expression of miR-33 and miR-370 upregulated the expression of CPT1A and SIRT1, reversely mimics. These results demonstrated for the first time that GLP-1 improve lipotoxic oxidative stress of pancreas by regulate expression of microRNAs.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Carnitine O-Palmitoyltransferase; Cell Line; Diabetes Mellitus; Dose-Response Relationship, Drug; Gene Expression Regulation; Glucagon-Like Peptide 1; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Oligonucleotides; Oxidative Stress; Pancreas; Rats; Sirtuin 1

Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically as therapeutic agents for the treatment of diabetes. To determine the rate of DPP-4 inhibition induced by these inhibitors, pharmacokinetic and pharmacodynamic parameters were used to theoretically examine the relationship between the rate of DPP-4 inhibition and clinical efficacy following the administration of four different DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in the level of glucagon-like peptide-1 (GLP-1) induced by their administration. On the basis of the relationship shown, changes in clinical efficacy in association with dose change were examined in order to discuss clinical dosage from the standpoint of proper usage. The results indicate that a high rate of DPP-4 inhibition is necessary for the onset of the effect of an administered the DPP-4 inhibitor and that the average value for the DPP-4 inhibition rate can be utilized as a common parameter of clinical efficacy. Furthermore, the efficacy profiles of the present DPP-4 inhibitors could be demonstrated on the basis of an increase in the GLP-1 level. It is considered that the present findings provide useful information for promoting the proper clinical use of DPP-4 inhibitors. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Adamantane; Algorithms; Area Under Curve; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Nitriles; Piperidines; Pyrrolidines; Treatment Outcome; Uracil; Vildagliptin

Biliopancreatic diversion (BPD) is a predominantly malabsorptive procedure. Glucagon-like peptide 2 (GLP-2) plays predominantly trophic effects on the gut. A significant increase in GLP-2 after BPD in rats was previously observed, but there are no studies investigating the effect of BPD in GLP-2 levels in humans.. The aim of this study is to evaluate the influence of BPD on the release of GLP-2.. This is a prospective cohort study that evaluated diabetic individuals with class I obesity which underwent BPD (Scopinaro operation) and were followed up for 12 months. Of 12 individuals, four did not comply with the proposed follow-up and were excluded from the analysis. GLP-2 levels were determined by means of an enzyme-linked immunosorbent assay (ELISA), and we collected serial lab samples through a standard meal tolerance test (MTT) in the immediate preoperative period and 12 months after surgery.. During standard MTT, we observed significant increases of GLP-2 levels from 15 to 60 min (respectively, at 15 min, 5.7 ± 3.4 versus 12.4 ± 4.3, p = 0.029; 30 min, 6 ± 3.5 versus 14.6 ± 3.9; p = 0.004; 45 min, 5.6 ± 4.1 versus 12.6 ± 5.2, p = 0.013; 60 min, 5.8 ± 2.9 versus 10.6 ± 5.6, p = 0.022); then it began to gradually decrease to levels close to the basal.. Our findings have confirmed that there is a significant increase in GLP-2 levels after BPD in humans. GLP-2 plays a number of roles which may be adaptive, compensatory, and beneficial in the context of BPD. The clinical implications of this finding remain to be completely understood.

Topics: Adult; Animals; Biliopancreatic Diversion; Diabetes Complications; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Male; Middle Aged; Obesity; Postprandial Period; Prospective Studies; Rats

Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4-5 on a scale of 1-9; n = 10), overweight (body condition score 6-8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4-wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined.

Topics: Animals; Cat Diseases; Cats; Diabetes Mellitus; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Insulin; Obesity; Overweight; Peptide YY; Postprandial Period

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins

Ghrelin was reported to enhance GLP-1 secretion after glucose load in mice.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Gastric Mucosa; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Intestinal Mucosa; Mice; Postprandial Period

Previous studies suggest that casein exerts various anti-diabetic effects. However, it is not known which casein proteins are bioactive, nor their effects on enteroendocrine cells. This study evaluated the effects of intact whole casein, intact individual proteins (alpha, beta and kappa casein) and hydrolysates on an enteroendocrine cell line. High content analysis accurately monitored changes in cell health and intracellular glucagon-like peptide-1 (GLP-1) content. Cheese ripening duration and GLP-1 secretory responses were also considered. Beta casein significantly stimulated enteroendocrine cell proliferation and all caseins were potent GLP-1 secretagogues (except kappa casein). Interestingly the GLP-1 secretory activity was almost always lost or significantly reduced upon hydrolysis with proteolytic enzymes. Only pepsin-derived beta casein hydrolysates had significantly increased potency compared with the intact protein, but this was diminished with prolonged hydrolysis. In conclusion casein proteins are not detrimental to enteroendocrine cells, and alpha and beta casein are particularly beneficial stimulating proliferation and GLP-1 secretion.

Topics: Caseins; Cell Line; Cell Proliferation; Chymotrypsin; Diabetes Mellitus; Enteroendocrine Cells; Glucagon-Like Peptide 1; Hydrolysis

The number of people living with HIV and AIDS (PLWHA) reached to almost 40 million, half of which are under antiretroviral treatment (ART). Although the introduction of this therapy significantly improved the life span and quality of PLWHA, metabolic complications of these people remains to be an important issue. These metabolic complications include hyperlipidemia, abnormal fat redistribution and diabetes mellitus, which are defined as lipodystrophy syndrome. Glucagon-like peptide-1 (GLP-1) is a neuropeptide secreted from intestinal L cells and recently developed GLP-1 receptor agonists (GLP-1RAs) stimulate insulin secretion, improve weight control and reduce cardiovascular outcomes. This class of drugs may be a valuable medication in the treatment of HIV-associated metabolic adverse effects and extend the life expectancy of patients infected with HIV.

Topics: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; HIV Infections; Humans; Hyperlipidemias; Hypoglycemic Agents; Life Expectancy; Lipodystrophy; Models, Theoretical; Subcutaneous Fat; Treatment Outcome

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Non-alcoholic Fatty Liver Disease; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Insulin

Bariatric surgery not only elicits weight loss but also rapidly resolves diabetes. However, the mechanisms remain unclear. The present study investigates how diabetes and liver steatosis are improved after duodenal-jejunal bypass (DJB) compared with a glucagon-like peptide-1 (GLP-1) analog and correlations between bile acids and GLP-1 secretion.. We initially determined the effects of bile acids on GLP-1 in vitro and then assigned 12 male 16-week-old Otsuka Long-Evans Tokushima Fatty rats to groups that underwent DJB, a sham operation, or were treated with the GLP-1 receptor agonist, liraglutide (n = 4 each). Blood glucose, insulin, GLP-1, serum bile acids, liver steatosis, and the number of GLP-1 positive cells (L cells) in the small intestine and colon were investigated in the three groups at eight weeks postoperatively.. Levels of GLP-1mRNA were upregulated and GLP-1 secretion increased in cells incubated with bile acids in vitro. Weight gain was suppressed more in the DJB than in the sham group in vivo. Diabetes was more improved and GLP-1 levels were significantly higher in the DJB than in the sham group. Serum bile acids were significantly increased, the number of L cells in the ileum was upregulated compared with the sham group, and liver steatosis was significantly improved in the DJB compared with the other two groups.. Duodenal-jejunal bypass might improve diabetes and liver steatosis by enhancing GLP-1 secretion through increasing serum bile acids and the proliferation of L cells in the ileum, compared with liraglutide.

Topics: Animals; Bariatric Surgery; Bile Acids and Salts; Cell Proliferation; Cells, Cultured; Diabetes Mellitus; Enteroendocrine Cells; Fatty Liver; Glucagon-Like Peptide 1; Ileum; Male; Mice; Rats, Long-Evans; RNA, Messenger; Up-Regulation

Patients with end-stage renal disease (ESRD) have increased fasting concentrations and disturbed postprandial responses of several glucoregulatory hormones. We aimed to evaluate the impact of high-flux haemodialysis (HD) and high-volume haemodiafiltration (HDF) on fasting and postprandial plasma levels of glucoregulatory pancreatic and gut peptide hormones in ESRD patients.. Ten non-diabetic HD-treated ESRD patients were included to undergo a 3-h standardized liquid mixed meal test 1 h into an HD and an HDF, respectively. On a third, optional, examination day, the meal test was performed without concurrent dialysis treatment. Concentrations of glucose, C-peptide, insulin, glucagon, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide were measured in plasma and dialysate.. Ten participants completed the meal test during HD, eight completed the meal test during HDF and four completed the optional meal test without dialysis. All plasma hormone concentrations declined significantly during the first fasting hour of dialysis with no differences between HD and HDF. Significant clearance of the investigated hormones was observed for both dialysis modalities with significantly higher clearance of insulin, C-peptide and GIP during HDF compared with HD. The fractional appearance of hormones entering the utilized dialysate was higher during HDF. Both dialysis modalities reduced postprandial plasma hormone concentrations in a similar manner.. Our findings show that HD and HDF, respectively, significantly remove glucoregulatory peptide hormones from plasma of non-diabetic ESRD patients; a phenomenon which may affect the glucose metabolism in dialysis-treated ESRD patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus; Dialysis Solutions; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Hemodiafiltration; Humans; Insulin; Kidney Failure, Chronic; Male; Middle Aged; Postprandial Period; Renal Dialysis; Young Adult

Glucagon-like peptide-1 (GLP-1) is an incretin that plays important physiological roles in glucose homeostasis. Produced from intestine upon food intake, it stimulates insulin secretion and keeps pancreatic β-cells healthy and proliferating. Because of these beneficial effects, it has attracted a great deal of attention in the past decade, and an entirely new line of diabetic therapeutics has emerged based on the peptide. In addition to the therapeutic applications, GLP-1 analogs have demonstrated a potential in molecular imaging of pancreatic β-cells; this may be useful in early detection of the disease and evaluation of therapeutic interventions, including islet transplantation. In this Perspective, we focus on GLP-1 analogs for their studies on improvement of biological activities, enhancement of metabolic stability, investigation of receptor interaction, and visualization of the pancreatic islets.

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Insulin-Secreting Cells; Molecular Imaging

Exenatide extended-release (ER) is a microencapsulated formulation of the glucagon-like peptide 1-receptor agonist exenatide. It has a protracted pharmacokinetic profile that allows a once-weekly injection with comparable efficacy to insulin with an improved safety profile in type II diabetic people. Here, we studied the pharmacology of exenatide ER in 6 healthy cats. A single subcutaneous injection of exenatide ER (0.13 mg/kg) was administered on day 0. Exenatide concentrations were measured for 12 wk. A hyperglycemic clamp (target = 225 mg/dL) was performed on days -7 (clamp I) and 21 (clamp II) with measurements of insulin and glucagon concentrations. Glucose tolerance was defined as the amount of glucose required to maintain hyperglycemia during the clamp. Continuous glucose monitoring was performed on weeks 0, 2, and 6 after injection. Plasma concentrations of exenatide peaked at 1 h and 4 wk after injection. Comparing clamp I with clamp II, fasting blood glucose decreased (mean ± standard deviation = -11 ± 8 mg/dL, P = 0.02), glucose tolerance improved (median [range] +33% [4%-138%], P = 0.04), insulin concentrations increased (+36.5% [-9.9% to 274.1%], P = 0.02), and glucagon concentrations decreased (-4.7% [0%-12.1%], P = 0.005). Compared with preinjection values on continuous glucose monitoring, glucose concentrations decreased and the frequency of readings <50 mg/dL increased at 2 and 6 wk after injection of exenatide ER. This did not correspond to clinical hypoglycemia. No other side effects were observed throughout the study. Exenatide ER was safe and effective in improving glucose tolerance 3 wk after a single injection. Further evaluation is needed to determine its safety, efficacy, and duration of action in diabetic cats.

Topics: Animals; Blood Glucose; Cat Diseases; Cats; Diabetes Mellitus; Drug Synergism; Exenatide; Fasting; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Clamp Technique; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Microspheres; Peptides; Venoms

The inactive full-length form of GLP-1(1-37) stimulates conversion of both rat and human intestinal epithelial cells into insulin-secreting cells. We investigated whether oral administration of human commensal bacteria engineered to secrete GLP-1(1-37) could ameliorate hyperglycemia in a rat model of diabetes by reprogramming intestinal cells into glucose-responsive insulin-secreting cells. Diabetic rats were fed daily with human lactobacilli engineered to secrete GLP-1(1-37). Diabetic rats fed GLP-1-secreting bacteria showed significant increases in insulin levels and, additionally, were significantly more glucose tolerant than those fed the parent bacterial strain. These rats developed insulin-producing cells within the upper intestine in numbers sufficient to replace ∼25-33% of the insulin capacity of nondiabetic healthy rats. Intestinal tissues in rats with reprogrammed cells expressed MafA, PDX-1, and FoxA2. HNF-6 expression was observed only in crypt epithelia expressing insulin and not in epithelia located higher on the villous axis. Staining for other cell markers in rats treated with GLP-1(1-37)-secreting bacteria suggested that normal function was not inhibited by the close physical proximity of reprogrammed cells. These results provide evidence of the potential for a safe and effective nonabsorbed oral treatment for diabetes and support the concept of engineered commensal bacterial signaling to mediate enteric cell function in vivo.

Topics: Animals; Cell Line; Cellular Reprogramming; Diabetes Mellitus; Diabetes Mellitus, Experimental; Epithelial Cells; Female; Gene Expression Regulation; Genetic Engineering; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Intestinal Mucosa; Lactobacillus; Rats

We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglutide, the MC4R agonist RM-493 or a combination of RM-493 and liraglutide. Co-treatment of DIO mice with RM-493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono-therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM-493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp-1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM-493 enhanced hypothalamic Mc4r expression. Hence, co-dosing with MC4R and GLP-1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP-1R agonism for the treatment of obesity and diabetes.

Topics: alpha-MSH; Animals; Diabetes Mellitus; Drug Synergism; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Liraglutide; Mice, Obese; Obesity; Receptor, Melanocortin, Type 4; Receptors, Glucagon; Treatment Outcome

Evidence indicates that subtle abnormalities in GC (glucocorticoid) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin GLP-1 (glucagon-like peptide 1). However, although defective GLP-1 secretion has been correlated with insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the present study, we sought to determine whether GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate that the GR (glucocorticoid receptor) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces SGK1 (serum- and glucocorticoid-inducible kinase 1) expression, but did not influence preproglucagon expression or cell viability. In addition, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, whereas the secretory response to a phorbol ester was unaltered. Furthermore, in vivo administration of dexamethasone to rats reduced the circulating levels of GLP-1 concurrent with induction of insulin resistance and glucose intolerance. We can conclude that GR activation in GLP-1-producing cells will diminish the secretory responsiveness of these cells to subsequent carbohydrate stimulation. These effects may not only elucidate the pathogenesis of steroid diabetes, but could ultimately contribute to the identification of novel molecular targets for controlling incretin secretion.

Topics: Animals; Blood Glucose; Cell Line; Dexamethasone; Diabetes Mellitus; Down-Regulation; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucocorticoids; Insulin; Insulin Resistance; Male; Mice; Rats, Wistar; Receptors, Glucocorticoid; Signal Transduction; Time Factors

Zinc plays an essential role in the regulation of pancreatic β cell function, affecting important processes including insulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in the zinc efflux transport protein ZnT8 have been linked with both type 1 and type 2 diabetes, further supporting an important role for zinc in glucose homeostasis. However, very little is known about how cytosolic zinc is controlled by zinc influx transporters (ZIPs). In this study, we examined the β cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human and mouse islets and MIN6 β cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic β cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this dysregulated cytosolic zinc homeostasis led to impaired insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast two-hybrid assay. Knock-down of ZIP6 but not ZIP7 in MIN6 β cells impaired the protective effects of GLP-1 on fatty acid-induced cell apoptosis, possibly via reduced activation of the p-ERK pathway. Therefore, our data suggest that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in β cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on β cell survival.

Topics: Animals; Apoptosis; Cation Transport Proteins; Cytosol; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; MAP Kinase Signaling System; Mice; Neoplasm Proteins; Receptors, Glucagon; Zinc

It is now clear that insulin signaling has important roles in regulation of neuronal functions in the brain. Dysregulation of brain insulin signaling has been linked to neurodegenerative disease, particularly Alzheimer's disease (AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid β (Aβ)-induced neurotoxicity for patients with AD. Linagliptin is an inhibitor of dipeptidylpeptidase-4 (DPP-4), which improves impaired insulin secretion and insulin downstream signaling in the in peripheral tissues. However, whether the protective effects of linagliptin involved in Aβ-mediated neurotoxicity have not yet been investigated.. In the present study, we evaluated the mechanisms by which linagliptin protects against Aβ-induced impaired insulin signaling and cytotoxicity in cultured SK-N-MC human neuronal cells.. Our results showed that Aβ impairs insulin signaling and causes cell death. However, linagliptin significantly protected against Aβ-induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3β (GSK3β) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated Aβ-induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of 5' AMP-activated protein kinase (AMPK)-Sirt1 signaling. This upregulation of Sirt1 expression was also observed in diabetic patients with AD coadministration of linagliptin.. Taken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by Aβ in neuronal cells, suggesting DPP-4 inhibitors may have therapeutic potential for reducing Aβ-induced impairment of insulin signaling and neurotoxicity in AD pathogenesis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Chromones; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Insulin-Like Growth Factor I; Linagliptin; Male; Membrane Potential, Mitochondrial; Morpholines; Neuroblastoma; Peptide Fragments; Reactive Oxygen Species; RNA, Messenger; Sirtuin 1; Superoxide Dismutase; Superoxide Dismutase-1

The glucagon-like peptide-1 receptor (GLP-1R) is an important physiologic regulator of insulin secretion and a major therapeutic target for diabetes mellitus. GLP-1 (7-36) amide (active form of GLP-1) is truncated to GLP-1 (9-36) amide, which has been described as a weak agonist of GLP-1R and the major form of GLP-1 in the circulation. New classes of positive allosteric modulators (PAMs) for GLP-1R may offer improved therapeutic profiles. To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide. Screening enabled identification of two compounds, HIT-465 and HIT-736, which possessed new patterns of modulation of GLP-1R. We investigated the ability of these compounds to modify GLP-1R signaling enhanced GLP-1 (9-36) amide- and/or GLP-1 (7-36) amide-mediated cyclic adenosine monophosphate (cAMP) accumulation. These compounds also had unique profiles with regard to allosteric modulation of multiple downstream signaling (PathHunter β-arrestin signaling, PathHunter internalization signaling, microscopy-based internalization assay). We found allosteric modulation patterns to be obviously different among HIT-465, HIT-736, and Novo Nordisk compound 2. This work may enable the design of new classes of drug candidates by targeting modulation of GLP-1 (7-36) amide and GLP-1 (9-36) amide.

Topics: Allosteric Regulation; Amides; Animals; Arrestins; beta-Arrestins; Calcium; Cell Line; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; High-Throughput Screening Assays; Humans; Hypoglycemic Agents; Mutagenesis, Site-Directed; Signal Transduction

Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist).. Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 μg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR.. HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05).. CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.

Topics: Adiposity; Animals; Blood Glucose; Coronary Circulation; Diabetes Mellitus; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Heart Diseases; Liver; Magnetic Resonance Imaging, Cine; Male; Mice, Inbred C57BL; Multimodal Imaging; Multivariate Analysis; Myocardial Contraction; Myocardial Perfusion Imaging; Myocardium; Obesity; Peptides; Predictive Value of Tests; Proton Magnetic Resonance Spectroscopy; Recovery of Function; Time Factors; Triglycerides; Venoms; Ventricular Function; Weight Gain

Glucagon-like peptide 1-based therapies, collectively described as incretins, produce glycemic benefits in the treatment of type 2 diabetes. Recent publications raised concern for a potential increased risk of pancreatitis and pancreatic cancer with incretins based in part on findings from a small number of rodents. However, extensive toxicology assessments in a substantial number of animals dosed up to 2 years at high multiples of human exposure do not support these concerns. We hypothesized that the lesions being attributed to incretins are commonly observed background findings and endeavored to characterize the incidence of spontaneous pancreatic lesions in three rat strains (Sprague-Dawley [S-D] rats, Zucker diabetic fatty [ZDF] rats, and rats expressing human islet amyloid polypeptide [HIP]; n = 36/group) on a normal or high-fat diet over 4 months. Pancreatic findings in all groups included focal exocrine degeneration, atrophy, inflammation, ductular cell proliferation, and/or observations in large pancreatic ducts similar to those described in the literature, with an incidence of exocrine atrophy/inflammation seen in S-D (42-72%), HIP (39%), and ZDF (6%) rats. These data indicate that the pancreatic findings attributed to incretins are common background findings, observed without drug treatment and independent of diet or glycemic status, suggesting a need to exercise caution when interpreting the relevance of some recent reports regarding human safety.

Topics: Animals; Diabetes Mellitus; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Incretins; Pancreas; Pancreatic Diseases; Pancreatitis; Rats; Rats, Sprague-Dawley; Rats, Zucker; Weight Gain

Fructus Arctii, called "Niubangzi" in China (Great burdock achene in English), is a well-known Chinese Materia Medica. It is the dried ripe fruit of Arctium lappa L. (family Asteraceae) and was included in the Chinese pharmacopoeia for its traditional therapeutic actions. Meanwhile it has been utilized extensively in a number of classical drug formulas as a major component for the treatment of noninsulin-dependent diabetes mellitus. It has also been reported recently that the clinical use of Fructus Arctii resulted in a satisfactory hypoglycemic effect in diabetic patients. The aim of this study was to investigate hypoglycemic activity of total lignans from Fructus Arctii (TLFA) in Goto-Kakizaki (GK) rats, a spontaneous type 2 diabetic animal model, and the mechanism of its hypoglycemic activity.. Male GK rats and normal Wistar rats were used in this study, GK rats fed twice daily were given TLFA (300 mg/kg) or nateglinide (50mg/kg) orally before each meal for 12 weeks. Besides common evaluation indexes of hypoglycemic activity such as blood glucose level, oral glucose tolerance test (OGTT), glycated hemoglobin, as well as lipid metabolism parameters such as cholesterol (CHOL), triglycerides (TG), et al., in rat serum. The effects of TLFA on insulin secretion and pancreas tissue sections, the levels of serum glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and the α-glucosidase inhibitory activity of TLFA in vitro were investigated.. TLFA demonstrated stable and long-lasting hypoglycemic activity in GK rats and showed significant improvement in glucose tolerance in glucose fed hyperglycemic GK rats. Both TLFA and nateglinide controlled the glycosylated hemoglobin levels of the experimental animals very well. Stimulation of insulin secretion was proved to be one of the hypoglycemic mechanism of TLFA, promoting the release of GLP-1 should be another one, and ɑ-glucosidase inhibitory activity of TLFA also contributes to its hypoglycemic activity. In this study, we didn't found that TLFA could effect the body weight of GK rats, which was also verified by the changes of biochemical parameters of blood in experimental rats.. The results of this study indicates that TLFA has significant hypoglycemic potential in GK rats, and it may be acting through stimulating insulin secretion, promoting the release of GLP-1, and decreasing intestinal absorption of glucose.

Topics: Animals; Arctium; Blood Glucose; C-Reactive Protein; Circadian Rhythm; Diabetes Mellitus; Drug Administration Schedule; Fruit; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Lignans; Male; Rats; Rats, Wistar

Glucagon-like peptide 1 (GLP1) agonists are promising therapeutic agents in the treatment of diabetes mellitus. This study examines the mechanism of the protective effects of exenatide in experimental diabetes, employing four groups of ten rats each, in which two groups were streptozotocin-induced diabetic and two were control groups. One control and one diabetic group were treated with exenatide (1 μg/kg body weight (BW)) for 10 weeks. Blood plasma was taken for biochemical analyses while pancreatic tissue was taken for immunofluorescence and immunoelectron microscopy studies and real-time PCR to examine the expression of genes. The results show that exenatide improved BW gain and reduced blood glucose in diabetic rats compared with controls. Similarly, exenatide enhanced insulin release from the pancreatic fragments and improved liver and kidney functions and lipid profile in diabetic rats compared with controls. Exenatide not only induced significant increases in serum insulin level but also elevated the number of insulin-, GLP1- and exenatide-positive cells compared with untreated controls. Exenatide also elevated the number of catalase- and glutathione reductase-positive cells in diabetic rat pancreas compared with controls. Exenatide caused significant elevation in the expressions of pancreatic duodenal homeobox-1, heat shock protein-70, glutathione peroxidase, insulin receptor and GLP1 receptor genes in the pancreas of both control and diabetic rats compared with untreated animals. The results have demonstrated that exenatide can exert its beneficial and protective effects by elevating the levels of endogenous antioxidants and genes responsible for the survival, regeneration and proliferation of pancreatic β-cell.

Topics: Animals; Antioxidants; Blood Glucose; Catalase; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glutathione Peroxidase; Homeodomain Proteins; Humans; Hypoglycemic Agents; Insulin; Male; Pancreas; Peptides; Rats; Rats, Wistar; Receptors, Glucagon; Trans-Activators; Venoms

To investigate the chronic effect of sitagliptin (7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-(3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate, SIT) on metabolism and cardiac function in genetic diabetic Akita mice, 10 weeks old Akita mice were either exposed for 4 months to a high fat and high cholesterol (HF-HC) diet, with or without 10mg/kg/day SIT, or were fed for 3 months with the same diet with or without 50mg/kg/day SIT. SIT treatment of Akita mice at either a low or high dose did not affect body or liver weight. A significant increase in subcutaneous and gonadal fat mass was only observed for the 50mg/kg/day dose of SIT. Furthermore, only the 50mg/kg/day SIT dose resulted in an improvement of glycemic control, as evidenced by a decrease in fasting blood HbA1c levels and an increase in plasma adiponectin levels. Echocardiographic analysis revealed that Akita mice kept on the HF-HC diet with 10mg/kg/day of SIT for 4 months showed an increase in ejection fraction and fractional shortening, whereas the higher dose (50mg/kg/day) had no effect on these parameters, but instead induced left ventricular (LV) hypertrophy as evidenced by an enlarged LV internal diameter, volume and mass. Thus, in the diabetic Akita mouse SIT is cardioprotective at a low dose (10mg/kg/day), whereas improvement of glycemic control requires a higher dose (50mg/kg/day) which, however, induces LV hypertrophy. This mouse model may thus be useful to study the safety of anti-diabetic drugs.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diet, High-Fat; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Heart; Heart Function Tests; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myocardium; Pyrazines; Sitagliptin Phosphate; Triazoles

Topics: Adolescent; Adult; Diabetes Mellitus; DNA; DNA Mutational Analysis; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glyburide; Humans; Hypoglycemic Agents; Mutation; Potassium Channels, Inwardly Rectifying; Pyrazines; Sitagliptin Phosphate; Time Factors; Triazoles

To determine whether fasting plasma Dipeptidyl Peptidase 4 (DPP4) activity and active Glucagon-Like Peptide-1 (GLP-1) were predictive of the onset of metabolic syndrome.. A prospective cohort study was conducted of 2042 adults (863 men and 1,179 women) aged 18-70 years without metabolic syndrome examined in 2007(baseline) and 2011(follow-up). Baseline plasma DPP4 activity was determined as the rate of cleavage of 7-amino-4- methylcoumarin (AMC) from the synthetic substrate H-glycyl-prolyl-AMC and active GLP-1 was determined by enzymoimmunoassay.. During an average of 4 years of follow-up, 131 men (15.2%) and 174 women (14.8%) developed metabolic syndrome. In multiple linear regression analysis, baseline DPP4 activity was an independent predictor of an increase in insulin resistance over a 4-year period (P<0.01). In multivariable-adjusted models, the odds ratio (OR) for incident metabolic syndrome comparing the highest with the lowest quartiles of DPP4 activity and active GLP-1 were 2.82, 0.45 for men and 2.48, 0.36 for women respectively. Furthermore, plasma DPP4 activity significantly improved the area under the ROC curve for predicting new-onset metabolic syndrome based on information from metabolic syndrome components (Both P<0.01).. DPP4 activity is an important predictor of the onset of insulin resistance and metabolic syndrome in apparently healthy Chinese men and women. This finding may have important implications for understanding the aetiology of metabolic syndrome.. #TR-CCH-Chi CTR-CCH-00000361.

Topics: Adult; Asian People; China; Diabetes Mellitus; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Humans; Linear Models; Male; Metabolic Syndrome; Middle Aged; Odds Ratio

We investigated whether KR-66195, a new synthetic dipeptidyl dipeptidase IV inhibitor, could prevent weight gain, as well as improving glycemic control in diet-induced obese (DIO) and ob/ob mice.. Male C57BL/6 mice were randomly assigned to the following groups: chow diet, high-fat diet, and high-fat diet with KR-66195. After KR-66195 treatment for eight weeks, intraperitoneal glucose tolerance tests were performed. A pair-feeding study was performed to investigate the mechanisms of the anti-obesity effects of KR-66195 in DIO mice. Female ob/ob mice were treated with KR-66195 for three weeks and compared to the vehicle-treated group.. In DIO mice, KR-66195 treatment increased the plasma glucagon-like peptide (GLP)-1 levels and improved glucose tolerance. This treatment also reduced body weight gain (5.38±0.94 g vs. 12.08±0.55 g, P<0.01) and food intake (2.41±0.09 g vs. 2.79±0.11 g, P<0.05). In ob/ob mice, KR-66195 treatment for three weeks resulted in comparable effects in DIO mice. In the pair-feeding study, KR-66195-treated mice exhibited a 16% increase in energy expenditure (kcal/h/kg lean body mass) without significant differences in body weight or activities compared with pair-fed mice. These results suggest that KR-66195 prevented weight gain in DIO mice by decreasing food intake, as well as increasing energy expenditure.. KR-66195 markedly increased plasma levels of GLP-1, resulting in the probable improvement in glucose tolerance and reduced body weight and food intake. Thus, KR-66195 might be further developed as a therapeutic drug to treat obesity, as well as diabetes.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Composition; Diabetes Mellitus; Diet, High-Fat; Dipeptidyl Peptidase 4; Eating; Energy Metabolism; Enzyme Inhibitors; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Random Allocation; Thiazolidines; Treatment Outcome; Valine; Weight Gain

We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group. RESULTS. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment. CONCLUSIONS. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.

Topics: Animals; Benzamides; Carrier Proteins; Diabetes Complications; Diabetes Mellitus; Dyslipidemias; Enteroendocrine Cells; Gastrointestinal Agents; Glucagon-Like Peptide 1; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Lipid Metabolism; Liver; Male; Malonates; Obesity; Organ Size; Pancreas; Rats; Rats, Zucker

The maintenance of glucose homeostasis is complex and involves, besides the secretion and action of insulin and glucagon, a hormonal and neural mechanism, regulating the rate of gastric emptying. This mechanism depends on extrinsic and intrinsic factors. Glucagon-like peptide-1 secretion regulates the speed of gastric emptying, contributing to the control of postprandial glycemia. The pharmacodynamic characteristics of various agents of this class can explain the effects more relevant in fasting or postprandial glucose, and can thus guide the individualized treatment, according to the clinical and pathophysiological features of each patient.

Topics: Blood Glucose; Diabetes Mellitus; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Postprandial Period

The incretin glucagon-like peptide 1 (GLP-1) enhances insulin secretion. The aim of this study was to assess GLP-1, glucose and insulin concentrations, Homeostatic Model Assessment (HOMA insulin sensitivity and HOMA β-cell function) in dogs with pituitary-dependent hyperadrenocorticism (PDH), and compare these values with those in normal and obese dogs. The Oral Glucose Tolerance Test was performed and the glucose, GLP-1 and insulin concentrations were evaluated at baseline, and after 15, 30, 60 and 120 minutes. Both basal concentration and those corresponding to the subsequent times, for glucose, GLP-1 and insulin, were statistically elevated in PDH dogs compared to the other groups. Insulin followed a similar behaviour together with variations of GLP-1. HOMA insulin sensitivity was statistically decreased and HOMA β-cell function increased in dogs with PDH. The higher concentrations of GLP-1 in PDH could play an important role in the impairment of pancreatic β-cells thus predisposing to diabetes mellitus.

Topics: Adrenocortical Hyperfunction; Animals; Blood Glucose; Diabetes Mellitus; Dog Diseases; Dogs; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Male; Obesity; Pituitary ACTH Hypersecretion; Risk Factors; Time Factors

The covariate-balancing propensity score (CBPS) extends logistic regression to simultaneously optimize covariate balance and treatment prediction. Although the CBPS has been shown to perform well in certain settings, its performance has not been evaluated in settings specific to pharmacoepidemiology and large database research. In this study, we use both simulations and empirical data to compare the performance of the CBPS with logistic regression and boosted classification and regression trees. We simulated various degrees of model misspecification to evaluate the robustness of each propensity score (PS) estimation method. We then applied these methods to compare the effect of initiating glucagonlike peptide-1 agonists versus sulfonylureas on cardiovascular events and all-cause mortality in the US Medicare population in 2007-2009. In simulations, the CBPS was generally more robust in terms of balancing covariates and reducing bias compared with misspecified logistic PS models and boosted classification and regression trees. All PS estimation methods performed similarly in the empirical example. For settings common to pharmacoepidemiology, logistic regression with balance checks to assess model specification is a valid method for PS estimation, but it can require refitting multiple models until covariate balance is achieved. The CBPS is a promising method to improve the robustness of PS models.

Topics: Bias; Cardiovascular Diseases; Comorbidity; Computer Simulation; Confounding Factors, Epidemiologic; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Likelihood Functions; Logistic Models; Pharmacoepidemiology; Propensity Score; Sulfonylurea Compounds

To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07.. A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment.. HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance.. The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Coumarins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Glycated Hemoglobin; HEK293 Cells; Humans; Hypoglycemic Agents; Male; Mice, Inbred C57BL; Mice, Knockout; Peptides; Receptors, Glucagon; Venoms

Saxagliptin was associated with an increased risk of hospitalization for heart failure (HHF) in diabetic patients with high cardiovascular risk. This study assessed the risk of HHF during an exposure to sitagliptin in general diabetic patients.. In Taiwan National Health Insurance research database, a study of the beneficiaries aged ≥ 45 years with diabetes treated with or without sitagliptin between March 2009 and July 2011 was conducted. Patients treated with sitagliptin were matched to patients never exposed to a dipeptidyl peptidase-4 (DPP-4) inhibitor by the propensity score methodology. The outcome measures were the first and the total number of HHF, and mortality for heart failure or all causes.. A total of 8288 matched pairs of patients were analyzed. During a median of 1.5 years, the first event of HHF occurred in 339 patients with sitagliptin and 275 patients never exposed to a DPP-4 inhibitor (hazard ratio: 1.21, 95% confidence interval: 1.04-1.42, P = 0.017); all-cause mortality was similar (hazard ratio: 0.87, 95% confidence interval: 0.74-1.03, P = 0.109). The risk for HHF was proportional to exposure (hazard ratio: 1.09, 95% confidence interval: 1.06-1.11, P < 0.001 for every 10% increase in adherence to sitagliptin). Overall, there were 935 events of HHF, in which the association between the number of HHF and the adherence to sitagliptin was linear. The greatest total number of HHF occurred in the patients with the highest adherence.. The use of sitagliptin was associated with a higher risk of HHF but no excessive risk for mortality was observed.

Topics: Diabetes Mellitus; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Morbidity; Population Surveillance; Propensity Score; Pyrazines; Retrospective Studies; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Taiwan; Triazoles

Topics: Adamantane; Diabetes Mellitus; Dipeptides; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Linagliptin; Pancreatitis; Purines; Pyrazines; Quinazolines; Sitagliptin Phosphate; Triazoles; United States

Topics: Diabetes Mellitus; Drug Industry; Europe; Glucagon-Like Peptide 1; Humans; Incretins; Pancreatic Diseases

Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against cytokine-induced dysfunction and destruction. The mechanisms through which GLP-1 exerts its effects are complex and still poorly understood. The aim of this study was to analyze the protein expression profiles of human islets of Langerhans treated with cytokines (IL-1β and IFN-γ) in the presence or absence of GLP-1 by 2D difference gel electrophoresis and subsequent protein interaction network analysis to understand the molecular pathways involved in GLP-1-mediated β-cell protection. Co-incubation of cytokine-treated human islets with GLP-1 resulted in a marked protection of β-cells against cytokine-induced apoptosis and significantly attenuated cytokine-mediated inhibition of glucose-stimulated insulin secretion. The cytoprotective effects of GLP-1 coincided with substantial alterations in the protein expression profile of cytokine-treated human islets, illustrating a counteracting effect on proteins from different functional classes such as actin cytoskeleton, chaperones, metabolic proteins, and islet regenerating proteins. In summary, GLP-1 alters in an integrated manner protein networks in cytokine-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic patients.

Topics: Adult; Aged; Apoptosis; Cells, Cultured; Cytoskeleton; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Interferon-gamma; Interleukin-1beta; Islets of Langerhans; Male; Middle Aged; Protein Interaction Maps; Proteolysis; Proteome; Proteomics; RNA, Transfer; Secretory Vesicles

Topics: Diabetes Mellitus; Drug Industry; Glucagon-Like Peptide 1; Humans; Incretins; Pancreatic Diseases

Topics: Adult; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Transplantation; Liraglutide; Tacrolimus; Young Adult

Endoplasmic reticulum (ER) stress is associated with the development of diabetes. The present study sought to investigate the effect of Liraglutide, a glucagon like peptide 1 analogue, on ER stress in β-cells. We found that Liraglutide protected the pancreatic INS-1 cells from thapsigargin-induced ER stress and the ER stress associated cell apoptosis, mainly by suppressing the PERK and IRE1 pathways. We further tested the effects of Liraglutide in the Akita mouse, an ER-stress induced type 1 diabetes model. After administration of Liraglutide for 8weeks, p-eIF2α and p-JNK were significantly decreased in the pancreas of the Akita mouse, while the treatment showed no significant impact on the levels of insulin of INS-cells. Taken together, our findings suggest that Liraglutide may protect pancreatic cells from ER stress and its related cell death.

Topics: Animals; Cell Death; Cytoprotection; Diabetes Mellitus; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Glucagon-Like Peptide 1; Insulin-Secreting Cells; JNK Mitogen-Activated Protein Kinases; Liraglutide; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Rats; Signal Transduction; Thapsigargin

To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes.. To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats.. We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day.. PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.

Topics: Animals; Delayed-Action Preparations; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Excipients; Exenatide; Fatty Acids; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin-Secreting Cells; Peptides; Polyethylene Glycols; Polylysine; Protein Stability; Rats; Rats, Sprague-Dawley; Rats, Zucker; Venoms

Glucagon like peptide 1 (GLP-1) is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It acts on target cells and exerts several functions as stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV) as an important regulatory mechanism. GLP-1 analogues are used as antidiabetic drugs in patients with type 2 diabetes. We served patients with cystic fibrosis (CF, n=29), cystic fibrosis related diabetes (CFRD, n=19) and healthy controls (n=18) a standardized breakfast (23 g protein, 25 g fat and 76 g carbohydrates) after an overnight fasting. Blood samples were collected before meal as well as 15, 30, 45 and 60 min after the meal in tubes prefilled with a DPP-IV inhibitor. The aim of the study was to compare levels of GLP-1 in patients with CF, CFRD and in healthy controls. We found that active GLP-1 was significantly decreased in patients with CF and CFRD compared to in healthy controls (p<0.01). However, levels in patients with CFRD tended to be lower but were not significantly lower than in patients with CF without diabetes (p=0.06). Total GLP-1 did not differ between the groups, which points to that the inactive form of GLP-1 is more pronounced in CF patients. The endogenous insulin production (measured by C-peptide) was significantly lower in patients with CFRD as expected. However, levels in non-diabetic CF patients did not differ from the controls. We suggest that the decreased levels of GLP-1 could affect the progression toward CFRD and that more studies need to be performed in order to evaluate a possible treatment with GLP-1 analogues in CF-patients.

Topics: Adult; C-Peptide; Comorbidity; Cystic Fibrosis; Diabetes Mellitus; Disease Progression; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Postprandial Period; Young Adult

Postprandial hypoglycaemia is a severe complication of Roux-en-Y gastric bypass (RYGBP). Acarbose, an α-glucosidase inhibitor (AGI), is employed in its treatment. Several studies have shown that AGIs increase the postprandial levels of glucagon-like peptide 1 (GLP-1). However, an excessive level of GLP-1 is one of the factors involved in the physiopathology of this condition. We analysed the effect of acarbose oral administration in eight RYBGP patients with clinically significant hypoglycaemia or dumping syndrome.. Glucose, insulin and GLP-1 plasma levels in fasting and after ingestion of a standard meal (Ensure Plus®; 13 g protein, 50 g carbohydrate, 11 g fat) were measured. The test was repeated the following week with the oral administration of 100 mg of acarbose 15 min prior to the meal.. Five patients developed asymptomatic hypoglycaemia during the test (glucose level <50 mg/dl) with inappropriately high insulin levels and exaggerated GLP-1 response. Acarbose ingestion avoided hypoglycaemia in all of the patients and increased the lowest plasma glucose level (46.4 ± 4.8 vs. 59.0 ± 2.6 mg/dl, p < 0.01). Acarbose ingestion decreased the area under the curve for serum insulin and GLP-1 levels at 15 min after the meal.. Acarbose avoided postprandial hypoglycaemia following RYGBP by decreasing the hyperinsulinemic response. This was associated with a decrease in early GLP-1 secretion, in contrast to that observed in non-surgical subjects. This finding could be explained by the reduction of glucose load in the jejunum produced by the α-glucosidase inhibition, which is the main stimulus for GLP-1 secretion.

Topics: Acarbose; Administration, Oral; Adult; Blood Glucose; Diabetes Mellitus; Dumping Syndrome; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Male; Obesity, Morbid; Postprandial Period; Treatment Outcome

Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.. Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.. Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P < .05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P < .01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P < .05). Expression of UCP1 was higher in IT than SH animals (P < .05).. These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin Resistance; Ion Channels; Jejunum; Leptin; Lipid Metabolism; Male; Mitochondrial Proteins; Obesity; Peptide YY; Rats, Inbred OLETF; Uncoupling Protein 1

The incretin based therapies are an emerging class of antidiabetic drugs, with two categories: one is glucagone like peptide-1 (GLP-1) agonists and the other one is dipeptidyl peptidase (CD26; DPP-IV) inhibitors. However, in the DPP-IV inhibitors category only few compounds are commercially available and also have some undesirable effects. Therefore, in the present work we tried to explore a naturally occurring compound naringin for its potential DPP-IV inhibition and antidiabetic potential. It is noteworthy that this compound is abundantly present in orange peel and thus may provide cost effective treatment for diabetes, especially type 2 diabetes mellitus. In the present study, we have conducted virtual docking study and observed tight binding of naringin, as shown by higher negative values of H bond lengths, while in vitro DPP-IV inhibition assay has also shown better inhibition by naringin. In vivo study, in response to 10 days administration of 40 mg/kg of naringin twice daily to Wistar albino rats, inhibited the serum levels of DPP-IV activity, random glucose concentration with concomitant increase in insulin levels. All the comparisons were made with the standard commercially available drug sitagliptin.

Topics: Animals; Blood Glucose; Computer Simulation; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Female; Flavanones; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin; Lipid Peroxidation; Male; Pancreas; Rats; Rats, Wistar

Topics: Blood Pressure; Cardiovascular System; Diabetes Mellitus; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins; Liraglutide; Practice Guidelines as Topic; Societies, Medical; South Africa

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins

Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic β-cells and stimulates β-cell hyperplasia. GLP-1 secretion causing hypoglycemia has been described once from an ovarian neuroendocrine tumor (NET) but has not been reported from a pancreatic NET (pNET).. A 56-yr-old male with a previous diagnosis of diabetes presented with fasting hypoglycemia and was found to have a metastatic pNET secreting glucagon. Neither the primary tumor nor metastases stained for insulin, whereas the resected normal pancreas showed histological evidence of islet cell hyperplasia. We provide evidence that GLP-1 secretion from the tumor was the cause of hyperinsulinemic hypoglycemia.. GLP-1 levels were determined in the patient, and immunohistochemistry for GLP-1 was performed on the tumor metastases. Ex vivo tissue culture and a bioassay constructed by transplantation of tumor into nude mice were performed to examine the tumor secretory products and their effects on islet cell function.. The patient had high levels of glucagon and GLP-1 with an exaggerated GLP-1 response to oral glucose. Immunohistochemistry and primary tissue culture demonstrated secretion of glucagon and GLP-1 from the tumor metastases, whereas insulin secretion was almost undetectable. Ex vivo coculture of the tumor with normal human islets resulted in inhibition of insulin release, and transplanted mice developed impaired glucose tolerance.. This is the first description of glucagon and GLP-1 secretion from a metastatic pNET causing sequential diabetes and hypoglycemia. Hypoglycemia was caused by insulin secretion from hyperplastic β-cells stimulated by tumor-derived GLP-1.

Topics: Adenoma, Islet Cell; Animals; Cells, Cultured; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Hepatectomy; Humans; Hyperinsulinism; Hypoglycemia; Immunohistochemistry; Male; Mice; Mice, Nude; Middle Aged; Neuroendocrine Tumors; Pancreatectomy; Pancreatic Neoplasms; Real-Time Polymerase Chain Reaction; Splenectomy

Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171-82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Drug Design; Exenatide; Glucagon-Like Peptide 1; Huntington Disease; Hypothalamus; Insulin; Male; Mice; Mice, Transgenic; Models, Animal; Models, Neurological; Oligonucleotide Array Sequence Analysis; Pancreas; Peptides; Serotonin Plasma Membrane Transport Proteins; Transcription, Genetic; Venoms

Optimal insulin secretion required to maintain glucose homeostasis is the summation of total pancreatic islet β cell mass and intrinsic secretory capacity of individual β cells, which are regulated by distinct mechanisms that could be amplified by glucagon-like-peptide-1 (GLP-1). Because of these actions of GLP-1 on islet β cells, GLP-1 has been deployed to treat diabetes. We employed SNARE protein VAMP8-null mice to demonstrate that VAMP8 mediates insulin granule recruitment to the plasma membrane, which partly accounts for GLP-1 potentiation of glucose-stimulated insulin secretion. VAMP8-null mice also exhibited increased islet β cell mass from increased β cell mitosis, with β cell proliferative activity greatly amplified by GLP-1. Thus, despite the β cell exocytotic defect, VAMP8-null mice have an increased total insulin secretory capacity, which improved glucose homeostasis. We conclude that these VAMP8-mediated events partly underlie the therapeutic actions of GLP-1 on insulin secretion and β cell growth.

Topics: Analysis of Variance; Animals; Blotting, Western; Diabetes Mellitus; Exocytosis; Glucagon-Like Peptide 1; Immunohistochemistry; Immunoprecipitation; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Knockout; Microscopy, Fluorescence; Patch-Clamp Techniques; R-SNARE Proteins

Previous studies addressing the changes of glucagon-like peptide-1 (GLP-1) concentrations in morbidly obese patients after bariatric surgery have demonstrated conflicting results. The aim of the present study was to investigate the changes in serum GLP-1 levels 9 months after biliopancreatic diversion in morbidly obese patients without diabetes mellitus.. A sample of 40 morbidly obese patients without diabetes mellitus was enrolled. Biochemical and anthropometrical evaluations were conducted at basal and 9 months after surgery.. The mean patient age was 46.6 ± 13.1 years, and the mean preoperative body mass index (BMI) was 47.1 ± 18.1. A significant decrease in BMI, weight, waist circumference, fat mass, glucose, LDL cholesterol, total cholesterol, and triglyceride levels was observed after 9 months. Serum basal GLP-1 levels did not change after surgery (0.65 ± 0.18 ng/ml vs. 0.66 ± 0.17 ng/ml; n.s.). Postsurgical correlation analysis showed a negative association between basal GLP-1 and HDL cholesterol (r = -0.57; p < 0.01).. Fasting GLP-1 concentrations did not change after massive weight loss with biliopancreatic diversion in morbidly obese patients without diabetes mellitus.

Topics: Adult; Biliopancreatic Diversion; Blood Glucose; Blood Pressure; Body Composition; Body Mass Index; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Risk Factors; Triglycerides; Waist Circumference; Weight Loss

Exenatide, a glucagon-like peptide-1 receptor agonist, is used twice daily (BID) as monotherapy or adjunctive therapy for the improvement of glycemic control in patients with type 2 diabetes mellitus. The purpose of this pooled analysis was to evaluate the safety and efficacy of exenatide BID in patients stratified by various demographic characteristics.. This post hoc analysis included data from 16 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with 10-μg exenatide BID. Each patient was classified into subgroups on the basis of his or her baseline values for age (< 65 or ≥ 65 years), sex (male or female), race (white, black, Asian, or Hispanic), duration of diabetes (< 10 years or ≥ 10 years), and body mass index (BMI; ≥ 20 to < 25, ≥ 25 to < 30, ≥ 30 to < 35, or ≥ 35 kg/m(2)).. A total of 2067 patients were included. All groups experienced significant improvements in glycated hemoglobin, fasting plasma glucose levels (other than black patients, who had a relatively low baseline fasting plasma glucose level), and body weight from baseline to endpoint. Most groups had significant improvements in systolic blood pressure. All of the age, sex, and duration of diabetes groups experienced significant improvements in lipid levels (other than high-density lipoprotein cholesterol). Whites and Asians generally experienced significant improvements in lipid levels, whereas blacks and Hispanics did not. Significant improvements in lipid levels were generally seen across BMI groups. The most common adverse events overall were nausea (38.6%), hypoglycemia (28.4%), and vomiting (14.0%). Hypoglycemia was more common overall in patients who were taking a concomitant sulfonylurea than it was in patients who were not.. In this pooled analysis, exenatide BID improved glycemic control and body weight, and had generally beneficial effects on blood pressure and lipid levels in patients regardless of baseline age, sex, race, duration of diabetes, or BMI. Gastrointestinal events were the most common adverse events.. www.ClinicalTrials.gov [NCT00039026, NCT00039013, NCT00082381, NCT00035984, NCT00082407, NCT00381342, NCT00360334, NCT00375492, NCT00603239, NCT00765817, NCT00577824, NCT00434954].

Topics: Age Factors; Blood Glucose; Body Mass Index; Diabetes Mellitus; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Peptides; Racial Groups; Retrospective Studies; Sex Factors; Treatment Outcome; Venoms

Enteroendocrine cells such as duodenal cholecystokinin (CCK cells) are generally thought to be confined to certain segments of the gastrointestinal (GI) tract and to store and release peptides derived from only a single peptide precursor. In the current study, however, transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the CCK promoter demonstrated a distribution pattern of CCK-eGFP positive cells that extended throughout the intestine. Quantitative PCR and liquid chromatography-mass spectrometry proteomic analyses of isolated, FACS-purified CCK-eGFP-positive cells demonstrated expression of not only CCK but also glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY), neurotensin, and secretin, but not somatostatin. Immunohistochemistry confirmed this expression pattern. The broad coexpression phenomenon was observed both in crypts and villi as demonstrated by immunohistochemistry and FACS analysis of separated cell populations. Single-cell quantitative PCR indicated that approximately half of the duodenal CCK-eGFP cells express one peptide precursor in addition to CCK, whereas an additional smaller fraction expresses two peptide precursors in addition to CCK. The coexpression pattern was further confirmed through a cell ablation study based on expression of the human diphtheria toxin receptor under the control of the proglucagon promoter, in which activation of the receptor resulted in a marked reduction not only in GLP-1 cells, but also PYY, neurotensin, GIP, CCK, and secretin cells, whereas somatostatin cells were spared. Key elements of the coexpression pattern were confirmed by immunohistochemical double staining in human small intestine. It is concluded that a lineage of mature enteroendocrine cells have the ability to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin, suggesting a potential therapeutic target for the treatment and prevention of diabetes and obesity.

Topics: Animals; Cell Lineage; Cell Separation; Cholecystokinin; Diabetes Mellitus; Enteroendocrine Cells; Flow Cytometry; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Ghrelin; Glucagon-Like Peptide 1; Green Fluorescent Proteins; Humans; Immunohistochemistry; Intestinal Mucosa; Mice; Mice, Transgenic; Neurotensin; Obesity; Peptide YY; Promoter Regions, Genetic

We investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice.. Male db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR.. Liraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/db mice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/db mice, but GSIS, insulin and triacylglycerol content were not affected. In db/db mice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/db mice islets were consistent with the results of the gene expression analysis.. Liraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.

Topics: Animals; Diabetes Mellitus; Eating; Endoplasmic Reticulum; Glucagon-Like Peptide 1; Humans; Immunohistochemistry; Insulin-Secreting Cells; Islets of Langerhans; Liraglutide; Male; Mice; Microdissection; Oxidative Stress; Polymerase Chain Reaction; Weight Gain

The hormone glucagon-like peptide 1 (GLP-1) is released in response to a meal from the intestinal L-cells, where it is processed from proglucagon by the proconvertase (PC)1/3. In contrast, in the adult islets proglucagon is processed to glucagon by the PC2 enzyme. The aim of the study was to evaluate if, during the development of diabetes, alpha cells produce GLP-1 that, in turn, might trigger beta cell growth.. Beta cell mass, GLP-1 and insulin levels were measured in the gerbil Psammomys obesus (P. obesus), a rodent model of nutritionally induced diabetes. Furthermore, the presence of biologically active forms of GLP-1 and PC1/3 in alpha cells was demonstrated by immunofluorescence, and the release of GLP-1 from isolated P. obesus, mouse and human islets was investigated.. During the development of diabetes in P. obesus, a significant increase in GLP-1 was detected in the portal vein (9.8 ± 1.5 vs 4.3 ± 0.7 pmol/l, p < 0.05), and in pancreas extracts (11.4 ± 2.2 vs 5.1 ± 1.3 pmol/g tissue, p < 0.05). Freshly isolated islets from hyperglycaemic animals released more GLP-1 following 24 h culture than islets from control animals (28.2 ± 4.4 pmol/l vs 5.8 ± 2.4, p < 0.01). GLP-1 release was increased from healthy P. obesus islets following culture in high glucose for 6 days (91 ± 9.1 pmol/l vs 28.8 ± 6.6, p < 0.01). High levels of GLP-1 were also found to be released from human islets. PC1/3 colocalised weakly with alpha cells.. GLP-1 release from alpha cells is upregulated in P. obesus during the development of diabetes. A similar response is seen in islets exposed to high glucose, which supports the hypothesis that GLP-1 released from alpha cells promotes an increase in beta cell mass and function during metabolic challenge such as diabetes.

Topics: Adaptation, Physiological; Adult; Animals; Cell Proliferation; Cells, Cultured; Diabetes Mellitus; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gerbillinae; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Middle Aged; Obesity; Up-Regulation

Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged β cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed β cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against β cell apoptosis, restored the β cell mass, and normalized islet morphology in Gck(+/-) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced β cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated β cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.

Topics: Administration, Oral; Animals; Apoptosis; Arachidonic Acid; Diabetes Mellitus; Dietary Carbohydrates; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Glucose; Haploinsufficiency; Insulin-Secreting Cells; Linoleic Acid; Male; Mice; Pyrazines; Receptors, Glucagon; Signal Transduction; Sitagliptin Phosphate; Sucrose; Triazoles

Diabetes mellitus is a complicated disease with a pathophysiology that includes hyperinsulinemia, hyperglycemia and other metabolic impairments leading to many clinical complications. It is necessary to develop appropriate treatments to manage the disease and reduce possible acute and chronic side effects. The advent of gene therapy has generated excitement in the medical world for the possible application of gene therapy in the treatment of diabetes. The glucagon-like peptide-1 (GLP-1) promoter, which is recognised by gut L-cells, is an appealing candidate for gene therapy purposes. The specific properties of L-cells suggest that L-cells and the GLP-1 promoter would be useful for diabetes therapy approaches.. In this study, L-cells were isolated from a primary intestinal cell line to create suitable target cells for insulin expression studies. The isolated cells displayed L-cell properties and were therefore used as an L-cell surrogate. Next, the isolated L-cells were transfected with the recombinant plasmid consisting of an insulin gene located downstream of the GLP-1 promoter. The secretion tests revealed that an increase in glucose concentration from 5 mM to 25 mM induced insulin gene expression in the L-cells by 2.7-fold. Furthermore, L-cells quickly responded to the glucose stimulation; the amount of insulin protein increased 2-fold in the first 30 minutes and then reached a plateau after 90 minutes.. Our data showed that L-cells efficiently produced the mature insulin protein. In addition, the insulin protein secretion was positively regulated with glucose induction. In conclusion, GLP-1 promoter and L-cell could be potential candidates for diabetes gene therapy agents.

Topics: Animals; Cell Line, Tumor; Diabetes Mellitus; Dose-Response Relationship, Drug; Epithelial Cells; Gene Expression; Genetic Engineering; Genetic Therapy; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Intestinal Mucosa; Intestines; Mice; Molecular Targeted Therapy; Plasmids; Promoter Regions, Genetic; Transfection

Improved glucagon-like peptide-1 (GLP-1) receptor activation is considered one of the most effective targets for antidiabetic therapy. For this purpose, we modified the GLP-1 analog of exendin-4 using two fatty acids (FA) either lauric acid (LUA, C12) or palmitic acid (PAA, C16) at its two lysine residues, to produce; Lys(12)-FA-Exendin-4 (FA-M2), Lys(27)-FA-Exendin-4 (FA-M1), or Lys(12,27)-diBA-Exendin-4 (FA-Di). The structural, biological, and pharmaceutical characteristics of these exendin-4 analogs were then investigated. Biological activity tests demonstrated that LUA-M1 had well-preserved in vivo antidiabetic activity and in vitro insulinotropic activity with minimum GLP-1 receptor binding affinity loss as compared with exendin-4. Furthermore, pharmacokinetic studies in rats revealed that s.c. administration of LUA-M1 significantly enhanced pharmacokinetic parameters, such as, elimination half-life, mean residence time, and AUC values as compared with exendin-4. The protracted antidiabetic effects of LUA-M1 were also confirmed by prolonged normoglycemia observed in type 2 diabetic mice (20nmol/mouse single injection of exendin-4 or LUA-M1 induced normoglycemia for 6 or 24h, respectively). These findings suggest that FA conjugated exendin-4s should be considered potential candidates for the treatment of diabetes.

Topics: Animals; Antigens; Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide; Fatty Acids; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Hypoglycemic Agents; Lysine; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Palmitic Acid; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms

Topics: Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Incretins; Liver Cirrhosis; Portasystemic Shunt, Transjugular Intrahepatic

Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells.. In Zucker diabetic fatty rats, a significant 2-fold higher level of vascular senescence was observed compared with control lean rats. Dipeptidyl-peptidase 4 (DPP-4) inhibition significantly increased GLP-1 levels in these animals and reduced senescence almost to lean animal levels. In vitro studies with human umbilical vein endothelial cells showed that GLP-1 had a direct protective effect on oxidative stress (H(2)O(2))-induced senescence and was able to attenuate oxidative stress-induced DNA damage and cellular senescence. The GLP-1 analogue exendin-4 provided similar results, whereas exendin fragment 9-39, a GLP-1 receptor antagonist, abolished this effect. Intracellular signaling by the phosphoinositide 3-kinase (PI3K)/Akt survival pathway did not appear to be involved. Further analysis revealed that GLP-1 activates the cAMP response element-binding (CREB) transcription factor in a cAMP/protein kinase A (PKA)-dependent manner, and inhibition of the cAMP/PKA pathway abolished the GLP-1 protective effect. Expression analysis revealed that GLP-1 can induce the oxidative defense genes HO-1 and NQO1.. Dipeptidyl-peptidase 4 inhibition protects against vascular senescence in a diabetic rat model. In vitro studies with human umbilical vein endothelial cells showed that reactive oxygen species-induced senescence was attenuated by GLP-1 in a receptor-dependent manner involving downstream PKA signaling and induction of antioxidant genes.

Topics: Adamantane; Animals; Cells, Cultured; Cellular Senescence; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Activation; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heme Oxygenase-1; Humans; Hydrogen Peroxide; Hypoglycemic Agents; Male; NAD(P)H Dehydrogenase (Quinone); Nitriles; Oxidants; Oxidative Stress; Peptides; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrrolidines; Rats; Rats, Zucker; Reactive Oxygen Species; Receptors, Glucagon; Signal Transduction; Venoms; Vildagliptin

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.. To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).. Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.. Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Chi-Square Distribution; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Japan; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Obesity, Abdominal; Odds Ratio; Risk Assessment; Risk Factors; Triglycerides; Up-Regulation; Uric Acid; Waist Circumference

Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic beta-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.

Topics: Animals; Blood Glucose; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus; Dipeptidyl Peptidase 4; Eating; Enzyme-Linked Immunosorbent Assay; Genes, fos; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Protein Engineering; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Recombinant Fusion Proteins; Saccharomyces cerevisiae; Transferrin

The aim of this study was to investigate the feasibility and mechanisms of controlling blood glucose using hepatic electrical stimulation (HES).. The study was performed in regular Sprague-Dawley (SD) rats, streptozotocin-induced type 1 diabetic rats and Zucker diabetic fatty (ZDF) rats chronically implanted with one pair of stimulation electrodes on two lobes of the liver tissues.. (i) Hepatic electrical stimulation was effective in reducing blood glucose by 27%-31% at time points 60, 75 and 90 min after oral glucose in normal rats; (ii) HES reduced blood glucose in both fasting and fed states in both type 1 and type 2 diabetic rats; (iii) Chronic HES decreased the blood glucose level, and, delayed gastric empty and increased plasma glucagon-like peptide-1 (GLP-1) level; and (iv) No adverse events were noted in any rats during HES. Histopathological analyses and liver function tests revealed no electrode dislodgement, tissue damages or liver enzyme changes with HES.. Hepatic electrical stimulation is capable of reducing both fasting and fed blood glucose in normal, and type 1 and type 2 diabetic rats and the effect may be partially mediated via an increase in GLP-1 release.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electric Stimulation; Electrodes, Implanted; Fasting; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrointestinal Transit; Glucagon-Like Peptide 1; Glucose Tolerance Test; Liver; Rats; Rats, Sprague-Dawley; Rats, Zucker

GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2<2 min). To circumvent this, we developed a long-lasting GLP-1 receptor agonist by the fusion of GLP-1 with human IgG2 Fc (GLP-1/hIgG2). ELISA-based receptor binding assay demonstrated that GLP-1/hIgG2 had high binding affinity to the GLP-1R in INS-1 cells (Kd = 13.90±1.52 nM). Upon binding, GLP-1/hIgG2 was rapidly internalized by INS-1 cells in a dynamin-dependent manner. Insulin RIA showed that GLP-1/IgG2 dose-dependently stimulated insulin secretion from INS-1 cells. Pharmacokinetic studies in CD1 mice showed that with intraperitoneal injection (i.p.), the GLP-1/hIgG2 peaked at 30 minutes in circulation and maintained a plateau for >168 h. Intraperitoneal glucose tolerance test (IPGTT) in mice showed that GLP-1/hIgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hIgG2 fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1/hIgG2 was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Together, the long-lasting bioactive GLP-1/hIgG2 retains native GLP-1 activities and thus may serve as a potent GLP-1 receptor agonist.

Topics: Animals; Cell Line, Tumor; Diabetes Mellitus; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Immunoglobulin G; Insulin; Kinetics; Male; Mice; Protein Binding; Rats; Receptors, Glucagon; Recombinant Fusion Proteins

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Leptin; Liver; Muscle, Skeletal

Topics: Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Guidelines as Topic; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems

To evaluate the impact of Medicare Part D coverage gap (donut hole) on adherence to diabetes medications.. Retrospective cohort analysis based on pharmacy claims data.. The sample included 12,881 Medicare Part D beneficiaries with diabetes who entered the coverage gap in 2008. Sample patients had 3 different levels of coverage in the donut hole: no coverage, generic drug coverage only, and both generic and brand-name drug coverage. Adherence was measured by the proportion of days covered. We used a difference-in-difference model to evaluate the effect of coverage gap on adherence.. In the donut hole, the average copayment for diabetes medications increased substantially for beneficiaries with no coverage and beneficiaries with generic drug coverage only, whereas the average copayment for beneficiaries with both generic and brand-name medication coverage declined slightly. Compared with beneficiaries with full coverage of both generic and brand-name drugs, beneficiaries with no coverage (odds ratio[OR] = 0.617, P <.0001, 95% confidence interval [CI] = 0.523, 0.728) and beneficiaries with generic drug coverage only (OR = 0.702, P <.0001, 95% CI = 0.604, 0.816) were significantly less likely to be adherent after entering the donut hole. The difference between having generic coverage and no coverage was not significant (P = .1586).. The coverage gap in the Medicare Part D program has a significant negative impact on medication adherence among beneficiaries with diabetes. Availability of brand-name drug coverage in the donut hole is critical to adherence to diabetes medications.

Topics: Aged; Cohort Studies; Confidence Intervals; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Health Services Accessibility; Humans; Hypoglycemic Agents; Incretins; Insulin; Insurance Claim Review; Insurance Coverage; Male; Medicare Part D; Medication Adherence; Metformin; Odds Ratio; Retrospective Studies; Sulfonylurea Compounds; Thiazolidinediones; United States

Antidiabetic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are exerted by potentiation of the biological activity of incretin hormones like glucagon-like peptide (GLP)-1. BI 1356 [proposed trade name Ondero; (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] is a novel competitive, selective, potent, and long-acting DPP-4 inhibitor under clinical development for the treatment of type 2 diabetes. The effect of 1 to 2 months of chronic dosing of BI 1356 in two different animal models was investigated. The first is a primarily genetic model (Zucker diabetic fatty rats), and the second is a nongenetic model (mice with diabetes induced by a combination of high-fat diet and low-dose streptozotocin). BI 1356 was shown to lower HbA1c after multiple dosing in both models. The improvement of glycemic control achieved in disease models of different etiology suggests that BI 1356 would also be efficacious in treating a broad spectrum of type 2 diabetic patients. In addition, multiple dosing of BI 1356 leads to a sustained increase in basal levels of active GLP-1 in the systemic circulation, with expected long-term benefits on pancreatic alpha- and beta-cells. The effects on HbA1c and GLP-1 were superior to the short-acting DPP-4 inhibitor vildagliptin, demonstrating the potential of BI 1356 as a once daily treatment for type 2 diabetes at low therapeutic doses.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hypoglycemic Agents; Linagliptin; Male; Mice; Purines; Quinazolines; Rats; Rats, Zucker; Tumor Cells, Cultured

Berberine (BBR), a hypoglycemic agent, has shown beneficial metabolic effects for anti-diabetes, but its precise mechanism was unclear. Glucagon-like peptide-1 (GLP-1) is considered to be an important incretin that can decrease hyperglycemia in the gastrointestinal tract after meals. The aim of this study was to investigate whether BBR exerts its anti-diabetic effects via modulating GCG secretion. Diabetes-like rats induced by streptozotocin received BBR (120 mg/kg per day, i.g) for 5 weeks. Two hours following the last dose, the rats were anaesthetized and received 2.5 g/kg glucose by gavage. At 15-minute and 30-minute after glucose load, blood samples, pancreas, and intestines were obtained to measure insulin and GCG using ELISA kit. The number of L cells in the ileum and beta-cells in the pancreas were identified using immunohistology. The expression of proglucagon mRNA in the ileum was measured by RT-PCR. The results indicated that BBR treatment significantly increased GCG levels in plasma and intestine (P<0.05) accompanied with the increase of proglucagon mRNA expression and the number of L-cell compared with the controls (P<0.05). Furthermore, BBR increased insulin levels in plasma and pancreas as well as beta-cell number in pancreas. The data support the hypothesis that the anti-diabetic effects of BBR may partly result from enhancing GCG secretion.

Topics: Animals; Antibiotics, Antineoplastic; Berberine; Diabetes Mellitus; Disease Models, Animal; Gene Expression; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Intestinal Mucosa; Peptide Fragments; Proglucagon; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Streptozocin

Combination therapies are increasingly common in the clinical management of type 2 diabetes. We investigated to what extent combined treatment with the human glucagon-like peptide-1 (GLP-1) analogue liraglutide and the dual PPARalpha/gamma agonist ragaglitazar would improve glycaemic control in overtly diabetic Zucker diabetic fatty (ZDF) rats.. Ninety overtly diabetic male ZDF rats were stratified into groups with matched haemoglobin A1c (HbA1c) (9.0+/-0.1%). Liraglutide (15 and 50 microg/kg subcutaneously twice daily), ragaglitazar (1 and 3 mg/kg perorally once daily) and their vehicles were studied as monotherapy and in combination in a 3x3 factorial design.. After 4-week treatment, synergistic effects on HbA1c, non-fasting morning blood glucose (BG) and/or 24-h BG profiles were observed with three of the four combinations. The relationship between plasma insulin and BG in combination-treated animals approached that of historical lean ZDF rats representing normal glucose homeostasis, suggesting that insulin secretion and insulin sensitivity were markedly improved. Increased insulin immunostaining in islets further supports the improved beta-cell function and/or insulin sensitivity in combination-treated animals. The synergistic effect on glycaemic control was found without a similar synergistic increase in beta-cell mass in the combination groups.. Our data demonstrate that combination treatment with a human GLP-1 analogue and a dual PPARalpha/gamma agonist through distinct mechanism of actions synergistically improves glycaemic control in the ZDF rat.

Topics: Animals; Blood Glucose; Cell Proliferation; Diabetes Mellitus; Disease Models, Animal; Drug Synergism; Glucagon-Like Peptide 1; Glycated Hemoglobin; Homeodomain Proteins; Homeostasis; Hypoglycemic Agents; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Liraglutide; Oxazines; Phenylpropionates; Rats; Rats, Zucker; Trans-Activators

Topics: Animals; Diabetes Mellitus; Drug and Narcotic Control; Drug Approval; Drug Industry; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Mice; Rats; Recombinant Proteins

We investigated to determine what effects, if any, the respective water extracts of Radix scutellariae (RS), Fructus schisandrae chinensis (FSC), Huang-Lian-Jie-Du-Tang (HLJDT), and HLJDT supplemented with FSC, and Rhizoma Polygonati odorati (HLJDT-M) would have on glucose tolerance by modulating glucose-stimulated insulin secretion, beta-cell mass, and morphometry in 90% pancreatectomized (Px) diabetic rats fed high-fat diets. Through the elevation of intracellular cAMP levels, FSC RS, HLJDT, and HLJDT-M increased insulin secretion in Min6 cells and GLP-1 secretion in NCI-H716 cells. After an 8-week period of treatment, it was found that HLJDT-M improved glucose tolerance in an oral glucose tolerance test in Px rats. HLJDT-M also potentiated first- and second-phase insulin secretion, but RS and HLJDT elevated only the second phase at hyperglycemic clamp. RS and HLJDT increased beta-cell mass by hyperplasia and hypertrophy, while HLJDT-M increased it only by hyperplasia. The rise in hyperplasia was associated with elevated IRS2 and PDX-1 expression in the islets. In conclusion, HLJDT-M worked as an anti-diabetic prescription by enhancing insulinotropic actions in diabetic rats.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cell Line; Cell Proliferation; Cyclic AMP; Diabetes Mellitus; Drugs, Chinese Herbal; Energy Intake; Epididymis; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Intracellular Space; Islets of Langerhans; Male; Pancreatectomy; Polygonatum; Rats; Rats, Sprague-Dawley; Schisandra

Topics: Animals; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Lizards

Topics: Bariatric Surgery; Body Mass Index; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Risk Assessment; Venoms

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dogs; Glucagon-Like Peptide 1; Humans; Incretins; Rats

Topics: Cell Proliferation; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Receptors, Glucagon; RNA Interference; RNA, Messenger; Signal Transduction

Cell-based treatments for insulin-dependent diabetes (IDD) may provide more physiologic regulation of blood glucose levels than daily insulin injections, thereby reducing the occurrence of secondary complications associated with diabetes. An autologous cell source is especially attractive for regulatory and ethical reasons in addition to eliminating the need for immunosuppression. This study uses non-beta-cells, genetically modified for physiologic insulin secretion. Enteroendocrine L-cells, exhibit regulated secretion in response to physiologic stimuli and their endogenous products are fully compatible with prandial metabolism. Murine GLUTag L-cells were transfected with a plasmid co-expressing human insulin and neomycin resistance and the stable cell line, GLUTag-INS, was established. Secretion properties of GLUTag-INS cells were investigated in vitro through induced secretion tests using meat hydrolysate or 3-isobutyl-1-methylxanthine and forskolin as secretagogues. GLUTag-INS cells rapidly co-secreted recombinant insulin and endogenous glucagon-like peptide in response to metabolic cues from the surrounding medium and demonstrated efficient processing of proinsulin to insulin.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Cell Line; Colforsin; Diabetes Mellitus; Drug Resistance; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Neomycin; Proinsulin; Transfection

Type II diabetes mellitus (T2D) develops as the consequence of relative insulin insufficiency. The onset of T2D is characterized by insulin resistance, and in most cases, with hyperinsulinemia for compensation. Extensive basic and clinical examinations have identified a large profile of T2D susceptibility genes and multiple risk factors, including obesity and sedentary life style, which are shared by colon cancer development. The intestinal endocrine L cells produce an incretin hormone, namely glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion in blood glucose dependent manner, pancreatic beta cell proliferation and neogenesis. It has been shown that in T2D patients, postprandial GLP-1 secretion level is reduced. I hypothesize that during the development of insulin resistance, intestinal endocrine L cells produce more GLP-1 for compensation. This compensatory response involves the activation of Wnt signaling pathway and the cross-talk between Wnt and insulin signaling pathways. A pathological consequence of this compensation will be the stimulated expression of proto-oncogenes, including c-Myc.

Topics: Apoptosis; Colonic Neoplasms; Comorbidity; Diabetes Complications; Diabetes Mellitus; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Models, Biological; Models, Theoretical; Signal Transduction; Wnt Proteins

Dipeptidyl peptidase IV (DPP IV) is the primary inactivator of glucoregulatory incretin hormones. This has lead to development of DPP IV inhibitors as a new class of agents for the treatment of type 2 diabetes. Recent reports indicate that other antidiabetic drugs, such as metformin, may also have inhibitory effects on DPP IV activity. In this investigation we show that high concentrations of several antidiabetic drug classes, namely thiazolidinediones, sulphonylureas, meglitinides and morphilinoguanides can inhibit DPP IV. The strongest inhibitor nateglinide, the insulin-releasing meglitinide was effective at low therapeutically relevant concentrations as low as 25 micromol/l. Nateglinide also prevented the degradation of glucagon-like peptide-1 (GLP-1) by DPP IV in a time and concentration-dependent manner. In vitro nateglinide and GLP-1 effects on insulin release were additive. In vivo nateglinide improved the glucose-lowering and insulin-releasing activity of GLP-1 in obese-diabetic ob/ob mice. This was accompanied by significantly enhanced circulating concentrations of active GLP-1(7-36)amide and lower levels of DPP IV activity. Nateglinide similarly benefited the glucose and insulin responses to feeding in ob/ob mice and such actions were abolished by co-administration of exendin(9-39) and (Pro(3))GIP to block incretin hormone action. These data indicate that the use of nateglinide as a prandial insulin-releasing agent may partly rely on inhibition of GLP-1 degradation as well as beta-cell K(ATP) channel inhibition.

Topics: Animals; Blood Glucose; Cell Line; Cyclohexanes; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Mice; Mice, Obese; Nateglinide; Peptide Fragments; Phenylalanine

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells, can effectively lower blood glucose levels in patients with diabetes. A fusion gene, consisting of 10 tandem repeated GLP-1 analog genes, was expressed at a high level in the yeast Pichia pastoris. SDS polyacrylamide gel electrophoresis (SDS-PAGE), and Western Blotting results showed that fusion protein migrated as a single protein band with a molecular weight of 36 kDa. A biological activity test showed that the GLP-1 analog could significantly lower the level of serum glucose when GLP-1 purified analog was injected into diabetic rats. A potential strategy for large-scale production of fusion protein containing the 10 GLP-1 analogs as discovered, and a single GLP-1 analog was obtained from fusion protein digested with trypsin. This should be inspired foreign expression of medicinal short peptides and be valuable in further research on GLP-1 analog drugs in the treatment of diabetes mellitus.

Topics: Animals; Blood Glucose; Cloning, Molecular; Diabetes Mellitus; Disease Models, Animal; Glucagon-Like Peptide 1; Pichia; Rats; Recombinant Fusion Proteins; Tandem Repeat Sequences

The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM).. To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT) (fasting plasma glucose (FPG): 5.5 (4.5-6.0) mM (mean (range); HbA(1c): 5.8 (5.4-6.3) %) and 8 patients with CP and secondary diabetes not requiring insulin (FPG: 7.1 (6.0-8.8) mM; HbA(1c): 7.0 (5.8-10.0) %) during three 15-mM hyperglycaemic clamps with continuous iv infusion of saline, glucagon-like peptide-1 (GLP-1) or GIP.. The initial (0-20 min) insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline (P<0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20-120 min compared with saline infusion. During GIP infusion the late-phase insulin response (20-120 min) was 3.1+/-1.0 fold greater than during saline infusion in the group of patients with CP and NGT (P<0.05), whereas there was no significant differences in patients with CP and DM.. The lack of GIP amplification of the late insulin response to iv glucose develops alongside the deterioration of glucose tolerance in patients with CP, suggesting that the same may be true for the loss of the GIP effect in patients with T2DM.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Male; Middle Aged; Pancreatitis, Chronic

Topics: Animals; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents

Topics: Diabetes Complications; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Insulin Secretion; Intestinal Mucosa; Intestines; Models, Biological; Polymorphism, Single Nucleotide; Signal Transduction; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein

Topics: Amyloid; Biguanides; Diabetes Mellitus; Dietary Supplements; Dipeptidyl-Peptidase IV Inhibitors; Fructose-Bisphosphatase; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Phytotherapy; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

Topics: Biguanides; Diabetes Complications; Diabetes Mellitus; Diet; Dietary Supplements; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Obesity; Thiazolidinediones

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Obesity; Peptide Hormones

Topics: Adamantane; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Nitriles; Pyrrolidines; Randomized Controlled Trials as Topic; Vildagliptin

Topics: Amyloid; Diabetes Mellitus; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Liraglutide; Peptides; Venoms

Topics: Adenosine Deaminase Inhibitors; Animals; Colipases; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Enzyme Precursors; Exenatide; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glycoproteins; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Liraglutide; Peptides; Protein Precursors; Societies, Medical; Taste Threshold; Venoms

Glucagon-like peptide 1 (GLP-1) is an insulinotropic protein. It was reported that the continuous infusion of GLP-1 normalized the blood glucose level in type 2 diabetes animal model. However, the short half-life of GLP-1 has limited its application in clinical settings and prompted us to develop a GLP-1 gene therapy system. Our previous results showed that the delivery of pbeta-GLP-1 using polyethylenimine (PEI) reduced the blood glucose level effectively. However, the glucose level was not completely normalized. In the present study, the more efficient GLP-1 expression system was developed using two-step transcription amplification (TSTA). To evaluate the TSTA system, pbeta-Gal4-p65 and pUAS-Luc were constructed. The pUAS-Luc/pbeta-Gal4-p65 system showed the highest transfection efficiency at a 2:1 pUAS-Luc/pbeta-Gal4-p65 weight ratio. In addition, the transgene expression by the TSTA system was at least 4 times higher than pbeta-Luc. To apply the TSTA system to the GLP-1 expression plasmid, pUAS-GLP-1 was constructed. The pUAS-GLP-1/pbeta-Gal4-p65 system showed higher mRNA level than pbeta-GLP-1. In addition, the level of GLP-1 by the pUAS-GLP-1/pbeta-Gal4-p65 system was more than 4 times higher than pbeta-GLP-1. Therefore, the TSTA GLP-1 expression system may be useful to develop gene therapy system for type 2 diabetes.

Topics: Cell Line; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Genes, Reporter; Genetic Therapy; Genetic Vectors; Glucagon-Like Peptide 1; Humans; Imines; Luciferases; Luminescent Agents; Plasmids; Polyethylenes; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Transfection

Glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3-42) and GLP-1(9-36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9-36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3-42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3-42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Eating; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Immunohistochemistry; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Obese; Obesity; Organ Size; Peptide Fragments; Peptides; Receptors, Gastrointestinal Hormone

The discoverers of secretin already thought of the existence of a chemical excitant for the internal secretion of the pancreas. Numerous experiments have been performed and published between 1906 and 1935 testing the effect of injected or ingested duodenal ("secretin") extracts on fasting or elevated blood glucose levels of normal or diabetic animals and humans with contradictory results. In 1940, after a series of negative dog experiments performed by an opinion leader, the existence of an incretin was considered questionable and further research stopped for more than 20 years. However, after the development of the radio-immunoassay, the incretin-concept has been revived in 1964, showing that significantly more insulin was released after ingestion of glucose than after intravenous injection. The possibility that nerves or one of the known gut hormones were responsible for the incretin effect could be ruled out. In 1970, glucose dependent insulinotropic polypeptide (GIP), and finally, in 1985 glucagon-like peptide 1 (GLP-1) and its truncated form GLP-1(7-36) were recognized as true incretins. Thereafter, multiple antidiabetic qualities and the therapeutic perspectives of GLP-1(7-36) and its analogues and mimetics have been demonstratred.

Topics: Animals; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Gastrin-Releasing Peptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; History, 20th Century; History, 21st Century; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Peptide Fragments; Peptides; Protein Precursors; Secretin

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.

Topics: Animals; Cell Line, Transformed; Cricetinae; Cyclic AMP; Diabetes Mellitus; Dipeptidyl Peptidase 4; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hypoglycemic Agents; Insulin; Mesocricetus; Mice; Mice, Obese; Peptide Fragments; Protein Precursors; Pyrrolidonecarboxylic Acid

Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated in the etiology of this condition; however, effective therapies to block glucagon signaling and thereby regulate glucose metabolism do not exist. To determine the extent to which blocking glucagon action would reverse hyperglycemia, we targeted the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2'-methoxyethyl-modified phosphorothioate-antisense oligonucleotide (ASO) inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. Importantly, in addition to decreasing expression of cAMP-regulated genes in liver and preventing glucagon-mediated hepatic glucose production, GCGR inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP-1) and insulin levels in pancreatic islets. Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic beta cell function.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Liver; Mice; Oligodeoxyribonucleotides, Antisense; Peptides; Rats; Receptors, Glucagon

The two major incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), are currently being considered as prospective drug candidates for treatment of type 2 diabetes. Interest in these gut hormones was initially spurred by their potent insulinotropic activities, but a number of other antihyperglycaemic actions are now established. One of the foremost barriers in progressing GLP-1 and GIP to the clinic concerns their rapid degradation and inactivation by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV). Here, we compare the DPP IV resistance and biological properties of Abu8/Abu2 (2-aminobutyric acid) substituted analogues of GLP-1 and GIP engineered to impart DPP IV resistance. Whereas (Abu8)GLP-1 was completely stable to human plasma (half-life >12 h), GLP-1, GIP, and (Abu2)GIP were rapidly degraded (half-lives: 6.2, 6.0, and 7.1 h, respectively). Native GIP, GLP-1, and particularly (Abu8)GLP-1 elicited significant adenylate cyclase and insulinotropic activity, while (Abu2)GIP was less effective. Similarly, in obese diabetic (ob/ob) mice, GIP, GLP-1, and (Abu8)GLP-1 displayed substantial glucose-lowering and insulin-releasing activities, whereas (Abu2)GIP was only weakly active. These studies illustrate divergent effects of penultimate amino acid Ala8/Ala2 substitution with Abu on the biological properties of GLP-1 and GIP, suggesting that (Abu8)GLP-1 represents a potential candidate for future therapeutic development.

Topics: Adenylyl Cyclases; Alanine; Aminobutyrates; Animals; Cells, Cultured; Chromatography, High Pressure Liquid; Cyclic AMP; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Obese; Models, Chemical; Peptide Fragments; Peptides; Protein Precursors; Protein Structure, Tertiary; Spectrometry, Mass, Electrospray Ionization; Time Factors

The 64th scientific congress of the American Diabetes Association had a special session devoted to the presentation of the results from three clinical trials: 1) the first multicentre international trial of pancreatic islet transplantation according to the so-called Edmonton protocol with the primary endpoint of restoring insulin independence in type 1 diabetic patients; 2) three pivotal studies of 30 weeks testing both the efficacy and safety of exenatide (exendin-4), a new insulin secretagogue that is a long-acting analogue of glucagon-like peptide-1, in patients with type 2 diabetes treated with either metformin, or a sulfonylurea, or a metformin-sulfonylurea combination; and 3) the "Collaborative AtoRvastatin Diabetes Study" (CARDS), a placebo-controlled primary prevention trial of cardiovascular complications using atorvastatin 10 mg in 2 838 at risk patients with type 2 diabetes. The main results and conclusions of these trials are briefly presented as they open new perspectives in the management of patients with type 1 or type 2 diabetes mellitus.

Topics: Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Exenatide; Glucagon; Glucagon-Like Peptide 1; Heptanoic Acids; Humans; Islets of Langerhans Transplantation; Peptide Fragments; Peptides; Protein Precursors; Pyrroles; Venoms

We have previously shown that type 2 diabetic patients have decreased plasma concentrations of glucagon-like peptide 1 (GLP-1) compared with healthy subjects after ingestion of a standard mixed meal. This decrease could be caused by differences in the metabolism of GLP-1. The objective of this study was to examine the pharmacokinetics of GLP-1 in healthy subjects and type 2 diabetic patients after iv bolus doses ranging from 2.5-25 nmol/subject. Bolus injections iv of 2.5, 5, 15, and 25 nmol of GLP-1 and a meal test were performed in six type 2 diabetic patients [age, mean (range): 56 (48-67) yr; body mass index: 31.2 (27.0-37.7) kg/m(2); fasting plasma glucose: 11.9 (8.3-14.3) mmol/liter; hemoglobin A(1C): 9.6 (7.0-12.5)%]. For comparison, six matched healthy subjects were examined. Peak plasma GLP-1 concentrations increased linearly with increasing doses of GLP-1 and were similar for type 2 diabetic patients and healthy subjects. The peak concentrations of total GLP-1 (C-terminal) after 2.5, 5, 15, and 25 nmol of GLP-1 were 357 +/- 56, 647 +/- 141, 1978 +/- 276, 3435 +/- 331 pmol/liter in the type 2 diabetic patients and 315 +/- 37, 676 +/- 64, 1848 +/- 146, 3168 +/- 358 pmol/liter, respectively, in the healthy subjects (not statistically significant). Peak concentrations of the intact GLP-1 peptide (N-terminal) were: 69 +/- 17, 156 +/- 44, 703 +/- 77, and 1070 +/- 117 pmol/liter in the type 2 diabetic patients and 75 +/- 14, 160 +/- 40, 664 +/- 79, 974 +/- 87 in the healthy subjects (not statistically significant). GLP-1 was eliminated rapidly with clearances of intact GLP-1 after 2.5, 5, 15, and 25 nmol of GLP-1 amounting to: 9.0 +/- 5.0, 8.1 +/- 6.0, 4.0 +/- 1.0, 4.0 +/- 1.0 liter/min in type 2 diabetic patients and 8.4 +/- 4.2, 7.6 +/- 4.5, 5.0 +/- 2.0, 5.0 +/- 1.0 liter/min in healthy subjects. The volume of distribution ranged from 9-26 liters per subject. No significant differences were found between healthy subjects and type 2 diabetic subjects. We conclude that elimination of GLP-1 is the same in obese type 2 diabetic patients and matched healthy subjects. The impaired incretin response seen after ingestion of a standard breakfast meal must therefore be caused by a decreased secretion of GLP-1 in type 2 diabetic patients.

Topics: Aged; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Injections, Intravenous; Male; Middle Aged; Obesity; Osmolar Concentration; Peptide Fragments; Protein Precursors; Reference Values

The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation-resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP-IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to albumin in vivo. The CJC-1131 albumin conjugate bound to the GLP-1 receptor (GLP-1R) and activated cAMP formation in heterologous fibroblasts expressing a GLP-1R. CJC-1131 lowered glucose in wild-type mice, but not in GLP-1R-/- mice. Basal glucose and glycemic excursion following glucose challenge remained significantly reduced 10-12 h following a single injection of CJC-1131. Twice daily administration of CJC-1131 to db/db mice significantly reduced glycemic excursion following oral and IP glucose challenge (P < 0.01 to 0.05) but did not significantly lower body weight during the 4-week study period. Levels of random fed glucose were significantly lower in CJC-1131-treated +/+ and db/db mice and remained significantly lower even 1 week following discontinuation of CJC-1131 administration. CJC-1131 increased levels of pancreatic proinsulin mRNA transcripts, percent islet area, and the number of bromodeoxyuridine-positive islet cells. These findings demonstrate that an albumin-conjugated DAC:GLP-1 mimics the action of native GLP-1 and represents a new approach for prolonged activation of GLP-1R signaling.

Topics: Animals; Blood Glucose; Body Weight; CHO Cells; Cricetinae; Cyclic AMP; Diabetes Mellitus; Dipeptidyl Peptidase 4; Fibroblasts; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Maleimides; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Peptides; Proinsulin; Protein Precursors; Receptors, Glucagon; Recombinant Proteins; RNA, Messenger; Serum Albumin; Transfection

This study examined the biological effects of the GIP receptor antagonist, (Pro3)GIP and the GLP-1 receptor antagonist, exendin(9-39)amide.. Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic ( ob/ ob) mice.. In GIP receptor-transfected fibroblasts, (Pro(3))GIP or exendin(9-39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0+/-3.5% and 73.5+/-3.2% at 10(-6) mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin(9-39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60+/-0.7% at 10(-6) mol/l, whereas (Pro(3))GIP had no effect. (Pro(3))GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9-39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro(3))GIP, exendin(9-39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro3)GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small.. These data show that (Pro(3))GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release.

Topics: Animals; Cells, Cultured; Cricetinae; Cricetulus; Cyclic AMP; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Mice; Obesity; Peptide Fragments; Postprandial Period; Protein Precursors; Spectrometry, Mass, Electrospray Ionization

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. beta-cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P = 0.19) and obese healthy subjects (22% P = 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the beta-cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Obesity; Peptide Fragments; Protein Precursors; Random Allocation

The incretin hormone GLP1 promotes islet-cell survival via the second messenger cAMP. Here we show that mice deficient in the activity of CREB, caused by expression of a dominant-negative A-CREB transgene in pancreatic beta-cells, develop diabetes secondary to beta-cell apoptosis. Remarkably, A-CREB severely disrupted expression of IRS2, an insulin signaling pathway component that is shown here to be a direct target for CREB action in vivo. As induction of IRS2by cAMP enhanced activation of the survival kinase Akt in response to insulin and IGF-1, our results demonstrate a novel mechanism by which opposing pathways cooperate in promoting cell survival.

Topics: Animals; Apoptosis; Cell Line; Cell Survival; Colforsin; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Mice; Mice, Transgenic; Peptide Fragments; Phosphoproteins; Phosphorylation; Promoter Regions, Genetic; Protein Precursors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Transfection; Transgenes; Tumor Cells, Cultured

Glucagon-like peptide-1 (GLP-1) increases gastric volume in humans possibly through the vagus nerve. Gastric volume response to feeding is preserved after vagal denervation in animals. We evaluated gastric volume responses to GLP-1 and placebo in seven diabetic patients with vagal neuropathy in a crossover study. We also compared gastric volume response to feeding in diabetes with that in healthy controls. We measured gastric volume using SPECT imaging. Data are median (interquartile range). In diabetic patients, GLP-1 did not increase gastric volume during fasting [5 mL (-3; 30)] relative to placebo [4 mL (-14; 50) P = 0.5], or postprandially [Delta postprandial minus fasting volume 469 mL (383; 563) with GLP-1 and 452 mL (400; 493) with placebo P = 0.3]. Change in gastric volume over fasting in diabetic patients on placebo was comparable to that of healthy controls [452 mL (400; 493)], P = 0.5. In contrast to effects in health, GLP-1 did not increase gastric volume in diabetics with vagal neuropathy, suggesting GLP-1's effects on stomach volume are vagally mediated. Normal gastric volume response to feeding in diabetics with vagal neuropathy suggests that other mechanisms compensate for vagal denervation.

Topics: Aged; Cross-Over Studies; Diabetes Mellitus; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Heart Rate; Humans; Male; Middle Aged; Peptide Fragments; Postprandial Period; Protein Precursors; Stomach; Tomography, Emission-Computed, Single-Photon; Vagus Nerve Diseases

We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH2 (ZP10A). Receptor binding studies demonstrated that the affinity of ZP10A for the human GLP-1 receptor was 4-fold greater than the affinity of GLP-1 (7-36) amide. ZP10A demonstrated dose-dependent improvement of glucose tolerance with an ED50 value of 0.02 nmol/kg i.p. in an oral glucose tolerance test (OGTT) in diabetic db/db mice. After 42 days of treatment, ZP10A dose-dependently (0, 1, 10, or 100 nmol/kg b.i.d.; n = 10/group), decreased glycosylated hemoglobin (HbA1C) from 8.4 +/- 0.4% (vehicle) to a minimum of 6.2 +/- 0.3% (100 nmol/kg b.i.d.; p < 0.05 versus vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA1C levels were significantly improved in mice treated with ZP10A for 90 days compared with vehicle-treated controls. Interestingly, these effects were preserved 40 days after drug cessation in db/db mice treated with ZP10A only during the first 50 days of the study. Real-time polymerase chain reaction measurements demonstrated that the antidiabetic effect of early therapy with ZP10A was associated with an increased pancreatic insulin mRNA expression relative to vehicle-treated mice. In conclusion, long-term treatment of diabetic db/db mice with ZP10A resulted in a dose-dependent improvement of FBG, glucose tolerance, and blood glucose control. Our data suggest that ZP10A preserves beta-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes.

Topics: Animals; Blood Glucose; Carrier Proteins; Diabetes Mellitus; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon; RNA, Messenger

Glucagon-like-peptide-1 (GLP-1) is strongly insulinotropic in patients with Type II (non-insulin-dependent) diabetes mellitus, whereas glucose-dependent insulinotropic polypeptide (GIP) is less effective. Our investigation evaluated "early" (protocol 1) - and "late phase" (protocol 2) insulin and C-peptide responses to GLP-1 and GIP stimulation in patients with Type II diabetes.. Protocol 1: eight Type II diabetic patients and eight matched healthy subjects received i.v. bolus injections of GLP-1(2.5 nmol) or GIP(7.5 nmol) concomitant with an increase of plasma glucose to 15 mmol/l. Protocol 2: eight Type II diabetic patients underwent a hyperglycaemic clamp (15 mmol/l) with infusion (per kg body weight/min) of either: 1 pmol GLP-1 (7-36) amide (n=8), 4 pmol GIP (n=8), 16 pmol GIP (n=4) or no incretin hormone (n=5). For comparison, six matched healthy subjects were examined.. Protocol 1: Type II diabetic patients were characterised by a decreased "early phase" response to both stimuli, but their relative response to GIP versus GLP-1 stimulation was exactly the same as in healthy subjects [insulin (C-peptide): patients 59+/-9% (74+/-6%) and healthy subjects 62+/-5% (71+/-9%)]. Protocol 2, "Early phase" (0-20 min) insulin response to glucose was delayed and reduced in the patients, but enhanced slightly and similarly by GIP and GLP-1. GLP-1 augmented the "late phase" (20-120 min) insulin secretion to levels similar to those observed in healthy subjects. In contrast, the "late phase" responses to both doses of GIP were not different from those obtained with glucose alone. Accordingly, glucose infusion rates required to maintain the hyperglycaemic clamp in the "late phase" period (20-120 min) were similar with glucose alone and glucose plus GIP, whereas a doubling of the infusion rate was required during GLP-1 stimulation.. Lack of GIP amplification of the late phase insulin response to glucose, which contrasts markedly to the normalising effect of GLP-1, could be a key defect in insulin secretion in Type II diabetic patients.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Synergism; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Injections, Intravenous; Insulin; Male; Middle Aged; Obesity; Peptide Fragments; Protein Precursors; Reference Values; Time Factors

Glucagon-like peptide-1 ameliorates the symptoms of diabetes through stimulation of insulin secretion and enhancement of beta-cell mass. We have therefore investigated the effects of glucagon-like peptide-1 on the development of diabetes, using db/db mice as a model of Type II diabetes.. The potent glucagon-like peptide-1 analogue Exendin-4 or vehicle (control) was administered (i.p.; 1 nmol/kg) to obese 6-week old db/db mice daily for 14 days ( n=10).. By 8 weeks of age, control db/db mice developed hyperglycaemia (fasting: 10.4+/-0.5 mmol/l), hyperinsulinaemia and impaired glucose tolerance. However, Exendin-4 treatment prevented hyperglycaemia (fasting: 6.1+/-1.0 mmol/l, p<0.01), with reduced plasma insulin concentrations ( p<0.001) and improved glucose tolerance ( p<0.05). Peripheral insulin sensitivity was not affected. However, insulin release in vivo and in vitro from the perfused pancreas was improved by Exendin-4, as were pancreatic insulin concentrations (0.54+/-0.02 vs 0.32+/-0.01 micro g/mg protein, p<0.05). These changes occurred in conjunction with increased beta-cell mass (3.01+/-0.31 vs 2.22+/-0.22 mg, p<0.05) and proliferation (BrdU(+) beta-cells: 1.08+/-0.20 vs 0.47+/-0.11%, p<0.05), as well as decreased apoptosis (Tunel (+) beta-cells: 0.37+/-0.06 vs 1.20+/-0.21%). Western blot demonstrated increased expression of Akt1 (by fivefold, p<0.01) and p44 MAP kinase (by sixfold, p<0.01), and decreased activation of caspase-3 (by 30%, p<0.05).. Our results suggest that Ex4 treatment delays the onset of diabetes in 6-8 week old db/db mice, through a mechanism involving Akt1 and expansion of the functional beta-cell mass.

Topics: Animals; Apoptosis; Blood Glucose; Cell Division; Diabetes Mellitus; Diabetes Mellitus, Type 1; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperglycemia; Insulin; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Peptide Fragments; Peptides; Protein Precursors; Venoms

A constant remodeling of islet cell mass mediated by proliferative and apoptotic stimuli ensures a dynamic response to a changing demand for insulin. In this study, we investigated the effect of glucagon-like peptide-1 (GLP-1) in Zucker diabetic rats, an animal model in which the onset of diabetes occurs when the proliferative potential and the rate of beta-cell apoptosis no longer compensate for the increased demand for insulin. We subjected diabetic rats to a 2-d infusion of GLP-1 and tested their response to an ip glucose tolerance test. GLP-1 produced a significant increase of insulin secretion, which was paralleled by a decrease in plasma glucose levels (P < 0.001 and P < 0.01, respectively). Four days after the removal of the infusion pumps, rats were killed and the pancreas harvested to study the mechanism by which GLP-1 ameliorated glucose tolerance. Ex vivo immunostaining with the marker of cell proliferation, Ki-67, showed that the metabolic changes observed in rats treated with GLP-1 were associated with an increase in cell proliferation of the endocrine and exocrine component of the pancreas. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining, a marker of cellular apoptosis, indicated a reduction of apoptotic cells within the islet as well in the exocrine pancreas in GLP-1-treated rats. Double immunostaining for the apoptotic marker caspase-3 and for insulin showed a significant reduction of caspase-3 expression and an increase in insulin content in GLP-1-treated animals. Finally, staining of pancreatic sections with the nuclear dye 4,6-Diaminidino-2-phenyl-dihydrochloride demonstrated a marked reduction of fragmented nuclei in the islet cells of rats treated with GLP-1. Our findings provide evidence that the beneficial effects of GLP-1 in Zucker diabetic rats is mediated by an increase in islet cell proliferation and a decrease of cellular apoptosis.

Topics: Animals; Apoptosis; Blood Glucose; Caspase 3; Caspases; Cell Division; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; In Situ Nick-End Labeling; Insulin; Insulin Secretion; Islets of Langerhans; Ki-67 Antigen; Kinetics; Male; Peptide Fragments; Protein Precursors; Rats; Rats, Zucker

To develop transplantable beta-cell lines for the treatment of diabetes mellitus, we have taken advantage of the property of INS-1 cells to synthesize and secrete not only insulin, but also small quantities of the insulinotropic hormone glucagon-like peptide-1 (GLP-1). In INS-1 cells over-expressing the beta-cell GLP-1 receptor (GLP-1-R), we have shown, by radioimmune assay and bioassay of conditioned medium, that an autocrine signaling mechanism of hormone action exists whereby self-secreted GLP-1 acts as a competence factor in support of insulin gene transcription. INS-1 cells also exhibit insulin gene promoter activity, as assayed in cells transfected with a rat insulin gene I promoter-luciferase construct (RIP1-Luc). The GLP-1-R agonist exendin-4 stimulates RIP1-Luc activity in a glucose-dependent manner, an effect mediated by endogenous GLP-1-Rs, and is blocked by the serine/threonine protein kinase inhibitor Ro 31-8220. Over-expression of GLP-1-R in transfected INS-1 cells reduces the threshold for exendin-4 agonist action, whereas basal RIP1-Luc activity increases 2.5-fold in the absence of added agonist. The increase of basal RIP1-Luc activity is a consequence of autocrine stimulation by self-secreted GLP-1 and is blocked by introduction of (1) an inactivating W39A mutation in the N-terminus ligand-binding domain of GLP-1-R or (2) mutations in the third cytoplasmic loop that prevent G protein coupling. No evidence for constitutive ligand-independent signaling properties of the GLP-1-R has been obtained. Over-expression of GLP-1-R increases the potency and efficacy of D-glucose as a stimulator of RIP1-Luc. Thus, INS-1 cells over-expressing the GLP-1-R recapitulate the incretin hormone effect of circulating GLP-1, thereby providing a possible strategy by which beta-cell lines may be engineered for efficient glucose-dependent insulin biosynthesis and secretion.

Topics: Animals; Autocrine Communication; Cell Line; Diabetes Mellitus; Enzyme Inhibitors; Exenatide; Gene Expression Regulation; Genetic Engineering; Glucagon; Glucagon-Like Peptide 1; Indoles; Insulin; Insulinoma; Islets of Langerhans; Islets of Langerhans Transplantation; Peptide Fragments; Peptides; Promoter Regions, Genetic; Protein Kinase C; Protein Precursors; Rats; Receptors, Peptide; Recombinant Proteins; Research Design; Second Messenger Systems; Tumor Cells, Cultured; Venoms

Acute suppression of dipeptidyl peptidase IV (DPP-IV) activity improves glucose tolerance in the Zucker fatty rat, a rodent model of impaired glucose tolerance, through stabilization of glucagon-like peptide (GLP)-1. This study describes the effects of a new and potent DPP-IV inhibitor, FE 999011, which is able to suppress plasma DPP-IV activity for 12 h after a single oral administration. In the Zucker fatty rat, FE 999011 dose-dependently attenuated glucose excursion during an oral glucose tolerance test and increased GLP-1 (7-36) release in response to intraduodenal glucose. Chronic treatment with FE 999011 (10 mg/kg, twice a day for 7 days) improved glucose tolerance, as suggested by a decrease in the insulin-to-glucose ratio. In the Zucker diabetic fatty (ZDF) rat, a rodent model of type 2 diabetes, chronic treatment with FE 999011 (10 mg/kg per os, once or twice a day) postponed the development of diabetes, with the twice-a-day treatment delaying the onset of hyperglycemia by 21 days. In addition, treatment with FE 999011 stabilized food and water intake to prediabetic levels and reduced hypertriglyceridemia while preventing the rise in circulating free fatty acids. At the end of treatment, basal plasma GLP-1 levels were increased, and pancreatic gene expression for GLP-1 receptor was significantly upregulated. This study demonstrates that DPP-IV inhibitors such as FE 999011 could be of clinical value to delay the progression from impaired glucose tolerance to type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Drinking; Eating; Fatty Acids, Nonesterified; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Insulin; Male; Nitriles; Obesity; Pancreas; Peptide Fragments; Protease Inhibitors; Protein Precursors; Pyrrolidines; Rats; Rats, Zucker; Receptors, Glucagon; Triglycerides; Weight Gain

The current studies were designed to examine the effect of aging and diabetes on the enteroinsular axis.. Healthy young control subjects (n = 10 young; age 23 +/- 1 years; body mass index [BMI] 24 +/- 1 kg/m(2)), healthy elderly subjects (n = 10; age 80 +/- 2 years; BMI 26 +/- 1 kg/m(2)), and elderly patients with type 2 diabetes (n = 10; age 76 +/- 2 years; BMI 26 +/- 2 kg/m(2)) underwent a 3-hour oral glucose tolerance test (glucose dose 40 gm/m(2)).. Insulin responses were not different between young controls and elderly patients with diabetes but were significantly lower in elderly patients with diabetes and young controls than in elderly controls (young control: 178 +/- 27 pM; elderly control: 355 +/- 57 pM; elderly diabetes: 177 +/- 30 pM; p <.05 elderly control vs young control and elderly diabetes). Total glucagon-like peptide 1 (GLP-1) responses were not significantly different between young and elderly controls and patients with diabetes (young control: 15 +/- 2 pM; old control: 8 +/- 2 pM; elderly diabetes: 12 +/- 3 pM; p = ns). Active GLP-1 responses were also not different between young and elderly controls and patients with diabetes (young control: 5 +/- 1 pM; old control: 6 +/- 1 pM; elderly diabetes: 7 +/- 1 pM; p = ns). However, the difference between total and active GLP levels was significantly greater in the young controls (young control: 10 +/- 2 pM; old control: 2 +/- 2 pM; elderly diabetes: 4 +/- 2 pM; p <.05, young vs elderly). Glucose-dependent insulinotropic polypeptide responses were not different between young and elderly controls and between elderly controls and patients with diabetes but were significantly higher in elderly patients with diabetes than in young controls (young control: 97 +/- 12 pM; elderly control: 121 +/- 16 pM; elderly diabetes: 173 +/- 27 pM; p <.05, young vs elderly diabetes). Glucagon responses were reduced in elderly controls but were similar in young controls and elderly patients with diabetes (young control: 15 +/- 1 pM; elderly control: 9 +/- 1 pM; elderly diabetes: 16 +/- 1 pM; p <.01 elderly control vs young control and elderly diabetes). Dipeptidyl peptidase IV levels were lower in both elderly controls and patients with diabetes when compared with young controls (young control: 0.17 +/- 0.01; elderly control: 0.15 +/- 0.01; elderly diabetes: 0.15 +/- 0.01 DeltaOD/20 minutes; p <.05, elderly vs young).. We conclude that normal aging and diabetes are associated with multiple changes in the enteroinsular axis.

Topics: Adult; Aged; Aged, 80 and over; Aging; Diabetes Mellitus; Dipeptidyl Peptidase 4; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Intestines; Islets of Langerhans; Male; Peptide Fragments; Protease Inhibitors; Protein Precursors

The present study explores the potential utility of peripheral versus central administration of glucagon-like peptide-1 (GLP-1) receptor agonists in the regulation of feeding behavior in Wistar and Zucker obese rats. Acute central (intracerebroventricular [i.c.v.]) and peripheral (subcutaneous [s.c.]) administration of both GLP-1 (7-36) amide and exendin-4 resulted in a reduction in food intake for at least 4 hours, exendin-4 being much more potent than GLP-1 (7-36) amide, especially after peripheral administration. Both Zucker obese rats (fa/fa) and their lean littermates (Fa/-) responded to acute central and peripheral administration of exendin-4. Moreover, in situ hybridization revealed specific labeling for the mRNA for GLP-1 receptors in several brain areas of both the obese and lean rats. The presence of this receptor was also detected by affinity cross-linking assays. Long-term s.c. administration of exendin-4 (1 single injection per day, 1 hour prior to the onset of the dark phase of the cycle) decreased daily food intake and practically blocked weight gain in obese rats. In contrast to previous studies, these findings show that peripheral (s.c.) administration of both GLP-1 receptor agonists also induces satiety and weight loss in rats, and suggest the potential usefulness of exendin-4 as a therapeutic tool for the treatment of diabetes and/or obesity.

Topics: Amines; Animals; Appetite; Body Weight; Brain; Diabetes Mellitus; Drinking; Eating; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; In Situ Hybridization; Injections, Intraventricular; Injections, Subcutaneous; Male; Obesity; Peptide Fragments; Peptides; Rats; Rats, Wistar; Rats, Zucker; Receptors, Glucagon; RNA, Messenger; Venoms

Diabetes is caused by a failure of the pancreas to produce insulin in amounts sufficient to meet the body's needs. A hallmark of diabetes is an absolute (type 1) or relative (type 2) reduction in the mass of pancreatic beta-cells that produce insulin. Mature beta-cells have a lifespan of approximately 48-56 days (rat) and are replaced by the replication of preexisting beta-cells and by the differentiation and proliferation of new beta-cells (neogenesis) derived from the pancreatic ducts. Here, we show that the insulinotropic hormone glucagon-like peptide (GLP)-1, which is produced by the intestine, enhances the pancreatic expression of the homeodomain transcription factor IDX-1 that is critical for pancreas development and the transcriptional regulation of the insulin gene. Concomitantly, GLP-1 administered to diabetic mice stimulates insulin secretion and effectively lowers their blood sugar levels. GLP-1 also enhances beta-cell neogenesis and islet size. Thus, in addition to stimulating insulin secretion, GLP-1 stimulates the expression of the transcription factor IDX-1 while stimulating beta-cell neogenesis and may thereby be an effective treatment for diabetes.

Topics: Animals; Diabetes Mellitus; Exenatide; Glucagon; Glucagon-Like Peptide 1; Homeodomain Proteins; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Peptide Fragments; Peptides; Promoter Regions, Genetic; Protein Precursors; Trans-Activators; Venoms

The hormone glucagon is secreted by the alpha-cells of the endocrine pancreas (islets of Langerhans) during fasting and is essential for the maintenance of blood glucose levels by stimulation of hepatic glucose output. Excessive production and secretion of glucagon by the alpha-cells of the islets is a common accompaniment to diabetes. The resulting hyperglucagonemia stimulates hepatic glucose production, thereby contributing to hyperglycemia of diabetes. The reduced insulin secretion in diabetes and resultant failure to suppress glucagon secretion by intra-islet paracrine mechanisms is believed to cause the hypersecretion of glucagon. Here, we report the discovery of a new mechanism by which glucagon suppresses insulin secretion. We show that glucagon, but not glucagon-like peptide 1 (GLP-1), or pituitary adenylyl cyclase-activating peptide (PACAP) specifically induces the expression of the transcriptional repressor inducible cAMP early repressor (ICER) in pancreatic beta-cells, resulting in a repression of the transcriptional expression of the insulin gene. Remarkably, glucagon, GLP-1, and PACAP all stimulate the formation of cAMP to a comparable extent in rat pancreatic islets, but only glucagon activates the expression of ICER and represses insulin gene transcription in beta-cells. These findings lead us to propose that hyperglucagonemia may additionally aggravate the diabetic phenotype via a suppression of insulin gene expression mediated by the transcriptional repressor ICER.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Binding Sites; Colforsin; Cyclic AMP; Cyclic AMP Response Element Modulator; Diabetes Mellitus; DNA; DNA-Binding Proteins; Female; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Insulin; Islets of Langerhans; Male; Neuropeptides; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Promoter Regions, Genetic; Protein Precursors; Rats; Rats, Sprague-Dawley; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The insulinotropic hormone, glucagon-like peptide-1 has been proposed for the treatment of patients with Type II (non-insulin-dependent) diabetes mellitus. As glucagon-like peptide-1 is rapidly cleaved at L-ala2 by dipeptidylpeptidase IV, D-ala2-glucagon-like peptide-1 was synthesized and shown to have dipeptidylpeptidase IV resistance in vitro and enhanced bioactivity in mice during an oral glucose challenge. The actions of D-ala2-glucagon-like peptide-1 were, however, lost within 4 h of injection, thus necessitating frequent and invasive treatment if it is to be used therapeutically. To circumvent this problem, a microsphere of D-ala2-glucagon-like peptide-1 that could be given orally was developed.. We encapsulated D-ala2-glucagon-like peptide-1 in poly(lactide-co-glycolide)-COOH with olive oil as a filler, using phase inversion. The microspheres were tested in vivo by oral gavage in mice at t = 0 h followed by repeated oral glucose tolerance tests at t = 0, 4 and 8 h.. The D-ala2-glucagon-like peptide-1-microspheres lowered the glycaemic response to the 4 h oral glucose challenge in both normal CD1 and diabetic db/db mice, by 41 +/- 12% (p <0.001) and 27 +/- 5% (p < 0.001), respectively and by 19 +/- 11% (p < 0.05) and 28 +/- 4% (p < 0.001), respectively during the 8-h test. At 4 h after the oral gavage, basal glycaemia in the diabetic mice was reduced from 13 +/- 1 mmol/l to 10 +/- 1 mmol/l and was reduced further 8h after treatment from 12 +/- 1 mmol/l to 8 +/- 1 mmol/l (p < 0.05). Giving D-ala2-glucagon-like peptide-1 alone orally had no effect on glycaemia.. The data presented here suggest that a similar microsphere preparation could be useful in the delivery of glucagon-like peptide-1 to patients with Type II diabetes.

Topics: 3-O-Methylglucose; Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Carriers; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Kinetics; Mice; Microspheres; Olive Oil; Peptide Fragments; Plant Oils; Polymers; Protein Precursors

To assess differences in circulating leptin and glucagon-like peptide (GLP)-1 concentrations before and after an oral glucose load, in euglycaemic and isoinsulinaemic conditions, between obese patients with and without Type 2 diabetes mellitus.. Ten male obese (body mass index (BMI) > 30 kg/m2) patients with Type 2 diabetes and 20 matched non-diabetic subjects were studied. Leptin, GLP-1(7-36)amide and GLP-1(7-37) concentrations were measured 0, 30, 60, and 90 min after a 50-g oral glucose load administered 90 min after the beginning of a euglycaemic hyperinsulinaemic clamp.. GLP-1(7-36)amide concentrations before the glucose load were significantly lower in diabetic patients than in controls (median (quartiles): 50.5 (44.7-53.2) vs. 128.7(100-172.5) pg/ml; P < 0.01), while no difference was observed in baseline GLP-1(7-37). In non-diabetic subjects, GLP-1(7-36)amide and GLP-1(7-37) concentrations increased significantly after the oral glucose load, while no glucose-induced increase in GLP-1 concentration was observed in diabetic patients. GLP-1(7-36)amide at 30, 60, and 90 min, and GLP-1(7-37) at 30 min, of the glucose challenge, were significantly lower in diabetic patients. Leptin concentrations were not significantly different in diabetic patients when compared to non-diabetic subjects, and they did not change after the oral glucose load.. Leptin concentrations are not significantly modified in obese Type 2 diabetic patients. GLP-1(7-36)amide baseline concentrations are reduced in Type 2 diabetes; moreover, diabetic subjects show an impaired response of GLP-1 to oral glucose in euglycaemic, isoinsulinaemic conditions. This impairment, which is not the result of differences in glycaemia or insulinaemia during assessment, could contribute to the pathogenesis of hyperglycaemia in Type 2 diabetes mellitus.

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin; Leptin; Male; Middle Aged; Obesity; Peptide Fragments; Protein Precursors

The Wistar fatty (WF) rat is a model of obese Type 2 diabetes mellitus (DM). These rats were bred by crossing Zucker fatty (ZF) and Wistar-Kyoto (WKY) rats. A homo-allelic leptin receptor gene mutation has been reported in ZF rats. We report here how these genetic factors contribute to plasma insulin regulation. The fasting plasma insulin levels were higher in WKY and Wistar lean (WL) rats than in Zucker lean (ZL) rats (p<0.05). The levels in WF and ZF rats were higher than in their respective lean littermates, WL and ZL rats (p<0.05). After intragastric glucose load, the plasma insulin increase was reduced upon pretreatment by intracerebroventricular (i. c.v.) methylatropine (an antagonist of the cholinergic receptor) injection in WL rats (p<0.05) but not in WF rats. Plasma glucagon-like peptide-1 (GLP-1) response to intragastric glucose load was not affected by methylatropine. After selective hepatic-vagotomy, plasma insulin levels increased in wild-type ZL rats (p<0.05). This increase was not observed in heterozygote ZL rats. Surprisingly, this response of plasma insulin was not shown in wild-type WL and WKY rats. ZF and WF rats did show a prominent decrease in insulin response (p<0.05). These results indicate that the genetic factor in ZF rats is associated with impaired vagal nerve-mediated control of insulin secretion. The genetic factor in WKY rats may diminish sensitivity to the vagal information of insulin release and contribute to insulin resistance. Therefore, we conclude that the presence of both genetic factors in a homo-allelic state is important to the development of DM in WF rats.

Topics: Animals; Atropine Derivatives; Blood Glucose; Carrier Proteins; Crosses, Genetic; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Mutation; Obesity; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred WKY; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Vagotomy; Vagus Nerve

This study investigates the mechanisms responsible for glucagon-like peptide-1 (GLP-1)-induced insulin secretion in Zucker diabetic fatty (ZDF) rats and their lean control (ZLC) littermates. Glucose, and 100 nmol/L GLP-1 (7-37 hydroxide) in the presence of stimulatory glucose concentrations, induced insulin secretion in islets from ZLC animals. In contrast, ZDF islets hypersecreted insulin at low glucose (5 mmol/L) and were poorly responsive to 15 mmol/L glucose stimulation, but increased insulin secretion following exposure to GLP-1. The insulin secretory response to 100 nmol/L GLP-1 was reduced by 88% in ZLC islets exposed to exendin 9-39. The intracellular Ca2+ concentration ([Ca2+]i) increased in fura-2-loaded ZLC islets following stimulation with 12 mmol/L glucose alone or GLP-1 in the presence of 12 mmol/L glucose. The increases in [Ca2+]i and insulin secretion in ZLC islets induced by GLP-1 were attenuated by 1 micromol/L nitrendipine. In contrast, neither glucose nor GLP-1 substantially increased [Ca2+]i in ZDF islets. Furthermore, insulin secretory responses to GLP-1 were not significantly inhibited in ZDF islets by nitrendipine. However, the insulin secretory response to GLP-1 in both ZLC and ZDF islets was ablated by cholera toxin. Our findings indicate that in ZLC islets, GLP-1 induces insulin secretion by a mechanism that depends on Ca2+ influx through voltage-dependent Ca2+ channels, whereas in ZDF islets, the action of GLP-1 is mediated by Ca2+-independent signaling pathways.

Topics: Animals; Calcium; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Insulin; Insulin Secretion; Islets of Langerhans; Obesity; Peptide Fragments; Protein Precursors; Rats; Rats, Zucker

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic beta-cells and an inhibition of insulin secretion by leptin via activation of ATP-sensitive potassium channels. Here we examine pancreatic islets isolated from pancreata of human donors for their responses to leptin. The presence of leptin receptors on islet beta-cells was demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nM) suppressed insulin secretion of normal islets by 20% at 5.6 mM glucose. Intracellular calcium responses to 16.7 mM glucose were rapidly reduced by leptin. Proinsulin messenger ribonucleic acid expression in islets was inhibited by leptin at 11.1 mM, but not at 5.6 mM glucose. Leptin also reduced proinsulin messenger ribonucleic acid levels that were increased in islets by treatment with 10 nM glucagon-like peptide-1 in the presence of either 5.6 or 11.1 mM glucose. These findings demonstrate direct suppressive effects of leptin on insulin-producing beta-cells in human islets at the levels of both stimulus-secretion coupling and gene expression. The findings also further indicate the existence of an adipoinsular axis in humans in which insulin stimulates leptin production in adipocytes and leptin inhibits the production of insulin in beta-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by beta-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.

Topics: Calcium; Carrier Proteins; Cells, Cultured; Diabetes Mellitus; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Obesity; Peptide Fragments; Potassium Channels; Proinsulin; Protein Precursors; Proteins; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

The purpose of the present study was to evaluate plasma glucagon-like peptide-1 (GLP-1) responses after oral glucose ingestion in patients with chronic pancreatitis and to clarify how GLP-1 secretion relates to pancreatic diabetes.. An oral glucose tolerance test (OGTT) was performed in 17 patients with chronic pancreatitis. Plasma glucose, immunoreactive insulin (IRI), C-peptide, glucagon, and GLP-1 levels at each time point during OGTT were measured. The diagnosis of chronic pancreatitis was made by the findings of endoscopic retrograde pancreatography (ERP): evident dilation of the main pancreatic duct with or without pancreatolithiasis.. The patients were divided into three groups according to the World Health Organization classification of diabetes based on plasma glucose levels after OGTT. The groups were: normal (three patients), impaired glucose tolerant (IGT) (six patients), and diabetic (DM) (eight patients). In the DM group, IRI and C-peptide response levels after oral glucose ingestion were significantly reduced as compared with those of the normal and IGT groups. No significant glucagon responses to oral glucose ingestion were found in the three groups. In contrast, plasma GLP-1 levels were significantly elevated after oral glucose ingestion in the DM groups as compared with normal and IGT groups.. The present study affords evidence that plasma GLP-1 levels become elevated with development of pancreatic diabetes, although the precise mechanism of this elevation remains undetermined.

Topics: C-Peptide; Case-Control Studies; Chronic Disease; Diabetes Mellitus; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Pancreatitis; Peptide Fragments; Protein Precursors; Time Factors

Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Dose-Response Relationship, Drug; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Kinetics; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Zucker; Sequence Homology; Venoms

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Obesity; Peptide Fragments; Protein Precursors

To study GIP and insulin release after a test meal in patients with chronic pancreatitis with and without secondary diabetes mellitus.. 28 patients with chronic pancreatitis were classified in groups I and II according to the presence or absence of secondary diabetes mellitus. Twelve healthy subjects were included as controls. After a test meal plasma GIP levels and serum insulin levels were determined at 0, 30, 60, 120 and 180 min.. A significant diminished GIP response was found in the groups of patients with respect to the control group. No association could be detected with severity of pancreatic insufficiency. Higher values of GIP were demonstrated at 60 and 120 min in patients without diabetes than in patients with it.. An abnormal GIP response is present in cases of chronic pancreatitis irrespective of the presence or severity of pancreatic insufficiency. This response is further affected if secondary diabetes mellitus is present.

Topics: Adult; Age Factors; Diabetes Mellitus; Digestion; Exocrine Pancreatic Insufficiency; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Pancreatitis; Peptide Fragments; Postprandial Period; Sex Factors

Pancreatic and gut hormone responses to oral glucose, and insulin sensitivity were studied in cystic fibrosis patients with normal (N = 14), impaired (N = 4), and diabetic (N = 12) glucose tolerance, and in 10 control subjects, and beta cell responses to oral glucose and intravenous glucagon were compared. Compared to control subjects, initial insulin and C-peptide responses to oral glucose were lower in all patient groups, and decreased with decreasing glucose tolerance. Insulin sensitivity in patients with impaired and diabetic glucose tolerance was lower than in control subjects. The 6 min post-glucagon C-peptide concentration was positively correlated with the initial insulin response to oral glucose. Fasting levels of pancreatic polypeptide, pancreatic glucagon, total glucagon, glucagon-like peptide-1 7-36 amide, and gastric inhibitory polypeptide were normal in all patient groups. Following oral glucose, pancreatic polypeptide responses were absent in all patients, suppressibility of pancreatic glucagon secretion was increasingly impaired with decreasing glucose tolerance, and gut hormone levels were normal. In conclusion, at cystic fibrosis (a) insulin secretion is impaired even when glucose tolerance and insulin sensitivity are within the normal range, (b) the glucagon test gives valid estimates of residual beta cell function, (c) pancreatic polypeptide response to oral glucose is absent, (d) glucagon suppressibility decreases with decreasing glucose tolerance, and (e) the enteroinsular axis is intact.

Topics: Administration, Oral; Adult; C-Peptide; Cystic Fibrosis; Diabetes Complications; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Tolerance Test; Hormones; Humans; Injections, Intravenous; Insulin; Intestinal Mucosa; Intestines; Male; Middle Aged; Pancreas; Pancreatic Polypeptide; Peptide Fragments; Proinsulin; Protein Precursors; Time Factors

Glucagon-like peptide-1 (7-36) amide (glucagon-like insulinotropic peptide, or GLIP) is a gastrointestinal peptide that potentiates the release of insulin in physiologic concentrations. Its effects in patients with diabetes mellitus are not known.. We compared the effect of an infusion of GLIP that raised plasma concentrations of GLIP twofold with the effect of an infusion of saline, on the meal-related release of insulin, glucagon, and somatostatin in eight normal subjects, nine obese patients with non-insulin-dependent diabetes mellitus (NIDDM), and eight patients with insulin-dependent diabetes mellitus (IDDM). The blood glucose concentrations in the patients with diabetes were controlled by a closed-loop insulin-infusion system (artificial pancreas) during the infusion of each agent, allowing measurement of the meal-related requirement for exogenous insulin. In the patients with IDDM, normoglycemic-clamp studies were performed during the infusions of GLIP and saline to determine the effect of GLIP on insulin sensitivity.. In the normal subjects, the infusion of GLIP significantly lowered the meal-related increases in the blood glucose concentration (P less than 0.01) and the plasma concentrations of insulin and glucagon (P less than 0.05 for both comparisons). The insulinogenic index (the ratio of insulin to glucose) increased almost 10-fold, indicating that GLIP had an insulinotropic effect. In the patients with NIDDM, the infusion of GLIP reduced the mean (+/- SE) calculated isoglycemic meal-related requirement for insulin from 17.4 +/- 2.8 to 2.0 +/- 0.5 U (P less than 0.001), so that the integrated area under the curve for plasma free insulin was decreased (P less than 0.05) in spite of the stimulation of insulin release. In the patients with IDDM, the GLIP infusion decreased the calculated isoglycemic meal-related insulin requirement from 9.4 +/- 1.5 to 4.7 +/- 1.4 U. The peptide decreased glucagon and somatostatin release in both groups of patients. In the normoglycemic-clamp studies in the patients with IDDM, the GLIP infusion significantly increased glucose utilization (saline vs. GLIP, 7.2 +/- 0.5 vs. 8.6 +/- 0.4 mg per kilogram of body weight per minute; P less than 0.01).. GLIP has an antidiabetogenic effect, and it may therefore be useful in the treatment of patients with NIDDM:

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Infusion Systems; Insulin Secretion; Male; Middle Aged; Obesity; Peptide Fragments; Peptides; Somatostatin