incretins and Disease-Models--Animal

Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym S

Topics: Administration, Intravenous; Adult; Aged; Animals; Biological Transport; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Mice; Middle Aged

The gut-brain hormone glucagon-like peptide-1 (GLP-1) has received immense attention over the last couple of decades for its widespread metabolic effects. Notably, intestinal GLP-1 has been recognized as an endogenous satiation signal. Yet, the underlying mechanisms and the pathophysiological relevance of intestinal GLP-1 in obesity remain unclear. This review first recapitulates early findings indicating that intestinal GLP-1 is an endogenous satiation signal, whose eating effects are primarily mediated by vagal afferents. Second, on the basis of recent findings challenging a paracrine action of intestinal GLP-1, a new model for the mediation of GLP-1 effects on eating by two discrete vagal afferent subsets will be proposed. The central mechanisms processing the vagal anorexigenic signals need however to be further delineated. Finally, the idea that intestinal GLP-1 secretion and/or effects on eating are altered in obesity and play a pathophysiological role in the development of obesity will be discussed. In summary, despite the successful therapeutic use of GLP-1 receptor agonists as anti-obesity drugs, the eating effects of intestinal GLP-1 still remain to be elucidated. Specifically, the findings presented here call for a further evaluation of the vago-central neuronal substrates activated by intestinal GLP-1 and for further investigation of its pathophysiological role in obesity.

Topics: Animals; Appetite; Brain; Disease Models, Animal; Eating; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Intestinal Mucosa; Liraglutide; Obesity; Satiation; Signal Transduction; Vagus Nerve

Nonalcoholic-fatty-liver-disease/nonalcoholic steatohepatitis (NAFLD/NASH) is expected to become the leading liver disease worldwide. Typical liver-related complications are fibrosis, cirrhosis, and the development of hepatocellular cancer (HCC) with the need for liver transplantation. Up to now there is no approved pharmacotherapy. Indeed, this might be due to the complexity of this disease. While the cheapest therapeutic approach is still a lifestyle change leading to weight loss, the proportion of people achieving sufficient weight reduction without additional support is low. Newly developed drugs are expensive and lack a breakthrough in therapeutic success. One reason might be that drugs developed often derive from murine models. Unfortunately, there is little overlap between genes in human and mice that are responsible for the development of NAFLD/NASH. This review aims at summarizing latest developments as well as stress again that more translational research is necessary.. Therapy of NAFLD/NASH is easy and very complex at the same time, as the current main target is weight reduction. Since this is in fact not easily achieved and maintained by many affected individuals, pharmacotherapy to halt the progression of NAFLD/NASH is urgently warranted. More translational studies are needed to understand the metabolic mechanisms and interactions between the liver, gut, oxidative stress and the processes leading to NAFLD progression and HCC development, even in the absence of cirrhosis.

Topics: Animals; Bariatric Surgery; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Humans; Hypolipidemic Agents; Incretins; Life Style; Lipogenesis; Liver; Liver Cirrhosis; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Species Specificity; Translational Research, Biomedical; Weight Loss; Weight Reduction Programs

Sepsis, a complex disorder characterized by a dysregulated immune response to an inciting infection, affects over one million Americans annually. Dysglycemia during sepsis hospitalization confers increased risk of organ dysfunction and death, and novel targets for the treatment of sepsis and maintenance of glucose homeostasis are needed. Incretin hormones are secreted by enteroendocrine cells in response to enteral nutrients and potentiate insulin release from pancreatic β cells in a glucose-dependent manner, thereby reducing the risk of insulin-induced hypoglycemia. Incretin hormones also reduce systemic inflammation in preclinical studies, but studies of incretins in the setting of sepsis are limited.. In this bench-to-bedside mini-review, we detail the evidence to support incretin hormones as a therapeutic target in patients with sepsis. We performed a PubMed search using the medical subject headings "incretins," "glucagon-like peptide-1," "gastric inhibitory peptide," "inflammation," and "sepsis.". Incretin-based therapies decrease immune cell activation, inhibit proinflammatory cytokine release, and reduce organ dysfunction and mortality in preclinical models of sepsis. Several small clinical trials in critically ill patients have suggested potential benefit in glycemic control using exogenous incretin infusions, but these studies had limited power and were performed in mixed populations. Further clinical studies examining incretins specifically in septic populations are needed.. Targeting the incretin hormone axis in sepsis may provide a means of not only promoting euglycemia in sepsis but also attenuating the proinflammatory response and improving clinical outcomes.

Topics: Animals; Clinical Trials as Topic; Diabetes Complications; Disease Models, Animal; Humans; Incretins; Sepsis; Translational Research, Biomedical; Treatment Outcome

The relationship between gut and skeleton is increasingly recognized as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism. We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify whether similar effects are present and clinically relevant in humans.

Topics: Animals; Bone and Bones; Bone Density; Bone Resorption; Diabetes Mellitus, Type 2; Disease Models, Animal; Fractures, Bone; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Obesity; Osteoblasts; Osteocalcin; Osteoclasts

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have attracted considerable scientific and clinical interest due largely to their insulin-releasing and glucose-lowering properties. Indeed, GLP-1-based therapies are now key treatment options for many people with diabetes worldwide. In contrast, GIP-based agents have yet to reach the clinic based primarily on the impaired insulinotropic action of GIP observed in people with diabetes. Nevertheless, GIP is a key physiological regulator of insulin secretion and stable forms of GIP show much promise in rodent models to alleviate diabetes-obesity. Recent studies suggest that GIP may have an important role to play in a combination therapeutic approach or bioengineered with other gut peptides. Moreover, recent experimental studies indicate that incretins also exert pleiotropic effects in regions of the brain associated with learning and memory, thereby supporting preclinical data demonstrating that incretin-based drugs improve cognitive function. This review article, based on the RD Lawrence Lecture presented at Diabetes UK Annual Professional Conference (2017), provides a brief overview of incretins with a major focus on GIP, the development of designer GIP analogues, and how these molecules can improve cognition. Thus, incretins can be considered as 'the intelligent hormones' and may hold the key to successfully treating the alarming rise in neurodegenerative disorders.

Topics: Alzheimer Disease; Animals; Cognition; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Learning; Memory; Nootropic Agents

Enzyme-resistant receptor agonists of the incretin hormone glucagon-like peptide-1 (GLP-1) have shown positive therapeutic effects in people with type 2 diabetes mellitus (T2DM). T2DM has detrimental effects on brain function and impairment of cognition and memory formation has been described. One of the underlying mechanisms is most likely insulin de-sensitization in the brain, as insulin improves cognitive impairments and enhances learning. Treatment with GLP-1 receptor agonists improves memory formation and impairment of synaptic plasticity observed in animal models of diabetes-obesity. Furthermore, it has been shown that diabetes impairs growth factor signalling in the brain and reduces energy utilization in the cortex. Inflammation and apoptotic signalling was also increased. Treatment with GLP-1 receptor agonists improved neuronal growth and repair and reduced inflammation and apoptosis as well as oxidative stress. In comparison with the diabetes drug metformin, GLP-1 receptor agonists were able to improve glycemic control and reverse brain impairments, whereas metformin only normalized blood glucose levels. Clinical studies in non-diabetic patients with neurodegenerative disorders showed neuroprotective effects following administration with GLP-1 receptor agonists, demonstrating that neuroprotective effects are independent of blood glucose levels.

Topics: Animals; Blood Glucose; Brain; Cognition; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Metformin; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress

Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology.

Topics: Animals; Bone Remodeling; Comorbidity; Diabetes Mellitus, Type 2; Disease Models, Animal; Fractures, Bone; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Mice; Mice, Knockout

The two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1), were discovered 45 and 30 years ago. Initially, only their insulinotropic effect on pancreatic β cells was known. Over the years, physiological and pharmacological effects of GIP and GLP1 in numerous extrapancreatic tissues were discovered which partially overlap, but may also be specific for GIP or GLP1 in certain target tissues. While the insulinotropic effect of GIP was found to be blunted in patients with type 2 diabetes, the function of GLP1 is preserved and GLP1 receptor agonists and dipeptidyl-peptidase 4 (DPP4) inhibitors, which prolong the half-life of incretins, are widely used in diabetes therapy. Wild-type and genetically modified rodent models have provided important mechanistic insights into the incretin system, but may have limitations in predicting the clinical efficacy and safety of incretin-based therapies. This review summarizes insights from rodent and non-rodent models (pig, non-human primate) into physiological and pharmacological incretin effects, with a focus on the pancreas. Similarities and differences between species are discussed and the increasing potential of genetically engineered pig models for translational incretin research is highlighted.

Topics: Animals; Animals, Genetically Modified; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Liraglutide; Mice; Mice, Knockout; Primates; Receptors, Gastrointestinal Hormone; Rodentia; Swine

Incretins are gastrointestinal-derived hormones released in response to a meal playing a key role in the regulation of postprandial secretion of insulin (incretin effect) and glucagon by the pancreas. Both incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), have several other actions by peripheral and central mechanisms. GLP-1 regulates body weight by inhibiting appetite and delaying gastric, emptying actions that are dependent on central nervous system GLP-1 receptor activation. Several other hormones and gut peptides, including leptin and ghrelin, interact with GLP-1 to modulate appetite. GLP-1 is rapidly degraded by the multifunctional enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 is involved in adipose tissue inflammation, which is associated with insulin resistance and diabetes progression, being a common pathophysiological mechanism in obesity-related complications. Furthermore, the incretin system appears to provide the basis for understanding the high weight loss efficacy of bariatric surgery, a widely used treatment for obesity, often in association with diabetes. The present review brings together new insights into obesity pathogenesis, integrating GLP-1 and DPP-4 in the complex interplay between obesity and inflammation, namely, in diabetic patients. This in turn will provide the basis for novel incretin-based therapeutic strategies for obesity and diabetes with promising benefits in addition to weight loss. © 2016 World Obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Secretion; Obesity; Weight Loss

Insulin secretion from the pancreatic β-cell (referred to as β-cell hereafter) plays a central role in glucose homeostasis. Impaired insulin secretion is a major factor contributing to the development of diabetes and, therefore, is an important target for treatment of the disease. Cyclic adenosine monophosphate is a key second messenger in β-cells that amplifies insulin secretion. Incretins released by the gut potentiate insulin secretion through cyclic adenosine monophosphate signaling in β-cells, which is the basis for the incretin-based diabetes therapies now being used worldwide. Despite its importance, the interaction between glucose metabolism and incretin/cyclic adenosine monophosphate signaling in β-cells has long been unknown. A recent study showed that cytosolic glutamate produced by glucose metabolism in β-cells is a key signal in incretin-induced insulin secretion. Here we review the physiological and pathophysiological roles of β-cell glutamate signaling in incretin-induced insulin secretion.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Glucose; Glutamic Acid; Humans; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Metabolomics; Obesity; Signal Transduction

We reported that native incretins, liraglutide and dipeptidyl peptidase-4 inhibitors (DPP-4i) all confer an anti-atherosclerotic effect in apolipoprotein E-null (Apoe (-/-)) mice. We confirmed the anti-atherogenic property of incretin-related agents in the mouse wire injury model, in which the neointimal formation in the femoral artery is remarkably suppressed. Furthermore, we showed that DPP-4i substantially suppresses plaque formation in coronary arteries with a marked reduction in the accumulation of macrophages in cholesterol-fed rabbits. DPP-4i showed an anti-atherosclerotic effect in Apoe (-/-) mice mainly through the actions of glucagon-like peptide-1 and glucose-dependent insulinotropic polypepide. However, the dual incretin receptor antagonists partially attenuated the suppressive effect of DPP-4i on atherosclerosis in diabetic Apoe (-/-) mice, suggesting an incretin-independent mechanism. Exendin-4 and glucose-dependent insulinotropic polypepide elicited cyclic adenosine monophosphate generation, and suppressed the lipopolysaccharide-induced gene expression of inflammatory molecules, such as interleukin-1β, interleukin-6 and tumor necrosis factor-α, in U937 human monocytes. This suppressive effect, however, was attenuated by an inhibitor of adenylate cyclase and mimicked by 8-bromo-cyclic adenosine monophosphate or forskolin. DPP-4i substantially suppressed the lipopolysaccharide-induced expression of inflammatory cytokines without affecting cyclic adenosine monophosphate generation or cell proliferation. DPP-4i more strongly suppressed the lipopolysaccharide-induced gene expression of inflammatory molecules than incretins, most likely through inactivation of CD26. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypepide suppressed oxidized low-density lipoprotein-induced macrophage foam cell formation in a receptor-dependent manner, which was associated with the downregulation of acyl-coenzyme A cholesterol acyltransferase-1 and CD36, as well as the up-regulation of adenosine triphosphate-binding cassette transporter A1. Our studies strongly suggest that incretin-related agents have favorable effects on macrophage-driven atherosclerosis in experimental animals.

Topics: Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Coronary Restenosis; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Foam Cells; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperplasia; Incretins; Inflammation; Inflammation Mediators; Liraglutide; Macrophages; Mice; Mice, Knockout; Monocytes

The new pharmacological classes of GLP-1 agonists and DPP-4 inhibitors are now widely used in diabetes and have been postulated as beneficial in heart failure. These proposed benefits arise from the inter-related pathophysiologies of diabetes and heart failure (diabetes increases the risk of heart failure, and heart failure can induce insulin resistance) and also in light of the dysfunctional myocardial energetics seen in heart failure. The normal heart utilizes predominantly fatty acids for energy production, but there is some evidence to suggest that increased myocardial glucose uptake may be beneficial for the failing heart. Thus, GLP-1 agonists, which stimulate glucose-dependent insulin release and enhance myocardial glucose uptake, have become a focus of investigation in both animal models and humans with heart failure. Limited pilot data for GLP-1 agonists shows potential improvements in systolic function, hemodynamics, and quality of life, forming the basis for current phase II trials.

Topics: Animals; Cardiovascular Agents; Clinical Trials as Topic; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Heart Failure; Humans; Incretins

Nutrient-specific sensor systems in enteroendocrine cells detect intestinal contents and cause gut hormone release upon activation. Among these peptide hormones, the incretins glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 are of particular interest by their role in glucose homeostasis, metabolic control and for proper ß-cell function. This review focuses on intestinal nutrient-sensing processes and their role in health and disease.. All macronutrients, respectively, their digestion products can cause incretin release by targeting specific sensors. Luminal glucose is the strongest stimulant for incretin release with the Na-dependent glucose transporter as the prime sensor. For peptides, the H-dependent peptide transporter together with calcium-sensing-receptor act as a sensing system. That transporters can function as nutrient-sensing 'transceptors' is conceptually new as G-protein coupled receptors so far were thought to be the sensing entities. This still holds true for GPR40 and GPR120 as sensors for medium/long-chain fatty acids and GPR41 and GPR43 for microbiota-derived short-chain fatty acids. Synthetic agonists for these receptors show impressive effects on glucagon-like peptide 1 output and glycemic control. Moreover, the remarkable and immediate antidiabetic effects of bariatric surgery/gastric bypass put intestinal nutrient sensing into focus of new strategies for metabolic control.. Targeting the intestinal nutrient-sensing machinery by dietary and/or pharmacological means holds promises in particular for treatment of type 2 diabetes. This interest may help to better understand the nutrient-sensing processes and the involvement of the intestine in overall endocrine, neuronal and metabolic control.

Topics: Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fiber; Dietary Proteins; Disease Models, Animal; Enteroendocrine Cells; Fatty Acids, Volatile; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Incretins; Intestinal Mucosa; Intestines

Pancreatic α-cell hyperplasia (ACH) was once an esoteric pathological entity, but it has become an important differential diagnosis of hyperglucagonemia after inactivating glucagon receptor (GCGR) genomic mutations were found in patients with ACH. Recently, the controversy over the pancreatic effects of incretins has stimulated much discussion of ACH that often includes inaccurate statements not supported by the literature.. Literature related to ACH was reviewed.. ACH is defined as a diffuse and specific increase in the number of α-cells. A dozen cases have been reported and fall into three clinical types: reactive, functional, and nonfunctional. Characterized by remarkable hyperglucagonemia without glucagonoma syndrome, reactive ACH is caused by inactivating GCGR mutations, and its main clinical significance is pancreatic neuroendocrine tumors diagnosed at middle age. The Gcgr(-/-) mice, a model of reactive ACH, exhibit a multistage tumorigenesis in their pancreata. Pharmacological agents that inhibit glucagon signaling also cause reactive ACH in animals and possibly in humans as well. The pancreata of incretin-treated humans and those of reactive ACH murine models share similarities. Functional ACH features hyperglucagonemia with glucagonoma syndrome. Nonfunctional ACH is associated with normal glucagon levels. The causes of functional and nonfunctional ACH are unknown as yet.. ACH is a histological diagnosis and clinically heterogeneous. Caused by GCGR mutations, reactive ACH is a preneoplastic lesion giving rise to slow-developing pancreatic neuroendocrine tumors. The effects of treatments targeting glucagon signaling in this regard remain controversial. The strong negative feedback control of glucagon signaling conserved in all mammals studied, including humans, makes long-term pancreatic tumor surveillance advisable for the glucagon signaling-targeting therapies.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Glucagon-Secreting Cells; Humans; Hyperplasia; Incretins; Mice; Mice, Knockout; Pancreatic Diseases; Receptors, Glucagon

Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9-36), a cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9-36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9-36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease.

Topics: Animals; Blood Glucose; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Disease Models, Animal; Enzyme Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Lipid Metabolism; Mice; Receptors, Glucagon; Treatment Outcome

Incretin mimetics, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as dipeptidyl peptidase-IV (DPP-IV) inhibitors, are used in the treatment of type 2 diabetes mellitus (T2DM). In addition to stimulating insulin secretion from pancreatic β cells, incretins have apparent extrapancreatic functions beyond glycemic control. This review summarizes the recent findings regarding the blood-pressure-lowering effects of incretins and DPP-IV inhibitors in patients who are obese, diabetic, or have metabolic syndrome.. Clinical studies have indicated that GLP-1 and its analogues lower blood pressure in patients with T2DM, particularly in patients with moderate-to-severe hypertension. DPP-IV inhibitors also appear to elicit a similar blood-pressure-lowering effect. In animal models of salt-sensitive hypertension, incretins appear to induce their antihypertensive effects by inhibiting the proximal tubular sodium reabsorption, and thereby increasing urinary excretion of sodium. These data suggest that the local actions of incretins may be via their key role in regulating natriuresis and lowering blood pressure.. Incretin mimetics and DPP-IV inhibitors are a novel class of antihypertensive drugs with natriuretic properties. They can be used in the treatment of salt-sensitive hypertension, which is characterized by edema.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Humans; Hypertension; Incretins; Kidney Tubules, Proximal; Molecular Mimicry; Natriuresis; Sodium; Sodium Chloride, Dietary; Treatment Outcome

This review summarizes key aspects of what has been learned about the physiology of pancreatic islets and leptin deficiency from studies in obese ob/ob mice. ob/ob Mice lack functional leptin. They are grossly overweight and hyperphagic particularly at young ages and develop severe insulin resistance with hyperglycemia and hyperinsulinemia. ob/ob Mice have large pancreatic islets. The beta-cells respond adequately to most stimuli, and ob/ob mice have been used as a rich source of pancreatic islets with high insulin release capacity. ob/ob Mice can perhaps be described as a model for the prediabetic state. The large capacity for islet growth and insulin release makes ob/ob mice a good model for studies on how beta-cells can cope with prolonged functional stress.

Topics: Animals; Disease Models, Animal; Glucose; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Mice, Obese; Models, Biological; Oscillometry

Pharmacologic intervention for the failing heart has traditionally targeted neurohormonal activation and ventricular remodeling associated with cardiac dysfunction. Despite the multitude of agents available for the treatment of heart failure, it remains a highly prevalent clinical syndrome with substantial morbidity and mortality, necessitating alternative strategies of targeted management. One such area of interest is the ability to modulate myocardial glucose uptake and its impact on cardioprotection. Glucose-insulin-potassium (GIK) infusions have been studied for decades, with conflicting results regarding benefit in acute myocardial infarction. Based on the same concepts, glucagon-like peptide-1-[7-36] amide (GLP-1) has recently been demonstrated to be a more effective alternative in left ventricular (LV) systolic dysfunction. This paper provides a review on the current evidence supporting the use of GLP-1 in both animal models and humans with ischemic and nonischemic cardiomyopathy.

Topics: Animals; Cardiomyopathy, Dilated; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose; Hemodynamics; Humans; Incretins; Myocardial Ischemia; Myocardium; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.

Topics: Adamantane; Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Humans; Hypoglycemic Agents; Incretins; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Many patients with type 2 diabetes fail to achieve adequate glycaemic control with available treatments, even when used in combination, and eventually develop microvascular and macrovascular diabetic complications. Even intensive interventions to control glycaemia reduce macrovascular complications only minimally. There is, therefore, a need for new agents that more effectively treat the disease, as well as target its prevention, its progression, and its associated complications. One emerging area of interest is centred upon the actions of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which enhance meal-induced insulin secretion and have trophic effects on the beta-cell. GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. Two new classes of agents have recently gained regulatory approval for therapy of type 2 diabetes; long-acting stable analogues of GLP-1, the so-called incretin mimetics, and inhibitors of dipeptidyl peptidase 4 (DPP-4, the enzyme responsible for the rapid degradation of the incretin hormones), the so-called incretin enhancers. This article focuses on DPP-4 inhibitors.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Mice; Rats

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Topics: Adult; Animals; Comorbidity; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Glucose; Hemodynamics; Humans; Incretins; Male; Middle Aged; Myocardium; Obesity; Oxygen Consumption; p38 Mitogen-Activated Protein Kinases; Physical Conditioning, Animal; Regional Blood Flow; Rest; Signal Transduction; Swine; Treatment Outcome

Long-term sleep deprivation (SD) is a bad lifestyle habit, especially among specific occupational practitioners, characterized by circadian rhythm misalignment and abnormal sleep/wake cycles. SD is closely associated with an increased risk of metabolic disturbance, particularly obesity and insulin resistance. The incretin hormone, glucagon-like peptide-1 (GLP-1), is a critical insulin release determinant secreted by the intestinal L-cell upon food intake. Besides, the gut microbiota participates in metabolic homeostasis and regulates GLP-1 release in a circadian rhythm manner. As a commonly recognized intestinal probiotic,

Topics: Animals; Bifidobacterium; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Circadian Rhythm; Dietary Supplements; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Incretins; Insulin; Insulin Resistance; Macaca mulatta; Male; Sleep Deprivation; Treatment Outcome; Triglycerides

The role of the incretin hormone, glucagon-like peptide (GLP-1), in Crohn's disease (CD), is still poorly understood. The aim of this study was to investigate whether colitis is associated with changes in blood glucose levels and the possible involvement of the incretin system as an underlaying factor.. We used a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Macroscopic and microscopic score and expression of inflammatory cytokines were measured. The effect of colitis on glucose level was studied by measurement of fasting glucose and GLP-1, dipeptidyl peptidase IV (DPP IV) levels, prohormone convertase 1/3 (PC 1/3) and GLP-1 receptor (GLP-1R) expression in mice. We also measured the level of GLP-1, DPP IV and expression of glucagon (GCG) and PC 1/3 mRNA in serum and colon samples from healthy controls and CD patients.. Fasting glucose levels were increased in animals with colitis compared to controls. GLP-1 was decreased in both serum and colon of mice with colitis in comparison to the control group. DPP IV levels were significantly increased in serum, but not in the colon of mice with colitis as compared to healthy animals. Furthermore, PC 1/3 and GLP-1R expression levels were increased in mice with colitis as compared to controls. In humans, no differences were observed in fasting glucose level between healthy subjects and CD patients. GLP-1 levels were significantly decreased in the serum. Interestingly, GLP-1 level was significantly increased in colon samples of CD patients compared to healthy subjects. No significant differences in DPP IV levels in serum and colon samples were observed between groups.. Changes in the incretin system during colitis seem to contribute to the impaired glucose levels. Differences in incretin levels seem to be modulated by degrading enzyme DPP-IV and PC 1/3. Obtained results suggest that the incretin system may become a novel therapeutic approach in the treatment of CD.

Topics: Adult; Animals; Blood Glucose; Case-Control Studies; Colitis; Crohn Disease; Dipeptidyl Peptidase 4; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Humans; Incretins; Inflammation; Male; Mice; Mice, Inbred C57BL; Middle Aged; Proprotein Convertase 1; Trinitrobenzenesulfonic Acid; Young Adult

Depression is a widespread, withering illness, resulting in a massive personal suffering and economic loss. The chronic exposure to stress may be involved in the etiology of human psychiatric disorders; such as depression. In the current study, the animals were subjected to chronic unpredictable mild stress (CUMS) for 14 days. Saxagliptin (SAXA) is a member of dipeptidyl peptidase-4 (DPP-4) inhibitors class. The current study was the first one to examine the anti-depressive effect of SAXA in an experimental model of CUMS-induced depression in rats and the possible underlying mechanisms. Animals were orally treated with SAXA (0.5, 1 and 2 mg/kg) for 14 days. SAXA treatment reversed the CUMS-induced alterations in the behavioral, biochemical as well as histopathological parameters. Moreover, it hindered the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers. On the other hand, it increased the monoamines levels and the neurogenic brain derived neurotrophic factor (BDNF). In addition, SAXA treatment increased the incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are linked to the activation of protein kinase B (AKT)/phosphatidylinositol3-kinase (PI3K) pathway. In conclusion, the current study revealed that the modulation of the interplay between the key events involved in depression, including oxidative stress, inflammation, and GLP-1/PI3K/AKT signaling pathway, can explain the anti-depressant activity of SAXA.

Topics: Adamantane; Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Brain; Brain-Derived Neurotrophic Factor; Caspase 3; Depression; Dipeptides; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Incretins; Inflammation; Male; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Stress, Psychological

This study evaluates the capacity of a bread enriched with fermentable dietary fibres to modulate the metabolism and nutrients handling between tissues, gut and peripheral, in a context of overfeeding. Net fluxes of glucose, lactate, urea, short chain fatty acids (SCFA), and amino acids were recorded in control and overfed female mini-pigs supplemented or not with fibre-enriched bread. SCFA in fecal water and gene expressions, but not protein levels or metabolic fluxes, were measured in muscle, adipose tissue, and intestine. Fibre supplementation increased the potential for fatty acid oxidation and mitochondrial activity in muscle (

Topics: Adipose Tissue; Amino Acids; Animals; Bread; Dietary Fiber; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Fatty Acids, Volatile; Feces; Female; Fermented Foods; Glucose; Incretins; Intestines; Lactic Acid; Muscle, Skeletal; Overnutrition; Swine; Swine, Miniature; Urea

This study evaluated if the cardioprotective effect of Exendin-4 against ischemia/reperfusion (I/R) injury in male rats involves modulation of AMPK and sirtuins. Adult male rats were divided into sham, sham + Exendin-4, I/R, I/R + Exendin-4, and I/R + Exendin-4 + EX-527, a sirt1 inhibitor. Exendin-4 reduced infarct size and preserved the function and structure of the left ventricles (LV) of I/R rats. It also inhibited oxidative stress and apoptosis and upregulated MnSOD and Bcl-2 in their infarcted myocardium. With no effect on SIRTs 2/6/7, Exendin-4 activated and upregulated mRNA and protein levels of SIRT1, increased levels of SIRT3 protein, activated AMPK, and reduced the acetylation of p53 and PGC-1α as well as the phosphorylation of FOXO-1. EX-527 completely abolished all beneficial effects of Exendin-4 in I/R-induced rats. In conclusion, Exendin-4 cardioprotective effect against I/R involves activation of SIRT1 and SIRT3. Graphical Abstract Exendin-4 could scavenge free radical directly, upregulate p53, and through upregulation of SIRT1 and stimulating SIRT1 nuclear accumulation. In addition, Exendin-4 also upregulates SIRT3 which plays an essential role in the upregulation of antioxidants, inhibition of reactive oxygen species (ROS) generation, and prevention of mitochondria damage. Accordingly, SIRT1 induces the deacetylation of PGC-1α and p53 and is able to bind p-FOXO-1. This results in inhibition of cardiomyocyte apoptosis through increasing Bcl-2 levels, activity, and levels of MnSOD; decreasing expression of Bax; decreasing cytochrome C release; and improving mitochondria biogenesis through upregulation of Mfn-2.

Topics: Acetylation; AMP-Activated Protein Kinases; Animals; Apoptosis; Disease Models, Animal; Enzyme Activation; Exenatide; Glucagon-Like Peptide-1 Receptor; Incretins; Male; Myocardial Reperfusion Injury; Myocytes, Cardiac; Nerve Tissue Proteins; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Rats, Wistar; Signal Transduction; Sirtuin 1; Sirtuins; Tumor Suppressor Protein p53; Up-Regulation; Ventricular Function, Left

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like glucagon-like peptide receptor agonist (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide (Lira) and the SGLT2i dapagliflozin (Dapa).. Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high-fat diet (HFD) for 12 weeks. After 8 weeks HFD, angiotensin II (ANGII), was administered for 4 weeks via osmotic mini pumps. HFD + ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling, and metabolic dysregulation with inflammation. The multiple hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement, lung congestion, and elevated blood pressures. Treatment with Lira attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapa treatment improved glucose handling, but had mild effects on the HFpEF phenotype.. We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of HFpEF.

Topics: Angiotensin II; Animals; Benzhydryl Compounds; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Female; Fibrosis; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Glucosides; Heart Failure, Diastolic; Hypertrophy, Left Ventricular; Incretins; Liraglutide; Mice, Inbred C57BL; Myocardium; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; Ventricular Function, Left; Ventricular Remodeling

The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders.. Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague-Dawley rats (n = 7) were injected only with a vehicle.. The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment.. Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

Topics: Albuminuria; Animals; Autophagy; Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Incretins; Kidney; Liraglutide; Male; Rats, Inbred Strains; Signal Transduction

Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9-39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO

Topics: Animals; Arterioles; Cerebrovascular Circulation; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hindlimb; Incretins; Infarction, Middle Cerebral Artery; Ischemic Preconditioning; Ischemic Stroke; Male; Neuroprotective Agents; Peptide Fragments; Rats, Sprague-Dawley; Regional Blood Flow; Vasodilation; Vasodilator Agents

Topics: Animals; Blood Glucose; Body Weight; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Fish Proteins; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Incretins; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Lampreys; Mice; Receptors, Glucagon

The role of exendin-4 in brown adipose tissue (BAT) activation was not very clear. This study is to verify the role of BAT involved in renal benefits of exendin-4 in diabetes mellitus (DM).. In vivo, C57BL/6 mice were randomly divided into nondiabetic (control) and diabetic groups (DM). The diabetic mice were randomized into a control group (DM-Con), BAT-excision group (DM+Exc), exendin-4-treated group (DM+E4), and BAT-excision plus exendin-4-treated group (DM+Exc+E4). The weight, blood glucose and lipids, 24 h urine albumin and 8-OH-dG, and renal fibrosis were analyzed. In vitro, we investigated the role of exendin-4 in the differentiation process of 3T3-L1 and brown preadipocytes and its effect on the rat mesangial cells induced by oleate.. The expressions of UCP-1, PGC-1. Exendin-4 could decrease the renal lipid deposit and improve diabetic nephropathy via activating the renal AMPK pathway independent of BAT activation.

Topics: 3T3-L1 Cells; 8-Hydroxy-2'-Deoxyguanosine; Adenylate Kinase; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Albuminuria; Animals; Blood Glucose; Blotting, Western; Body Weight; CD36 Antigens; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Exenatide; Fibrosis; Gene Expression; Incretins; Kidney; Lipase; Mesangial Cells; Mice; Mice, Inbred C57BL; Myofibroblasts; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Rats; Real-Time Polymerase Chain Reaction; Triglycerides; Uncoupling Protein 1

Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl).. Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting.. We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably.. In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.

Topics: Animals; Coronary Artery Disease; Coronary Circulation; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hypertension; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Male; Microcirculation; Nitric Oxide; Obesity; Oxidative Stress; Rats, Zucker; Sodium Chloride, Dietary; Ventricular Remodeling

Sirt1 is a potent inhibitor of both poly(ADP-ribose) polymerases1 (PARP1) and NF-kB. This study investigated the cardioprotective effect of exendin-4 on cardiac function and remodeling in rats after an expreimentally-induced myocardial infarction (MI) and explored if this protection involves SIRT1/PARP1 axis. Rats were divided into five groups (n = 10/each): sham, sham + exendin-4 (25 nmol/kg/day i.p.), MI (induced by LAD occlusion), MI + exendin-4, and sham + exendin-4 + EX527 (5 mg/2×/week) (a SIRT1 inhibitor). All treatments were given for 6 weeks post the induction of MI. In sham-operated and MI-induced rats, exendin-4 significantly upregulated Bcl-2 levels, enhanced activity, mRNA, and levels of SIRT1, inhibited activity, mRNA, and levels of PARP1, and reduced ROS generation and PARP1 acetylation. In MI-treated rats, these effects were associated with improved cardiac architectures and LV function, reduced collagen deposition, and reduced mRNA and total levels of TNF-α and IL-6, as well as, the activation of NF-κB p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-β1, Smad3, and NF-κB p65 and signficantly reduced mRNA and protein levels of collagen I/III and protein levels of MMP2/9. In conclusion, exendin-4 is a potent cardioprotective agent that prevents post-MI inflammation and cardiac remodeling by activating SIRT1-induced inhibition of PARP1.

Topics: Acetylation; Animals; Anti-Inflammatory Agents; Apoptosis; Disease Models, Animal; Exenatide; Fibrosis; Glucagon-Like Peptide-1 Receptor; Incretins; Male; Myocardial Infarction; Myocytes, Cardiac; NF-kappa B; Poly (ADP-Ribose) Polymerase-1; Rats, Wistar; Signal Transduction; Sirtuin 1; Ventricular Function, Left; Ventricular Remodeling

Mammalian target of rapamycin (mTOR) and a ribosomal protein S6 kinase (p70S6K) mediate tissue fibrosis and negatively regulate autophagy. This study aims to investigate whether glucagon-like peptide-1 (GLP-1) analog liraglutide protects the heart against aortic banding-induced cardiac fibrosis and dysfunction through inhibiting mTOR/p70S6K signaling and promoting autophagy activity. Male SD rats were randomly divided into four groups (n = 6/each group): sham operated control; abdominal aortic constriction (AAC); liraglutide treatment during AAC (0.3 mg/kg, injected subcutaneously twice daily); rapamycin treatment during AAC (0.2 mg/kg/day, administered by gastric gavage). Relative to the animals with AAC on week 16, liraglutide treatment significantly reduced heart/body weight ratio, inhibited cardiomyocyte hypertrophy, and augmented plasma GLP-1 level and tissue GLP-1 receptor expression. Phosphorylation of mTOR/p70S6K, populations of myofibroblasts and synthesis of collagen I/III in the myocardium were simultaneously inhibited. Furthermore, autophagy regulating proteins: LC3-II/LC3-I ratio and Beclin-1 were upregulated, and p62 was downregulated by liraglutide. Compared with liraglutide group, treatment with rapamycin, a specific inhibitor of mTOR, compatibly augmented GLP-1 receptor level, inhibited phosphorylation of mTOR/p70S6K and expression of p62 as well as increased level of LC3-II/LC3-I ratio and Beclin-1, suggesting that there is an interaction between GLP-1 and mTOR/p70S6K signaling in the regulation of autophagy. In line with these modifications, treatment with liraglutide and rapamycin significantly reduced perivascular/interstitial fibrosis, and preserved systolic/diastolic function. These results suggest that the inhibitory effects of liraglutide on cardiac fibrosis and dysfunction are potentially mediated by inhibiting mTOR/p70S6K signaling and enhancing autophagy activity.

Topics: Animals; Aorta, Abdominal; Autophagy; Autophagy-Related Proteins; Disease Models, Animal; Fibrosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypertrophy, Left Ventricular; Incretins; Ligation; Male; Myocytes, Cardiac; Myofibroblasts; Phosphorylation; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Function, Left; Ventricular Remodeling

Methylglyoxal was shown to impair adipose tissue capillarization and insulin sensitivity in obese models. We hypothesized that glyoxalase-1 (GLO-1) activity could be diminished in the adipose tissue of type 2 diabetic obese patients. Moreover, we assessed whether such activity could be increased by GLP-1-based therapies in order to improve adipose tissue capillarization and insulin sensitivity. GLO-1 activity was assessed in visceral adipose tissue of a cohort of obese patients. The role of GLP-1 in modulating GLO-1 was assessed in type 2 diabetic GK rats submitted to sleeve gastrectomy or Liraglutide treatment, in the adipose tissue angiogenesis assay and in the HUVEC cell line. Glyoxalase-1 activity was decreased in visceral adipose tissue of pre-diabetic and diabetic obese patients, together with other markers of adipose tissue dysfunction and correlated with increased HbA1c levels. Decreased adipose tissue GLO-1 levels in GK rats were increased by sleeve gastrectomy and Liraglutide, being associated with overexpression of angiogenic and vasoactive factors, as well as insulin receptor phosphorylation (Tyr1161). Moreover, GLP-1 increased adipose tissue capillarization and HUVEC proliferation in a glyoxalase-dependent manner. Lower adipose tissue GLO-1 activity was observed in dysmetabolic patients, being a target for GLP-1 in improving adipose tissue capillarization and insulin sensitivity.

Topics: Adipose Tissue; Adult; Aged; Animals; Capillaries; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gastrectomy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Human Umbilical Vein Endothelial Cells; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lactoylglutathione Lyase; Liraglutide; Male; Middle Aged; Neovascularization, Physiologic; Obesity; Rats, Wistar; Signal Transduction

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (

Topics: Adipocytes; Adipokines; Adult; Animals; Bariatric Surgery; Bile Acids and Salts; Cells, Cultured; Disease Models, Animal; Down-Regulation; Female; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Incretins; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Obesity; Tumor Necrosis Factors; Weight Loss

To study the relationship between the amount of surgery-induced gastric volume reduction and long-term weight loss and glucose tolerance.. Vertical sleeve gastrectomy (VSG) has recently surpassed gastric bypass to become the most popular surgical intervention to induce sustained weight loss. Besides inducing significant weight loss, VSG also improves glucose tolerance. Although no clear correlation has been observed between the size of the residual stomach and sustained weight loss, this begs the question whether less aggressive gastric volume reduction may provide sufficient efficacy when weight loss is not the major goal of the surgical intervention.. A series of strategies to reduce gastric volume were developed and tested in Long Evans male rats, namely: VSG, Fundal (F)-Resection, Gastric Sleeve Plication (GSP), Fundal-Plication, and Fundal-Constrained.. All surgical interventions resulted in a reduction of gastric volume relative to sham, but none of the interventions were as effective as the VSG. Gastric volume was linearly correlated to increased gastric emptying rate as well as increased GLP-1 response. Overall, cumulative food intake was the strongest correlate to weight loss and was logarithmically related to gastric volume. Regression modeling revealed a nonlinear inverse relation between body weight reduction and gastric volume, confirming that VSG is the only effective long-term weight loss strategy among the experimental operations tested.. The data suggest a minimum threshold volume of the residual stomach that is necessary to induce sustained weight loss. Although all gastric volume interventions increased the GLP-1 response, none of the interventions, except VSG, significantly improved glucose tolerance. In conclusion, if weight loss is the primary goal of surgical intervention, significant volume reduction is required, and this most likely requires excising gastric tissue.

Topics: Animals; Bariatric Surgery; Blood Glucose; Disease Models, Animal; Gastric Emptying; Glucagon-Like Peptide 1; Glucose Tolerance Test; Incretins; Male; Obesity; Organ Size; Rats; Rats, Long-Evans; Stomach; Weight Loss

Reverse cholesterol transport (RCT) is an important cardioprotective mechanism and the decrease in cholesterol efflux can result in the dyslipidemia. Although liraglutide, a glucagon like peptide-1 analogue, has mainly impacted blood glucose, recent data has also suggested a beneficial effect on blood lipid. However, the exact mechanism by which liraglutide modulates lipid metabolism, especially its effect on RCT, remain undetermined. Hence, the aim of the present study was to investigate the potential impacts and potential underlying mechanisms of liraglutide on the cholesterol efflux in both db/db mice and HepG2 cells.. Liraglutide could improve lipid metabolism and hepatic lipid accumulation in db/db mice fed with HFD by promoting reversal of cholesterol transport, which was associated with the up-regulation of ABCA1 mediated by the ERK1/2 phosphorylation.

Topics: Animals; ATP Binding Cassette Transporter 1; Blood Glucose; Cholesterol; Diabetes Mellitus; Diet, High-Fat; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Liver; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Signal Transduction

A substantial number of ischaemic stroke patients who receive reperfusion therapy in the acute phase do not ever fully recover. This reveals the urgent need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy. Previous experimental studies demonstrated the potential of glucagon-like peptide-1 (GLP-1) to reduce acute ischaemic damage in the brain. Here, we examined the neuroprotective effects of two GLP-1 analogues, liraglutide and semaglutide.. A non-diabetic rat model of acute ischaemic stroke involved 90, 120 or 180 min of middle cerebral artery occlusion (MCAO). Liraglutide or semaglutide was administered either i.v. at the onset of reperfusion or s.c. 5 min before the onset of reperfusion. Infarct size and functional status were evaluated after 24 h or 72 h of reperfusion.. Liraglutide, administered as a bolus at the onset of reperfusion, reduced infarct size by up to 90% and improved neuroscore at 24 h in a dose-dependent manner, following 90-min, but not 120-min or 180-min ischaemia. Semaglutide and liraglutide administered s.c. reduced infarct size by 63% and 48%, respectively, and improved neuroscore at 72 h following 90-min MCAO. Neuroprotection by semaglutide was abolished by GLP1-R antagonist exendin(9-39).. Infarct-limiting and functional neuroprotective effects of liraglutide are dose-dependent. Neuroprotection by semaglutide is at least as strong as by liraglutide and is mediated by GLP-1Rs.

Topics: Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Incretins; Infarction, Middle Cerebral Artery; Liraglutide; Male; Neuroprotective Agents; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Time Factors

Glucagon-like peptide-1 (GLP-1) reduces cardiovascular events in diabetic patients; however, its counter-protective effects have also been suggested in patients with heart failure and the clear explanation for its mechanisms have not yet been offered.. The effects of GLP-1 analog on cardiac function and energy metabolism, especially glycemic and lipid metabolisms were elucidated using non-diabetic J2N-k hamsters which showed spontaneous dilated cardiomyopathy. J2N-k hamsters were treated with PBS (HF group), low-dose (HF-L group) or high-dose liraglutide (HF-H group).. In failing heart, GLP-1 analog exerted further deteriorated cardiac function (e.g. positive and negative dP/dt; p = 0.01 and p = 0.002, respectively) with overt fibrosis and cardiac enlargement (heart/body weight, 5.7 ± 0.2 in HF group versus 7.6 ± 0.2 in HF-H group; p = 0.02). The protein expression of cardiac muscles indicated the energy starvation status. Indirect calorimetry showed that failing hearts consumed higher energy and carbohydrate than normal hearts; moreover, this tendency was augmented by GLP-1 analog administration. Upon 10% glucose solution loading with GLP-1 analog administration (HF-H-G group) as complementary experiments, the cardiac function and fibrosis significantly ameliorated, whereas carbohydrate utilization augmented further and lipid utilization reduced more. The prognosis of HF-H-G group also significantly improved (p = 0.025).. Glucagon-like peptide-1 analog caused the relative but desperate shortage of glycemic energy source for the failing cardiac muscles and it may restrict ATP synthesis, resulting in cardiac function deterioration. Therefore, appropriate energy supply and amount of carbohydrate intake should be carefully considered when administrating incretin-related drugs to patients with heart failure.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathy, Dilated; Cricetinae; Disease Models, Animal; Energy Metabolism; Fibrosis; Heart Failure; Incretins; Liraglutide; Male; Myocytes, Cardiac; Risk Assessment; Stroke Volume; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production.. Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out.. Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics.

Topics: 1-Deoxynojirimycin; Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Dynamins; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycoside Hydrolase Inhibitors; GTP Phosphohydrolases; Heart Failure; Ileum; Incretins; Male; Membrane Proteins; Mitochondria, Heart; Mitochondrial Dynamics; Mitochondrial Proteins; Myocytes, Cardiac; Paracrine Communication; Peptide Fragments; Rats, Inbred Dahl; Rats, Sprague-Dawley; Signal Transduction; Sodium Chloride, Dietary; Ventricular Function, Left

Insulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF.. We tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets.. Fasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels.. These results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF.

Topics: Animals; Cystic Fibrosis; Disease Models, Animal; Female; Ferrets; Ghrelin; Hyperglycemia; Incretins; Insulin Secretion; Male

Topics: Animal Feed; Animals; Copepoda; Disease Models, Animal; Energy Metabolism; Exenatide; Fatty Acids; Female; Glucose; Incretins; Isolated Heart Preparation; Mice, Inbred C57BL; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Obesity; Oils; Recovery of Function; Ventricular Function, Left; Ventricular Pressure

Herein, the potential of hydrolysates of chicken feet proteins as natural dipeptidyl-peptidase IV (DPP-IV) inhibitors was investigated; moreover, three hydrolysates were selected due to their high DPP-IV inhibitory capacity (>80% inhibition), showing the IC50 values of around 300 μg estimated protein per mL; one of them (named p4H) was selected for the posterior analysis. In addition, its effect on glucose tolerance was investigated in two rat models (diet and age-induced) of glucose-intolerance and healthy animals; the amount of 300 mg estimated peptide per kg body weight improved the plasma glucose profile in both glucose-intolerance models. Moreover, it stimulated active GLP-1 release in the enteroendocrine STC-1 cells and rat ileum tissue. In conclusion, our results indicate that chicken feet proteins are a good source of bioactive peptides as DPP-IV inhibitors. Moreover, our results highlight the potential of the selected hydrolysate p4H in the management of type 2 diabetes due to its dual function of inhibition of the DPP-IV activity and induction of the GLP-1 release.

Topics: Animals; Blood Glucose; Body Weight; Cell Line; Chickens; Diabetes Mellitus, Type 2; Diet; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Drug Delivery Systems; Female; Foot; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Incretins; Inhibitory Concentration 50; Male; Protein Hydrolysates; Rats; Rats, Wistar

Despite excellent results of bariatric surgery in the treatment of type 2 diabetes and weight loss in human subjects, some patients do not obtain desired results. One of the reasons for this is that not all patients follow caloric intake recommendations.. The aim of this study was to investigate the effect of duodenojejunal omega switch (DJOS) surgery on body weight, glucose tolerance, and incretins in rats.. DJOS and SHAM surgery were performed on rats maintained for 8 weeks on high-fat diet (HF) and control diet (CD), respectively. After surgery, four groups were kept on the same diet as before the surgery, and four groups had a changed diet (CD vs. HF and HF vs. CD) for the next 8 weeks. Glucose tolerance, insulin tolerance, glucose-stimulated insulin, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) secretion, food intake, and body weight were measured.. A change of diet after surgery resulted in reduced glucose tolerance. Plasma insulin levels were lowered between DJOS and SHAM surgeries for the HF/HF and CD/HF groups. DJOS surgery did not reduce body weight in the studied groups, irrespective of diet. In the HF/HF group, ΔGLP-1 was lower for DJOS surgery in comparison with other groups. Differences of weight changes were observed for groups HF/HF and HF/CD. After DJOS surgery, ΔGIP was lower in the CD/HF group compared with HF/HF.. Our results show that applications of different types of diets, before and after surgery, is a sensitive method for studies of mechanism of glucose intolerance after DJOS surgery.

Topics: Anastomosis, Surgical; Animals; Bariatric Surgery; Biopsy; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; Disease Models, Animal; Duodenum; Glucose Intolerance; Glucose Tolerance Test; Incretins; Jejunum; Liver; Male; Obesity, Morbid; Rats; Rats, Sprague-Dawley

The distribution of glucose and fatty-acid transporters in the heart is crucial for energy consecution and myocardial function. In this sense, the glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, improves glucose homeostasis but it could also trigger direct cardioprotective actions, including regulation of energy substrate utilization.. Type-II diabetic GK (Goto-Kakizaki), sitagliptin-treated GK (10 mg/kg/day) and wistar rats (n = 10, each) underwent echocardiographic evaluation, and positron emission tomography scanning for [. Besides of its anti-hyperglycemic effect, sitagliptin-enhanced GLP-1 may ameliorate diastolic dysfunction in type-II diabetes by shifting fatty acid to glucose utilization in the cardiomyocyte, and thus, improving cardiac efficiency and reducing lipolysis.

Topics: Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Energy Metabolism; Fatty Acids; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Incretins; Male; Mice; Myocytes, Cardiac; Protein Transport; Rats, Wistar; Signal Transduction; Sitagliptin Phosphate

Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon-like peptide-1 (GLP-1)-a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accompanied by a moderate reduction in GLP-1 secretion. To compensate for the reduced incretin effect, a human immunodeficiency virus-based lentiviral vector was generated to deliver DNA encoding human GLP-1 (LentiGLP-1), and the anti-diabetic efficacy of LentiGLP-1 was tested in a high-fat diet/streptozotocin-induced model of T2DM. Therapeutic administration of LentiGLP-1 reduced blood glucose levels in obese diabetic Sprague Dawley rats, along with improving insulin sensitivity and glucose tolerance. Normoglycemia was correlated with increased blood GLP-1 and pancreatic beta cell regeneration in LentiGLP-1-treated rats. Plasma triglyceride levels were also normalized after LentiGLP-1 injection. Collectively, these data suggest the clinical potential of GLP-1 gene transfer therapy for the treatment of T2DM.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Therapy; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Islets of Langerhans; Lentivirus; Obesity; Rats

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disability Evaluation; Disease Models, Animal; Endpoint Determination; Evidence-Based Medicine; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Recovery of Function; Stroke; Translational Research, Biomedical; Treatment Outcome

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol homeostasis, is associated with glucose metabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist, can increase insulin secretion in a glucose-dependent manner and lower blood glucose. We aimed to investigate the relationship between liraglutide and PCSK9.. At the cellular level, the expressions of PCSK9 and hepatocyte nuclear factor 1 alpha (HNF1α) protein in HepG2 cells stimulated by liraglutide was examined using Western blot. Seven-week old db/db mice and wild type (WT) mice were administered either liraglutide (200 μg/kg) or equivoluminal saline subcutaneously, twice daily for 7 weeks. Fasting glucose level, food intake and body weight were measured every week. After the 7-week treatment, the blood was collected for lipid and PCSK9 levels detection and the liver was removed from the mice for oil red O staining, immunohistochemical analysis, immunofluorescence test and Western bolt.. Firstly, liraglutide suppressed both PCSK9 and HNF1α expression in HepG2 cells in a time and concentration dependent manner. Secondly, liraglutide induced weight loss in WT and db/db mice, decreased serum PCSK9, glucose and lipid levels and improved hepatic accumulation in db/db but not WT mice. Thirdly, liraglutide reduced both hepatic PCSK9 and low-density lipoprotein receptor (LDLR) expression with a decrease in HNF1α in db/db mice but not in WT mice.. Liraglutide suppressed PCSK9 expression through HNF1α-dependent mechanism in HepG2 cells and db/db mice, and decreased LDLR possibly via PCSK9-independent pathways in db/db mice.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Hep G2 Cells; Hepatocyte Nuclear Factor 1-alpha; Hepatocytes; Humans; Hypoglycemic Agents; Incretins; Lipids; Liraglutide; Male; Mice; Proprotein Convertase 9; Receptors, LDL; Signal Transduction; Time Factors

One of the new current treatment options for Diabetes Mellitus is about increasing glucagon-like peptide-1 (GLP-1) activity. GLP-1 with its incretin effect showed major role in glucose homeostasis. Gastroileostomy can increase GLP-1 secretion by rapid delivery of undigested food to the terminal ileum. We studied the early effects of a gastroileostomy on serum levels of GLP-1, glucose, and insulin in rats.. Gastroileostomies with side-to-side anastomosis were performed on 15 male New Zealand rats. Blood samples were obtained before and 1 week after the gastroileostomy.. Our results showed that the rats lost a lot of weight from start (330 ± 15 g) to the end (240 ± 25 g) of the experiment (p = 0.048). The data analysis showed that the gastroileostomy surgery elevates the level of GLP-1in plasma significantly (89.1852 vs. 177.440 respectively; p < 0.001) and caused a significant decrease in plasma glucose as well (92.00 and 66.29 mg/dL respectively; p < 0.001). However, the insulin state elevated after the surgery significantly (8.03 vs. 9.89; p < 0.001).. In this study, we showed the effectiveness of gastroileostomy treatment to decrease body weight and plasma glucose with increased GLP-1 in rats. This small rat model suggests the potential of this surgery to treat type 2 diabetes mellitus.

Topics: Animals; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Bypass; Glucagon-Like Peptide 1; Ileostomy; Incretins; Insulin; Male; Rats

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; CHO Cells; Cricetulus; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Endocannabinoids; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Glycolysis; Incretins; Male; Mice, Inbred C57BL; Obesity; Oleic Acids; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Weight Loss

Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WFS1 (Wolframin1) gene. The syndrome first manifests as diabetes mellitus, followed by optic nerve atrophy, deafness, and neurodegeneration. The underlying mechanism is believed to be a dysregulation of endoplasmic reticulum (ER) stress response, which ultimately leads to cellular death. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to normalize ER stress response in several in vitro and in vivo models. Early chronic intervention with the GLP-1 receptor agonist liraglutide starting before the onset of metabolic symptoms prevented the development of glucose intolerance, improved insulin and glucagon secretion control, reduced ER stress and inflammation in Langerhans islets in Wfs1 mutant rats. Thus, treatment with GLP-1 receptor agonists might be a promising strategy as a preventive treatment for human WS patients.

Topics: Animals; Blood Glucose; Calmodulin-Binding Proteins; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Knockout Techniques; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Injections, Subcutaneous; Insulin; Islets of Langerhans; Liraglutide; Male; Membrane Proteins; Rats; Rats, Transgenic; Treatment Outcome; Wolfram Syndrome

We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -mediated dopaminergic neurodegeneration. The use of GLP-1 or Exendin-4 for Parkinson's disease (PD) patients is limited by their short half-lives. The purpose of this study was to evaluate a new extended release Exendin-4 formulation, PT302, in a rat model of PD. Subcutaneous administration of PT302 resulted in sustained elevations of Exendin-4 in plasma for >20 days in adult rats. To define an efficacious dose within this range, rats were administered PT302 once every 2 weeks either before or following the unilaterally 6-hydroxydopamine lesioning. Pre- and post-treatment with PT302 significantly reduced methamphetamine-induced rotation after lesioning. For animals given PT302 post lesion, blood and brain samples were collected on day 47 for measurements of plasma Exendin-4 levels and brain tyrosine hydroxylase immunoreactivity (TH-IR). PT302 significantly increased TH-IR in the lesioned substantia nigra and striatum. There was a significant correlation between plasma Exendin-4 levels and TH-IR in the substantia nigra and striatum on the lesioned side. Our data suggest that post-treatment with PT302 provides long-lasting Exendin-4 release and reduces neurodegeneration of nigrostriatal dopaminergic neurons in a 6-hydroxydopamine rat model of PD at a clinically relevant dose.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Delayed-Action Preparations; Disease Models, Animal; Dopaminergic Neurons; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Humans; Incretins; Male; Oxidopamine; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; Substantia Nigra; Treatment Outcome; Tyrosine 3-Monooxygenase

Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE/PS1ΔE9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE/PS1ΔE9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Autophagy; Cognitive Dysfunction; Disease Models, Animal; Endoplasmic Reticulum Stress; Female; Incretins; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Presenilin-1

Dipeptidyl peptidase-4 (DPP-4) inhibitors have various cellular effects that are associated with vascular protection. Here, we examined whether teneligliptin alters the pro-inflammatory phenotype of perivascular adipose tissue (PVAT) and inhibits atherogenesis.. Teneligliptin (60mg/kg/day) was administered orally to apolipoprotein-E-deficient (ApoE. Teneligliptin inhibited atherogenesis with attenuation of the inflammatory phenotype in PVAT. A GLP-1 analog suppressed pro-inflammatory activation of macrophages and adipocytes. Suppression of the pro-inflammatory phenotype of PVAT might contribute, at least partially, to the cardioprotective effects of teneligliptin.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Anti-Inflammatory Agents; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Cytokines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Exenatide; Female; Genetic Predisposition to Disease; Incretins; Inflammation Mediators; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Peptides; Phenotype; Plaque, Atherosclerotic; Pyrazoles; RAW 264.7 Cells; Signal Transduction; Thiazolidines; Time Factors; Vasodilation; Venoms

Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Hepatic Stellate Cells; Humans; Incretins; Liraglutide; Liver; Liver Cirrhosis; Male; Microvessels; Rats, Wistar

Exposure to psychosocial stress is a risk factor for cardiovascular disorders. Because the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist prevents cardiovascular injury, we investigated the beneficial effects and mechanism of the GLP-1 analogue exenatide on stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE. ApoE. Chronic stress enhanced vascular endothelial senescence and atherosclerotic plaque growth. The stress increased the levels of plasma depeptidyl peptidase-4 activity and decreased the levels of plasma GLP-1 and both plasma and adipose adiponectin (APN). As compared with the mice subjected to stress alone, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, broken elastin, and enhanced plaque collagen volume, and lowered levels of peroxisome proliferator-activated receptor-α, gp91phox osteopontin, C-X-C chemokine receptor-4, toll-like receptor-2 (TLR2), TLR4, and cathepsins K, L, and S mRNAs and/or proteins. Exenatide reduced aortic matrix metalloproteinase-9 (MMP-9) and MMP-2 gene expression and activities. Exenatide also stimulated APN expression of preadipocytes and inhibited ox-low density lipoprotein-induced foam cell formation of monocytes in stressed mice.. These results indicate that the exenatide-mediated beneficial vascular actions are likely attributable, at least in part, to the enhancement of APN production and the attenuation of plaque oxidative stress, inflammation, and proteolysis in ApoE

Topics: Adiponectin; Age Factors; Animals; Aorta; Aortic Diseases; Atherosclerosis; Cells, Cultured; Cellular Senescence; Chronic Disease; Diet, High-Fat; Dipeptidyl Peptidase 4; Disease Models, Animal; Endothelial Cells; Exenatide; Foam Cells; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Incretins; Inflammation Mediators; Male; Mice, Knockout, ApoE; Oxidative Stress; Peptide Hydrolases; Peptides; Phenotype; Plaque, Atherosclerotic; Proteolysis; Signal Transduction; Stress, Psychological; Venoms

Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance.. By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a high-fat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes.. Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

Topics: Animals; Biomarkers; Blood Glucose; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Exenatide; Fatty Acid Synthase, Type I; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Hepatocytes; Hyperlipidemias; Incretins; Insulin; Insulin Resistance; Intestinal Mucosa; Intestines; Lipoproteins, VLDL; Liver; Male; Mice, Inbred C57BL; Obesity; Peptides; RNA, Messenger; Signal Transduction; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Time Factors; Triglycerides; Up-Regulation; Vagotomy; Vagus Nerve; Venoms

Acute STEMI is routinely treated by acute PCI. This treatment may itself damage the tissue (reperfusion injury). Conditioning with GLP-1 analogs has been shown to reduce reperfusion injury. Likewise, ischemic postconditioning provides cardioprotection following STEMI. We tested if combined conditioning with the GLP-1 analog liraglutide and ischemic postconditioning offered additive cardioprotective effect after reperfusion of 45 min coronary occlusion of left anterior descending artery (LAD).. Fifty-eight non-diabetic female Danish Landrace pigs (60 ± 10kg) were randomly assigned to four groups. Myocardial infarction (MI) was induced by occluding the LAD for 45 min. Group 1 (n = 14) was treated with i.v. liraglutide after 15 min of ischemia. Group 2 (n = 17) received liraglutide treatment concomitant with ischemic postconditioning, after 45 min of ischemia. Group 3 (n = 15) recieved ischemic postconditioning and group 4 (n = 12) was kept as controls.. No intergroup differences in relative infarct size were detected (overall mean 57 ± 3%; p = 0.68). Overall mortality was 34% (CI 25-41%) including 26% post-intervention, with no intergroup differences (p = 0.99). Occurrence of ventricular fibrillation (VF) was 59% (CI 25-80%) including 39% postintervention with no intergroup differences (p = 0.65).. In our closed-chest pig-model, we were unable to detect any cardioprotective effect of liraglutide or ischemic postconditioning either alone or combined.

Topics: Animals; Balloon Occlusion; Combined Modality Therapy; Disease Models, Animal; Female; Incretins; Ischemic Postconditioning; Liraglutide; Myocardial Infarction; Myocardium; Percutaneous Coronary Intervention; Reperfusion Injury; Swine; Ventricular Fibrillation

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

Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed "twincretin," was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.

Topics: Animals; Body Temperature; Brain Injuries, Traumatic; Cell Line, Tumor; Cells, Cultured; CREB-Binding Protein; Disease Models, Animal; Embryo, Mammalian; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Neuroblastoma; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Gastrointestinal Hormone; Recognition, Psychology; Signal Transduction

Glucagon-like peptide-1 receptor agonists may have a role in modulation of cardiac fibrosis. Our study aimed to determine the effect of the glucagon-like peptide-1 receptor agonist liraglutide in obesity, hypertension and age-induced murine models of cardiac fibrosis and identify associated molecular mechanisms.. C57Bl/6J mice on a high-fat diet and C57Bl/6J mice on a normal chow diet treated with angiotensin II were used to induce obesity and hypertension-mediated cardiac fibrosis, respectively. C57Bl/6J mice 20 months old were used to study age-induced cardiac fibrosis. Liraglutide treatment of 30 µg/kg/day-300 µg/kg s.c. twice daily was administered for 4 weeks.. Liraglutide treatment attenuated obesity, hypertension and age-induced increases in interstitial cardiac fibrosis and expression of inflammatory and oxidative stress markers.. These observations identify a potential role for liraglutide in the prevention of cardiac fibrosis and identify molecular mechanisms associated with these effects.

Topics: Aging; Angiotensin II; Animals; Aorta; Blood Pressure; Body Weight; Chemokine CCL2; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Fibrosis; Glucagon-Like Peptide-1 Receptor; Heart; Heart Diseases; Hypertension; I-kappa B Proteins; Immunohistochemistry; Incretins; Inflammation; Interleukin-10; Liraglutide; Macrophages; Male; Mice; Mice, Inbred C57BL; Myocardium; NF-kappa B p50 Subunit; Obesity; Oxidative Stress; Real-Time Polymerase Chain Reaction; Vasoconstrictor Agents; Vimentin

Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cardiotonic Agents; Collagen; Cytokines; Cytoprotection; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Hypertrophy, Left Ventricular; Incretins; Inflammation Mediators; Linagliptin; Liraglutide; Male; Mice, Inbred C57BL; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NADPH Oxidases; Oxidative Stress; Reactive Oxygen Species; Ventricular Function, Left; Ventricular Remodeling

Inflammation associated with blood-retinal barrier (BRB) breakdown is a common feature of several retinal diseases. Therefore, the development of novel nonsteroidal anti-inflammatory approaches may provide important therapeutic options. Previous studies demonstrated that inhibition of dipeptidyl peptidase-IV, the enzyme responsible for the degradation of glucagon-like peptide-1 (GLP-1), led to insulin-independent prevention of diabetes-induced increases in BRB permeability, suggesting that incretin-based drugs may have beneficial pleiotropic effects in the retina. In the current study, the barrier protective and anti-inflammatory properties of exendin-4 (Ex-4), an analog of GLP-1, after ischemia-reperfusion (IR) injury were examined.. Ischemia-reperfusion injury was induced in rat retinas by increasing the intraocular pressure for 45 minutes followed by 48 hours of reperfusion. Rats were treated with Ex-4 prior to and following IR. Blood-retinal barrier permeability was assessed by Evans blue dye leakage. Retinal inflammatory gene expression and leukocytic infiltration were measured by qRT-PCR and immunofluorescence, respectively. A microglial cell line was used to determine the effects of Ex-4 on lipopolysaccharide (LPS)-induced inflammatory response.. Exendin-4 dramatically reduced the BRB permeability induced by IR injury, which was associated with suppression of inflammatory gene expression. Moreover, in vitro studies showed that Ex-4 also reduced the inflammatory response to LPS and inhibited NF-κB activation.. The present work suggests that Ex-4 can prevent IR injury-induced BRB breakdown and inflammation through inhibition of inflammatory cytokine production by activated microglia and may provide a novel option for therapeutic intervention in diseases involving retinal inflammation.

Topics: Animals; Blood-Retinal Barrier; Cattle; Cells, Cultured; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Immunoblotting; Immunohistochemistry; Incretins; Inflammation; Ischemia; Male; Peptides; Rats; Rats, Long-Evans; Reperfusion Injury; Retinal Diseases; Venoms

Cerebral malaria from Plasmodium falciparum infection is major cause of death in the tropics. The pathogenesis of the disease is complex and the contribution of reactive oxygen and nitrogen species (ROS/RNS) in the brain is incompletely understood. Insulinotropic glucagon-like peptide-1 (GLP-1) mimetics have potent neuroprotective effects in animal models of neuropathology associated with ROS/RNS dysfunction. This study investigates the effect of the GLP-1 analogue, liraglutide against the clinical outcome of experimental cerebral malaria (ECM) and Plasmodium falciparum growth. Furthermore the role of oxidative stress on ECM pathogenesis is evaluated.. ECM was induced in Plasmodium berghei ANKA-infected C57Bl/6j mice. Infected Balb/c (non-cerebral malaria) and uninfected C57Bl/6j mice were included as controls. Mice were treated twice-daily with vehicle or liraglutide (200 μg/kg). ROS/RNS were quantified with in vivo imaging and further analyzed ex vivo. Brains were assayed for cAMP, activation of cAMP response element binding protein (CREB) and nitrate/nitrite. Plasmodium falciparum was cultivated in vitro with increasing doses of liraglutide and growth and metabolism were quantified.. The development and progression of ECM was not affected by liraglutide. Indeed, although ROS/RNS were increased in peripheral organs, ROS/RNS generation was not present in the brain. Interestingly, CREB was activated in the ECM brain and may protect against ROS/RNS stress. Parasite growth was not adversely affected by liraglutide in mice or in P. falciparum cultures indicating safety should not be a concern in type-II diabetics in endemic regions.. Despite the breadth of models where GLP-1 is neuroprotective, ECM was not affected by liraglutide providing important insight into the pathogenesis of ECM. Furthermore, ECM does not induce excess ROS/RNS in the brain potentially associated with activation of the CREB system.

Topics: Animals; Brain; Brain Chemistry; Disease Models, Animal; Female; Humans; Incretins; Liraglutide; Malaria, Cerebral; Mice, Inbred BALB C; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Plasmodium berghei; Plasmodium falciparum; Reactive Nitrogen Species; Reactive Oxygen Species; Treatment Outcome

Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown.. We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1)-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane.. Crif1(beta-/-) mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1(beta-/-) mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1(beta-/-) mice.. Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1(beta-/-) mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.

Topics: Age Factors; Animals; Autophagy; Blood Glucose; Cell Cycle Proteins; Cell Line; Diabetes Mellitus; Disease Models, Animal; Disease Progression; Exenatide; Genotype; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oxidative Phosphorylation; Peptides; Phenotype; Time Factors; Venoms

Experimental evidence suggested that Exendin-4 (Exe4), an agonist at glucagon like receptor-1 (GLP-1R), promoted tissue regeneration. We aimed to verify the effect of Exe4, in the absence or in the presence of Exendin-4(9-39), an antagonist at GLP-1R, on the healing of abraded skin. Two wounds (approximately 1.1×1.1 cm(2); namely "upper" and "lower" in respect of the head) were produced by abrasion on the back of 12 mice, which were then randomly assigned to receive an intradermal injection (20 μl) of Group 1: saline (NT) or Exe4 (62 ng) in the upper and lower wound respectively; Group 2: Exendin-4(9-39) (70 ng) in the upper and Exendin-4(9-39) (70 ng) and, after 15 min, Exe4 (62 ng) in the lower wound. Wounds were measured at the time of abrasion (T0) and 144 h (T3) afterward taking pictures with a ruler and by using a software. The inflammatory cell infiltrate, fibroblasts/myofibroblasts, endothelial cells and GLP-1R expression, were each labeled by immunofluorescence in each wound, pERK1/2 was evaluated by Western-blot in wound lysates. At T3, the percentage of healing surface was 53% and 92% for NT and Exe4 wounds respectively and 68% and 79% for those treated with Exendin-4(9-39) and Exendin-4(9-39)+Exe4 respectively. Exe4, but not Exendin-4(9-39) induced quantitative increase in fibroblasts/myofibroblasts and vessel density when compared to NT wounds. This increase was not evident in wounds treated with Exendin-4(9-39)+Exe4. Exe4 promotes wound healing opening to the possible dermatological use of this incretin analogue.

Topics: Animals; Cell Proliferation; Cell Transdifferentiation; Dermatologic Agents; Disease Models, Animal; Endothelial Cells; Enzyme Activation; Exenatide; Fibroblasts; Glucagon-Like Peptide-1 Receptor; Incretins; Male; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myofibroblasts; Peptide Fragments; Peptides; Phosphorylation; Skin; Time Factors; Venoms; Wound Healing; Wounds and Injuries

Glipitins are widely used for the treatment of type 2 diabetic patients. In addition to their improvement of glycemic control, animal studies have suggested an independent anti-atherosclerotic effect of gliptins. Nevertheless, recent clinical trials regarding long-term effects of gliptin therapy on vascular events have been disappointing. This discrepancy led us to better dissect the functional role of SDF-1/CXCR4 signaling as a potential mechanism underlying gliptin action. The study should give improved understanding of the potential of gliptin therapy in the prevention and treatment of atherosclerosis.. In an ApoE-/- mouse model on high cholesterol diet, long-term treatment with the DPP-4 inhibitor Sitagliptin significantly reduced atherosclerosic plaque load in the aorta. Flow cytometry analyses showed an enrichment of M2 macrophages in the aortic wall under gliptin therapy. Importantly, the number of recruited CD206+ macrophages was inversely correlated with total plaque area while no correlation was found for the overall macrophage population or M1 macrophages. Blockade of CXCR4/SDF-1 signaling by AMD3100 inhibited aortic M2 accumulation and the therapeutic effect of Sitagliptin. Correspondingly, Sitagliptin shifted the polarization profile of macrophages towards a M2-like phenotype.. Sitagliptin-mediated inhibition of early atherosclerosis is based on M2-polarization during monocyte differentiation via the SDF-1/CXCR4 signaling. In contrast to earlier assumptions gliptin treatment might be especially effective in prevention of atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Chemokine CXCL12; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Flow Cytometry; Hypercholesterolemia; Incretins; Insulin Resistance; Macrophages; Male; Mice; Monocytes; Plaque, Atherosclerotic; Receptors, CXCR4; Repetition Priming; Sitagliptin Phosphate

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), enhance postprandial insulin secretion, promote adipogenesis, and regulate gastrointestinal motility and food intake. To date, a consensus on how the incretin response is altered in obesity is lacking. We investigated the effects of chronic high-fat (HF) feeding on incretin secretion in the lymph fistula rat model. Male Sprague-Dawley rats (8 wk) were provided a semipurified AIN93M HF or low-fat (LF) diet ad libitum for 3 or 13 wk; a HF pair-fed (HF-PF) group was included as a control during the 3-wk feeding trial. Energy intake, body weight, and body composition were regularly monitored. At the culmination of the feeding period, an intestinal lymphatic duct cannula and duodenal infusion tube were installed. All animals were challenged with a 3-ml Ensure bolus (3.125 kcal/animal) to measure lymphatic incretin secretion. Despite a significantly higher energy intake, both the 3-wk and 13-wk HF-fed animals did not have an increase in body weight and only a slight increase in body fat compared with LF-fed rats. Following the duodenal Ensure challenge, the 3-wk and 13-wk HF-fed rats had significantly greater lymphatic GIP and GLP-1 secretion than the LF-fed animals. Additionally, the HF-PF group displayed a secretion profile similar to the HF-fed animals for GIP but a similar pattern to the LF-fed animals for GLP-1. The HF-PF data suggest that the increased GIP secretion is driven by the greater percentage of fat intake, whereas the increased GLP-1 secretion is driven by the excess caloric intake.

Topics: Adipogenesis; Animals; Body Composition; Body Weight; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Gastric Inhibitory Polypeptide; Gastrointestinal Motility; Glucagon-Like Peptide 1; Incretins; Insulin; Insulin Secretion; Male; Obesity; Postprandial Period; Rats; Rats, Sprague-Dawley

Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects.. Male Sprague-Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham).. After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response.. A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO.

Topics: Animals; Blood Glucose; Diet; Disease Models, Animal; Gastrectomy; Glucagon-Like Peptide 1; Incretins; Male; Obesity; Rats; Rats, Sprague-Dawley

Traumatic brain injury (TBI), either as an isolated injury or in conjunction with other injuries, is an increasingly common event. An estimated 1.7 million injuries occur within the USA each year and 10 million people are affected annually worldwide. Indeed, nearly one third (30.5%) of all injury-related deaths in the USA are associated with TBI, which will soon outpace many common diseases as the major cause of death and disability. Associated with a high morbidity and mortality and no specific therapeutic treatment, TBI has become a pressing public health and medical problem. The highest incidence of TBI occurs in young adults (15-24 years age) and in the elderly (≥75 years of age). Older individuals are particularly vulnerable to these types of injury, often associated with falls, and have shown increased mortality and worse functional outcome after lower initial injury severity. In addition, a new and growing form of TBI, blast injury, associated with the detonation of improvised explosive devices in the war theaters of Iraq and Afghanistan, are inflicting a wave of unique casualties of immediate impact to both military personnel and civilians, for which long-term consequences remain unknown and may potentially be catastrophic. The neuropathology underpinning head injury is becoming increasingly better understood. Depending on severity, TBI induces immediate neuropathologic effects that, for the mildest form, may be transient; however, with increasing severity, these injuries cause cumulative neural damage and degeneration. Even with mild TBI, which represents the majority of cases, a broad spectrum of neurologic deficits, including cognitive impairments, can manifest that may significantly influence quality of life. Further, TBI can act as a conduit to longer term neurodegenerative disorders. Prior studies of glucagon-like peptide-1 (GLP-1) and long-acting GLP-1 receptor agonists have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of chronic neurodegenerative (Alzheimer's and Parkinson's diseases) and acute cerebrovascular (stroke) disorders. In view of the mechanisms underpinning these disorders as well as TBI, we review the literature and recent studies assessing GLP-1 receptor agonists as a potential treatment strategy for mild to moderate TBI.

Topics: Animals; Brain Injuries; Cell Survival; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Neurons; Receptors, Glucagon

Several recent reports have revealed that dipeptidyl peptidase (DPP)-4 inhibitors have suppressive effects on atherosclerosis in apolipoprotein E-null (Apoe (-/-)) mice. It remains to be seen, however, whether this effect stems from increased levels of the two active incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).. Nontreated Apoe (-/-) mice, streptozotocin-induced diabetic Apoe (-/-) mice, and db/db diabetic mice were administered the DPP-4 inhibitor vildagliptin in drinking water and co-infused with either saline, the GLP-1 receptor blocker, exendin(9-39), the GIP receptor blocker, (Pro(3))GIP, or both via osmotic minipumps for 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages were determined.. Vildagliptin increased plasma GLP-1 and GIP levels without affecting food intake, body weight, blood pressure, or plasma lipid profile in any of the animals tested, though it reduced HbA1c in the diabetic mice. Diabetic Apoe (-/-) mice exhibited further-progressed atherosclerotic lesions and foam cell formation compared with nondiabetic counterparts. Nondiabetic and diabetic Apoe (-/-) mice showed a comparable response to vildagliptin, namely, remarkable suppression of atherosclerotic lesions with macrophage accumulation and foam cell formation in peritoneal macrophages. Exendin(9-39) or (Pro(3))GIP partially attenuated the vildagliptin-induced suppression of atherosclerosis. The two blockers in combination abolished the anti-atherosclerotic effect of vildagliptin in nondiabetic mice but only partly attenuated it in diabetic mice. Vildagliptin suppressed macrophage foam cell formation in nondiabetic and diabetic mice, and this suppressive effect was abolished by infusions with exendin(9-39)+(Pro(3))GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation.. Vildagliptin confers a substantial anti-atherosclerotic effect in both nondiabetic and diabetic mice, mainly via the action of the two incretins. However, the partial attenuation of atherosclerotic lesions by the dual incretin receptor antagonists in diabetic mice implies that vildagliptin confers a partial anti-atherogenic effect beyond that from the incretins.

Topics: Adamantane; Alternative Splicing; Animals; Apolipoproteins E; Atherosclerosis; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Foam Cells; Gene Expression Profiling; Gene Expression Regulation; Gene Order; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Incretins; Macrophages; Male; Mice; Mice, Inbred NOD; Mice, Knockout; Nitriles; Pyrrolidines; Receptors, Glucagon; Vildagliptin

[corrected] Glucagon-like peptide-1 (GLP-1) based therapies are new treatment options for patients with type 2 diabetes. Recent reports suggest vasoprotective actions of GLP-1. Similar beneficial effects might be reached by GLP-1(9-37) and the c-terminal GLP-1 split product (28-37) although both peptides do not activate the GLP-1 receptor. We therefore investigated the actions of GLP-1(7-37), GLP-1(9-37) as well as GLP-1(28-37) on vascular lesion formation in a mouse model of atherosclerosis.. GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) and LacZ (control) were overexpressed for a period of 12 weeks in apoe(-/-) mice on high-fat diet (n = 10/group) using an adeno-associated viral vector system. Neither of the constructs changed overall lesion size. However, GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) significantly reduced plaque macrophage infiltration (GLP-1(7-37): 40.6%, GLP-1(9-37): 47.0%, GLP-1(28-37): 40.1% decrease, p < 0.05) and plaque MMP-9 expression (GLP-1(7-37): 41.6%, GLP-1(9-37): 50.2%, GLP-1(28-37): 44.0% decrease, p < 0.05) compared to LacZ in the aortic arch. Moreover, all GLP-1 constructs increased plaque collagen content (GLP-1(7-37): 49.3%, GLP-1(9-37): 86.0%, GLP-1(28-37): 81.9% increase, p < 0.05) and increased fibrous cap thickness (GLP-1(7-37): 188.0%, GLP-1(9-37): 179.9% GLP-1(28-37): 111.0% increase, p < 0.05). These effects of GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) on plaque macrophage infiltration, MMP-9 expression and plaque collagen content were confirmed in the aortic root.. GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) reduce plaque inflammation and increase phenotypic characteristics of plaque stability in a murine model of atherosclerosis. Future studies are needed to determine whether these effects translate into improved plaque stability and less cardiovascular events in high-risk patients with type 2 diabetes.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Collagen; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Glucagon-Like Peptide 1; Incretins; Inflammation; Lipids; Macrophages; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Phenotype; Plaque, Atherosclerotic; Transgenes

Mild traumatic brain injury (mTBI) represents a major and increasing public health concern and is both the most frequent cause of mortality and disability in young adults and a chief cause of morbidity in the elderly. Albeit mTBI patients do not show clear structural brain defects and, generally, do not require hospitalization, they frequently suffer from long-lasting cognitive, behavioral, and emotional problems. No effective pharmaceutical therapy is available, and existing treatment chiefly involves intensive care management after injury. The diffuse neural cell death evident after mTBI is considered mediated by oxidative stress and glutamate-induced excitotoxicity. Prior studies of the long-acting GLP-1 receptor agonist, exendin-4 (Ex-4), an incretin mimetic approved for type 2 diabetes mellitus treatment, demonstrated its neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer's and Parkinson's diseases, and, consequent to commonalities in mechanisms underpinning these disorders, Ex-4 was assessed in a mouse mTBI model. In neuronal cultures in this study, Ex-4 ameliorated H2O2-induced oxidative stress and glutamate toxicity. To evaluate in vivo translation, we administered steady-state Ex-4 (3.5 pM/kg/min) or saline to control and mTBI mice over 7 days starting 48 h prior to or 1 h post-sham or mTBI (30 g weight drop under anesthesia). Ex-4 proved well-tolerated and fully ameliorated mTBI-induced deficits in novel object recognition 7 and 30 days post-trauma. Less mTBI-induced impairment was evident in Y-maze, elevated plus maze, and passive avoidance paradigms, but when impairment was apparent Ex-4 induced amelioration. Together, these results suggest that Ex-4 may act as a neurotrophic/neuroprotective drug to minimize mTBI impairment.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain; Brain Injuries; Cell Line; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Memory; Mice; Neuroprotective Agents; Oxidative Stress; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Recognition, Psychology; Trauma Severity Indices; Venoms

Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). Insulin is a neuroprotective growth factor, and an impairment of insulin signalling has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling and also acts as a neuroprotective growth factor. GIP plays an important role in memory formation, synaptic plasticity and cell proliferation. We have shown previously that the long-lasting incretin hormone analogue D-Ala(2)GIP protects memory formation and synaptic plasticity, reduces plaques, normalises the proliferation of stem cells, reduces the activation of microglia, and prevents the loss of synapses in the cortex of the APPswe/PS1deltaE9 mouse model of Alzheimer's disease. D-Ala(2)GIP was injected for 35 days at 25 nmol/kg i.p. once daily in APP/PS1 male mice and wild-type (WT) littermates aged 6, 12 and 19 months. In a follow-up study, we analysed plaque load, the activation of astrocytes as a means of chronic inflammation in the brain, and oxidative stress in the brains of these mice (8-oxoguanine levels). D-Ala(2)GIP reduced the amyloid plaque load in 12- and 19-month-old mice, and the inflammation response as shown in the reduction of activated astrocytes in 12- and 19-month old APP/PS1 mice. Chronic oxidative stress in the brain was reduced in 12- and 19-month-old mice as shown in the reduction of 8-oxoguanine levels in the cortex of D-Ala(2)GIP-injected APP/PS1 mice. The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key markers found in Alzheimer's disease. This finding shows that novel GIP analogues have the potential to be developed as novel therapeutics for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Female; Gastric Inhibitory Polypeptide; Gliosis; Incretins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; Plaque, Amyloid; Presenilin-1

Glucagon-like peptide-1 (GLP-1) treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure-prone (SHHF) rats progress to advanced heart failure and death over a 15-month period. The authors sought to determine whether a continuous infusion of GLP-1 would reduce mortality in this model.. At 9 months of age, 50 SHHF rats were randomized to receive a 3-month, continuous infusion of either GLP-1 or saline. Metabolic parameters were measured and cardiac ultrasounds performed at study initiation and completion of treatment. Surviving rats were euthanized at 12 months. Hearts were perfused in an isolated, isovolumic heart preparation, and Tunel staining of myocardial samples was performed. Baseline metabolic and cardiac functional parameters were comparable. GLP-1-treated SHHF rats had greater survival (72% versus 44%, P=0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved left ventricular (LV) function. GLP-1-treated rats demonstrated decreased myocyte apoptosis by Tunel staining as well as reduced caspase-3 activation. No increase in p-BAD expression was seen. In isolated hearts, the LV systolic pressure and LV-developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1-treated SHHF rats.. Chronic GLP-1 treatment prolongs survival in obese SHHF rats. This is associated with preserved LV function and LV mass index, increased myocardial glucose uptake, and reduced myocyte apoptosis.

Topics: Animals; Disease Models, Animal; Glucagon-Like Peptide 1; Heart Failure; Incretins; Infusions, Intravenous; Prone Position; Rats; Rats, Inbred SHR; Survival Rate; Systole; Treatment Outcome; Ventricular Function, Left

Glucagon Like Peptide-1 (GLP-1), one of the most potent incretin hormones, has potential beneficial actions on the ischaemic and failing heart. This study sought to further identify the mechanisms of action of GLP-1 on the ischaemic heart using an in vitro isolated perfused rat heart model of ischaemic-reperfusion injury (measuring infarct size to area of risk (%)) subjected to 35 min regional ischaemia and 2 h reperfusion. To examine the effect of intact GLP-1 we used an inhibitor of GLP-1 breakdown, Valine pyrrolidide (VP). The downstream target of phosphatidylinositol 3-kinase includes the mTOR/p70s6 kinase pathway which was pharmacologically inhibited by rapamycin.. GLP-1 alone did not decrease myocardial infarction (54.4 +/- 3.1%). VP alone did not decrease myocardial infarction (52.5 +/- 4%). GLP-1 in the presence of VP produced significant reduction in myocardial infarction compared to control hearts (28.4 +/- 2.7% vs. 56.4 +/- 3.9% vs. P < 0.05). Inhibiting p70s6 Kinase with rapamycin completely abolished GLP-1 induced protection (57.1 +/- 4.9% vs. 28.4 +/- 2.7% P < 0.05). There was no detectable increase in the phosphorylated p70s6k after either 5 or 10 min of treatment with GLP-1/VP or with VP alone in comparison to control blots. In conclusion we show for the first time that the protective effects of GLP-1 are mediated by intact GLP-1 and can be inhibited by blocking the p70s6 kinase.

Topics: Animals; Blotting, Western; Disease Models, Animal; Enzyme Inhibitors; Glucagon-Like Peptide 1; In Vitro Techniques; Incretins; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Protein Kinases; Pyrroles; Random Allocation; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Valine