glucagon-like-peptide-1 and Dyslipidemias

Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Lipids

The introduction of sodium glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus treatment has shown an unexpectedly significant improvement in heart disease outcome trials. Although they have very different modes of action, a portion of the salutary cardiovascular disease improvement may be related to their impact on diabetic dyslipidemia. As discussed in this focused review, the sodium glucose transporter-2 inhibitors as a class show a mild increase in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, while triglycerides (TG) decrease inconsistently. In particular, the rise in LDL appears to be related to the less atherogenic, large buoyant LDL particles. The glucagon-like peptide-1 receptor agonists show more of an impact on weight loss and improvement in the underlying low HDL and high TG dyslipidemia. The effect of sodium glucose transporter-2 inhibitors and glucagon-like peptide 1 receptor agonists when used in combination remains largely unknown. Also unexplored is difference in effect of these medications among various ethnicities and metabolic syndrome.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metabolic Syndrome; Sodium-Glucose Transporter 2 Inhibitors; Triglycerides

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

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

Derangements in triglyceride and cholesterol metabolism (dyslipidemia) are major risk factors for the development of cardiovascular diseases in obese and type-2 diabetic (T2D) patients. An emerging class of glucagon-like peptide-1 (GLP-1) analogues and next generation peptide dual-agonists such as GLP-1/glucagon or GLP-1/GIP could provide effective therapeutic options for T2D patients. In addition to their role in glucose and energy homeostasis, GLP-1, GIP and glucagon serve as regulators of lipid metabolism. This review summarizes the current knowledge in GLP-1, glucagon and GIP effects on lipid and lipoprotein metabolism and frames the emerging therapeutic benefits of GLP-1 analogs and GLP-1-based multiagonists as add-on treatment options for diabetes associated dyslipidemia.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Intestinal Mucosa; Lipid Metabolism; Lipoproteins

Dysglycaemia (i.e. type 2 diabetes mellitus or impaired glucose tolerance) is not only common in patients with cardiovascular disease but increases the risk for future cardiovascular complications. Hyperglycaemia, the hallmark of diabetes, has since long been considered to be the link between diabetes and cardiovascular disease. Diabetes is, however, a complex, multifactorial disorder to which, for example, insulin resistance, endothelial dysfunction and factors such as increased thrombogenicity, hypertension and dyslipidaemia contribute. Thus, treatment needs to be multifactorial and to take cardiovascular aspects into account. Life-style adjustments are, together with blood pressure, lipid and glucose control, important parts of such management. Recent trial data reveal a beneficial effect on cardiovascular prognosis and mortality of blood glucose lowering agents belonging to the classes: sodium-glucose-transporter 2 inhibitors and glucagon-like peptide 1 agonists. The precise mechanisms by which certain sodium-glucose-transporter 2 inhibitors and glucagon-like peptide receptor agonists lead to these beneficial effects are only partly understood. An important impact of the benefits of sodium-glucose-transporter 2 inhibitors is a reduction in heart failure while glucagon-like peptide receptor agonists may retard the development of atherosclerotic vascular disease or stabilising plaques. Although there has been a considerable improvement in the prognosis for people with atherosclerotic diseases over the last decades there is still a gap between those with dysglycaemia, who are at higher risk, than those without dysglycaemia. This residual risk is reasonably related to two major factors: a demand for improved management and a need for new and improved therapeutic opportunities of type 2 diabetes, both routes to an improved prognosis that are at hands. This review is a comprehensive description of the possibilities to improve the prognosis for patients with dysglycaemia by a multifactorial management according to the most recent European guidelines issued in 2019 by the European Society of Cardiology in collaboration with the European Association for the Study of Diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Europe; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Resistance; Practice Guidelines as Topic; Prognosis; Risk Factors; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors

In type 2 diabetes mellitus there is an overproduction of chylomicron in the postprandial state that is associated with increased cardiovascular risk. Current evidence points out a leading role of enterocyte in dyslipidemia of type 2 diabetes mellitus, since it increases the production of apolipoprotein B-48 in response to a raise in plasma free fatty acids and glucose. The chylomicron metabolism is regulated by many factors apart from ingested fat, including hormonal and metabolic elements. More recently, studies about the role of gut hormones, have demonstrated that glucagon-like peptide-1 decreases the production of apolipoprotein B-48 and glucagon-like peptide-2 enhances it. Insulin acutely inhibits intestinal chylomicron production in healthy humans, whereas this acute inhibitory effect on apolipoprotein B-48 production is blunted in type 2 diabetes mellitus. Understanding these emerging regulators of intestinal chylomicron secretion may offer new mechanisms of control for its metabolism and provide novel therapeutic strategies focalized in type 2 diabetes mellitus postprandial hyperlipidemia with the reduction of cardiovascular disease risk.

Topics: Chylomicrons; Diabetes Mellitus, Type 2; Dyslipidemias; Enterocytes; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Postprandial Period; Triglycerides

The purpose of the study is to review the use of statins and the role of both non-statin lipid-lowering agents and diabetes-specific medications in the treatment of diabetic dyslipidemia.. Statins have a primary role in the treatment of dyslipidemia in people with type 2 diabetes, defined as triglyceride levels >200 mg/dl and HDL cholesterol levels <40 mg/dL. A number of clinical trials suggest that treatment with a fibrate may reduce cardiovascular events. However, the results of these trials are inconsistent, probably because many of their participants did not have dyslipidemia. The choice of medications used to treat diabetes can have major implications regarding management of dyslipidemia; metformin, GLP-1 agonists, and pioglitazone all have favorable lipid effects. These agents, as well as the new SGLT2 inhibitors, may reduce cardiovascular events. Management of dyslipidemia in people with type 2 diabetes should start with statin therapy and optimal glycemic control with agents that have favorable lipid and cardiovascular effects. We believe that there is a role for adding fenofibrate to moderate-intensity statins in selected patients with true dyslipidemia. We propose an algorithm for selecting add-on medications for diabetes (after metformin) based on lipid status.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Fenofibrate; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Metformin; Pioglitazone; Thiazolidinediones

Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of dyslipidemia. Here we review recent developments in this field and present evidence that intestinal lipoprotein production is a process with metabolic plasticity and that modulation of intestinal lipoprotein secretion may be a feasible therapeutic strategy in the treatment of dyslipidemia and possibly prevention of atherosclerosis.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Atherosclerosis; Bile Acids and Salts; Cholesterol; Chylomicrons; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Dyslipidemias; Exenatide; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Resistance; Intestine, Small; Lipoproteins; Microbiota; Peptides; Receptors, Glucagon; Resveratrol; Secretory Rate; Stilbenes; Triglycerides; Venoms

Insulin resistance and the metabolic syndrome are associated with fasting and postprandial dyslipidemia. This involves the hepatic and intestinal overproduction of very low density lipoproteins (VLDL) and chylomicron particles, respectively, which give rise to atherogenic remnants upon lipolysis in the circulation. Recently, the insulin secretagogue glucagon-like peptide-1 (GLP-1) has received attention not only as an anti-diabetic therapy for regulating glycaemia, but also as a regulator of lipid and lipoprotein metabolism. In fact, agents that raise endogenous bioactive levels of GLP-1 (dipeptidyl peptidase 4 inhibitors) and agents that directly stimulate GLP-1 receptors (GLP-1 receptor agonists) have been assessed in both preclinical and clinical trials for their ability to modulate plasma lipid parameters. Here we describe current evidence supporting a role for GLP-1 in preventing elevated intestinal chylomicron output and postprandial hypertriglyceridemia--an independent predictor of cardiovascular risk. Furthermore, we examine a role for GLP-1 in regulating fasting hepatic VLDL production and hindering the development of a potentially devastating comorbidity, hepatic steatosis. Possible mechanisms of action of GLP-1 are discussed including a reduction in intestinal absorption of dietary lipid and enhanced hepatic fatty acid oxidation or autophagy. Finally, we discuss the current controversy over whether these effects could occur via direct receptor stimulation or alternative, indirect pathways. We conclude that GLP- 1-based therapies appear promising in the management of diabetic dyslipidemia, and further studies are warranted to elucidate their mechanisms of action in both the intestine and liver.

Topics: Animals; Cardiovascular Diseases; Chylomicrons; Dyslipidemias; Fasting; Fatty Liver; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Intestinal Mucosa; Lipid Metabolism; Lipoproteins; Liver; Postprandial Period; Risk Factors; Triglycerides

Glucagon-like peptide-1 (GLP-1), is a hormone secreted by small intestine. Consumption of food or glucose stimulates synthesis and secretion of GLP-1 in the bloodstream, which in turn stimulates insulin secretion from pancreas and delays gastric emptying. Owing to the favorable spectrum of effects on reduction of hyperglycemia and body weight, GLP-1 mimetics are intensely pursued as therapies for the treatment of type 2 diabetes (T2DM). Even after intensive control of hyperglycemia, the propensity for cardiovascular disease cannot be totally negated in diabetic patients. A major reason for the cardiovascular disease risk in diabetic patients is underlying dyslipidemia, also termed as diabetic dyslipidemia. It is characterized by high concentrations of triglycerides and LDL cholesterol, and lowered HDL cholesterol in plasma, which are associated with hyperglycemia. Increased insulin resistance gives rise to increased free fatty acids in bloodstream, which is the main reason for the lipid changes appearing in diabetic dyslipidemia. The secondary complications like atherosclerosis and other cardiovascular diseases may be predicted with the blood concentrations of triglycerides and cholesterol, due to the correlation proven in clinic. Hence, new drugs that target diabetic dyslipidemia will always be useful in therapy. Apart from its actions on body weight and glucose, GLP-1 can also regulate cholesterol and triglycerides by numerous ways. Acute and long term treatment with either GLP-1 or its stable analogs reduced fasting as well as postprandial lipids in healthy as well as T2DM patients. GLP-1R signaling reduces VLDL-TG production rate from liver, reduces hepatic TG content by modulating key enzymes of lipid metabolism in liver, and impairs hepatocyte de novo lipogenesis and β-oxidation. GLP-1 can also modulate reverse cholesterol transport. Apart from these direct effects on lipid metabolism, GLP-1 also reduces atherosclerotic events by inhibiting expression of atherogenic inflammatory mediators, suppressing smooth muscle cell proliferation and stimulating NO production. This review mainly deliberates the association of GLP-1 in lipid regulation via lipid absorption, hepatic cholesterol metabolism, reverse cholesterol transport and progression of atherosclerosis.

Topics: Anticholesteremic Agents; Body Weight; Cholesterol; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance; Lipid Metabolism; Receptors, Glucagon; Risk Factors; Signal Transduction; Treatment Outcome; Triglycerides

Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue.

Topics: Blood Glucose; Brain; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dyslipidemias; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Heart; Humans; Hypertension; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Liraglutide; Liver; Meta-Analysis as Topic; Obesity; Peptides; Risk; Venoms; Weight Loss

In prediabetes and diabetes, hyperglycemia is often accompanied by fasting and postprandial hyperlipidemia. Incretin-based therapies are in increasing clinical use for treating hyperglycemia, but recent evidence emphasizes their ability to improve lipoprotein abnormalities. This is significant as heightened postprandial chylomicron levels during insulin resistance contribute to atherogenic diabetic dyslipidemia. This review summarises the evidence supporting a beneficial effect of incretin-based therapies on diabetic dyslipidemia through modulation of intestinal lipoprotein metabolism.. Preclinical and clinical trials have involved administering dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists to healthy and insulin-resistant individuals. Results indicate that enhancing GLP-1R signalling decreases postprandial apoB48-containing triglyceride-rich lipoproteins. These effects may be direct or may be secondary to reduced gastric emptying, increased insulin secretion, or enhanced chylomicron clearance.. Enhancing GLP-1R activity improves intestinal lipoprotein metabolism. GLP-1-mediated control of postprandial chylomicron production may be lost in type 2 diabetes in which the incretin response is impaired and in which associated dyslipidemia involves an excess of atherogenic chylomicron remnants. Further human studies are needed to better establish the impact of incretin-based therapies on dyslipidemia, as this offers a major new therapeutic approach to reduce cardiovascular risk in type 2 diabetic patients.

Topics: Animals; Chylomicrons; Dyslipidemias; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins; Insulin Resistance; Intestinal Absorption; Lipid Metabolism; Postprandial Period

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

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

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

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

Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes mellitus. The objectives of this study were to evaluate metabolic effects of elobixibat. Effects on plasma lipids and BA synthesis were evaluated utilizing a 4-week, placebo-controlled study in patients with dyslipidemia while changes of glucagon-like peptide-1 (GLP-1) by elobixibat was assayed in samples from a 14 day high-dose elobixibat study in patients with CC.. Thirty-six dyslipidemic patients, 21 females, mean age 63 years, were randomized to 2.5 mg or 5 mg elobixibat or placebo once daily for four weeks. The primary endpoint was the change in low density lipoprotein (LDL) cholesterol. Secondary endpoints included other lipid parameters and serum 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA (bile acid) synthesis. Another study, in 36 patients with CC treated with high dose elobixibat; 15 mg or 20 mg/day or placebo for 14 days, was evaluated for changes in GLP-1.. In the dyslipidemia study LDL cholesterol was reduced by 7.4 % (p = 0.044), and the LDL/HDL ratio was decreased by 18 % (p = 0.004). Serum C4 increased, indicating that BA synthesis was induced. No serious adverse events were recorded. In the CC study, GLP-1 increased significantly in both the 15 mg (20.7 ± 2.4 pmol/L; p = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; p = 0.02).. Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans.. ClinicalTrial.gov: NCT01069783 and NCT01038687 .

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bile Acids and Salts; Cholestenones; Cholesterol, HDL; Cholesterol, LDL; Chronic Disease; Constipation; Dipeptides; Dyslipidemias; Female; Glucagon-Like Peptide 1; Humans; Lipids; Male; Middle Aged; Thiazepines; Triglycerides; Young Adult

With increased rates of obesity and insulin resistance in youth, development of postprandial dyslipidemia, an important cardiovascular disease risk factor, is a concern. Glucagon-like peptides (ie, GLP-1 and GLP-2) and bile acids have been shown to regulate dietary fat absorption and postprandial lipids in animal models and humans. We hypothesize that the physiological response of GLPs and bile acids to dietary fat ingestion is impaired in adolescents with obesity and this associates with marked postprandial dyslipidemia and insulin resistance.. In this cross-sectional study, normal weight adolescents and adolescents with obesity underwent a 6-hour oral fat tolerance test. The postprandial lipoprotein phenotype profile was determined using various assays, including nuclear magnetic resonance spectroscopy, to characterize lipoprotein particle number, size, lipid content, and apolipoproteins. GLP-1 and GLP-2 were quantified by electrochemiluminescent immunoassays. Total bile acids were measured by an automated enzymatic cycling colorimetric method and the bile acid profile by mass spectrometry.. Adolescents with obesity exhibited fasting and postprandial dyslipidemia, particularly augmented postprandial excursion of large triglyceride-rich lipoproteins. Postprandial GLPs were reduced and inversely correlated with postprandial dyslipidemia and insulin resistance. Postprandial bile acids were also diminished, particularly lithocholic acid, a potent stimulator of GLP-1 secretion.. Blunted postprandial GLP and bile acid response to dietary fat ingestion strongly associates with marked postprandial dyslipidemia. Further investigation is needed to assess their potential utility as early biomarkers for postprandial dyslipidemia in adolescents with obesity.

Topics: Adolescent; Adult; Bile Acids and Salts; Biomarkers; Canada; Child; Cross-Sectional Studies; Dyslipidemias; Female; Follow-Up Studies; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Hyperinsulinism; Male; Pediatric Obesity; Postprandial Period; Prognosis; Young Adult

The gut microbiota might critically modify metabolic disease development. Dietary fibers such as galacto-oligosaccharides (GOS) presumably stimulate bacteria beneficial for metabolic health. This study assesses the impact of GOS on obesity, glucose, and lipid metabolism.. Following Western-type diet feeding (C57BL/6 mice) with or without β-GOS (7% w/w, 15 weeks), body composition, glucose and insulin tolerance, lipid profiles, fat kinetics and microbiota composition are analyzed. GOS reduces body weight gain (p < 0.01), accumulation of epididymal (p < 0.05), perirenal (p < 0.01) fat, and insulin resistance (p < 0.01). GOS-fed mice have lower plasma cholesterol (p < 0.05), mainly within low-density lipoproteins, lower intestinal fat absorption (p < 0.01), more fecal neutral sterol excretion (p < 0.05) and higher intestinal GLP-1 expression (p < 0.01). Fecal bile acid excretion is lower (p < 0.01) in GOS-fed mice with significant compositional differences, namely decreased cholic, α-muricholic, and deoxycholic acid excretion, whereas hyodeoxycholic acid increased. Substantial changes in microbiota composition, conceivably beneficial for metabolic health, occurred upon GOS feeding.. GOS supplementation to a Western-type diet improves body weight gain, dyslipidemia, and insulin sensitivity, supporting a therapeutic potential of GOS for individuals at risk of developing metabolic syndrome.

Topics: Animals; Bile Acids and Salts; Body Weight; Diet, High-Fat; Diet, Western; Dietary Supplements; Dyslipidemias; Energy Metabolism; Feces; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice, Inbred C57BL; Obesity; Oligosaccharides; Sterols

Coagonists of Glucagon-like peptide-1 (GLP-1) and glucagon receptors are under clinical investigation for treatment of obesity associated with diabetes. In addition to their role in glucose homeostasis, GLP-1 and glucagon modulate lipid metabolism. In this study, we have investigated the role of central GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) activation in regulation of lipid metabolism in cholesterol-fed hamsters. Hamsters were treated with coagonist alone (0.3 μg) or in combination with either GLP-1R antagonist (0.15 μg) or GCGR antagonist (0.3 μg) for 4 weeks by intracerebroventricular route (icv). A pair-fed control to coagonist was included in the experiment. In a separate experiment, vagotomized hamsters were treated with coagonist (0.3 μg) for four weeks. At the end of the treatment, plasma and hepatic lipids, bile homeostasis, and hepatic gene expression were determined. Coagonist treatment caused a reduction in plasma and liver lipids, and reduced triglyceride absorption from intestine. Also, hepatic triglyceride secretion, bile flow, and biliary cholesterol excretion were increased by the coagonist treatment. Coagonist treatment exhibited increased energy expenditure and reduced the expression of SREBP-1C, HMG-CoA reductase, SCD-1, FAS and ACC in liver. Increase in the expression of LDLR, ACOX1, CPT-1, PPAR-α, CYP7A1, ABCA1 and ABCB11 was also observed in liver. The effect of coagonist on lipids was partially blocked by either GLP-1R or GCGR antagonist. Coadministration of GLP-1R antagonist blocked the effect of coagonist on bile flow, while effect of coagonist on biliary cholesterol was blocked by co-administration of GCGR antagonist. Coagonist did not affect lipid metabolism in vagotomized hamsters. It appears that central administration of coagonist reduces dyslipidemia by activation of GLP-1R and GCGR, independent of its anorectic effect.

Topics: Animals; Cholesterol; Dyslipidemias; Energy Metabolism; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Lipid Metabolism; Liver; Male; Mesocricetus; Obesity; Receptors, Glucagon; Signal Transduction; Triglycerides

Dyslipidemia enhances progression of atherosclerosis. Coagonist of GLP-1 and glucagon are under clinical investigation for the treatment of obesity and diabetes. Earlier, we have observed that coagonist reduced circulating and hepatic lipids, independent of its anorexic effects. Here, we investigated the role of coagonist of GLP-1 and glucagon receptors in complications of diet-induced dyslipidemia in hamsters and humanized double transgenic mice. Hamsters fed on high fat high cholesterol diet were treated for 8 weeks with coagonist of GLP-1 and glucagon receptors (75 and 150 μg/kg). Pair-fed control was maintained. Cholesterol fed transgenic mice overexpressing hApoB100 and hCETP with coagonist (300 μg/kg) for 4 weeks. After the completion of treatment, biochemical estimations were done. Coagonist treatment reduced triglycerides in plasma, liver and aorta, plasma cholesterol and hepatic triglyceride secretion rate. Expressions of HMG-CoA reductase and SBREBP-1C were reduced and expressions of LDLR, CYP7A1, ABCA1 and ABCB11 were increased in liver, due to coagonist treatment. Coagonist treatment increased bile flow rate and biliary cholesterol excretion. IL-6 and TNF-α were reduced in plasma and expression of TNF-α, MCP-1, MMP-9 and TIMP-1 decreased in liver. Treatment with coagonist reduced oxidative stress in liver and aorta. Energy expenditure was increased and respiratory quotient was reduced by coagonist treatment. These changes were correlated with reduced hepatic inflammation and lipids in liver and aorta in coagonist treated hamsters. Coagonist treatment also reduced lipids in cholesterol-fed transgenic mice. These changes were independent of glycaemia and anorexia observed after coagonist treatment. Long term treatment with coagonist of GLP-1 and glucagon receptor ameliorated diet-induced dyslipidemia and atherosclerosis by regulating bile homeostasis, liver inflammation and energy expenditure.

Topics: Animals; Atherosclerosis; Cholesterol; Cricetinae; Dyslipidemias; Glucagon; Glucagon-Like Peptide 1; Inflammation; Lipid Metabolism; Liver; Male; Mice; Mice, Transgenic; Receptors, Glucagon

Pancreatic lipidosis (nonalcoholic fatty pancreas disease, NAFPD) causes insulin resistance and dysfunction of pancreatic β-cells, with the risk of type 2 diabetes mellitus (T2DM). However, the prevalence and pathogenic factors associated with NAFPD are not clear. The aim of the study was to explore the prevalence of NAFPD in a Chinese adult population, and investigate factors associated with NAFPD aggravation.This was a cross-sectional study; 4419 subjects were enrolled for NAFPD screening and were divided into NAFPD (n = 488) and without NAFPD (n = 3930) groups. The sex, age, related concomitant diseases, general physical parameters, and serum glucose and lipid metabolism were compared between the 2 groups.The overall NAFPD prevalence was 11.05%, but increased with age. In those <55 years NAFPD prevalence was lower in females than males (P < .05), but prevalence was similar >55 years. Nonalcoholic fatty liver disease (NAFLD), T2DM, homeostasis model assessment-insulin resistance index, total cholesterol, triglyceride, lipoprotein, adiponectin, and glucagon-like peptide 1 (GLP-1) were the independent risk factors for NAFPD (P < .05). Analaysis of mild NAFPD (MN) and severe NAFPD (SN) subgroups, according to the extent of fat deposition, suggested that NAFLD, triglyceride, lipoprotein, and adiponectin were independent risk factors for NAFPD aggravation (P < .05).The NAFPD prevalence was about 11% in Chinese adults. Its development and progression was related to NAFLD, T2DM, insulin resistance, dyslipidemia, and GLP-1 levels. Severe NAFPD was associated with NAFLD and dyslipidemia.

Topics: Adiponectin; Adult; Age Factors; China; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Insulin Resistance; Lipoproteins; Male; Middle Aged; Overweight; Pancreatic Diseases; Prevalence; Risk Factors; Sex Factors; Triglycerides

Diabetes and obesity are characterized by glucose intolerance, fat deposition, inflammation, and dyslipidemia. Recent reports postulated that distinct gut microbiota alterations were observed in obese/diabetic subjects and modulating gut microbiota beneficially through specific probiotics could be a potential therapeutic option for type 2 diabetes/obesity. Therefore, we attempted to study the efficacy of probiotics of Indian gut origin (Lactobacillus plantarum MTCC5690 and Lactobacillus fermentum MTCC5689) along with a positive control, Lactobacillus rhamnosus (LGG) on glucose/lipid homeostasis in high-fat-diet-induced diabetic animal model.. C57BL/6J male mice were divided into seven groups (n = 6 per group) comprising feeding on: (1) Normal Pellet Diet (NPD), (2) High-Fat Diet (HFD), (3) HFD with LGG, (4) HFD with MTCC5690, (5) HFD with MTCC5689, (6) HFD with metformin, and 7) HFD with vildagliptin for a period of 6 months. Biochemical markers, glucose tolerance, insulin resistance, and GLP-1 and LPS levels were assessed by standard protocols. Gut integrity was measured by intestinal permeability test. Transcriptional levels of tight junction proteins (TJPs) were probed in small intestinal tissues while inflammatory signals and other pathway specific genes were profiled in liver, visceral adipose tissue, and skeletal muscle.. Mice fed with HFD became insulin resistant, glucose intolerant, hyperglycemic, and dyslipidemic. Diabetic mice were characterized to exhibit decreased levels of GLP-1, increased gut permeability, increased circulatory levels of LPS, decrease in the gene expression patterns of intestinal tight junction markers (occludin and ZO-1), and increased proinflammatory gene markers (TNFα and IL6) in visceral fat along with decreased mRNA expression of FIAF and adiponectin. Diabetic mice also exhibited increased mRNA expression of ER stress markers in skeletal muscle. In addition, liver from HFD-fed diabetic mice showed increased gene expressions of proinflammation, lipogenesis, and gluconeogenesis. Probiotic interventions (most prominently the MTCC5689) resisted insulin resistance and development of diabetes in mice under HFD feeding and beneficially modulated all the biochemical and molecular alterations in a mechanistic way in several tissues. The metabolic benefits offered by the probiotics were also more or less similar to that of standard drugs such as metformin and vildagliptin.. Native probiotic strains MTCC 5690 and MTCC 5689 appear to have potential against insulin resistance and type 2 diabetes with mechanistic, multiple tissue-specific mode of actions.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dyslipidemias; Endoplasmic Reticulum Stress; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose Intolerance; India; Inflammation; Insulin Resistance; Lactobacillus plantarum; Limosilactobacillus fermentum; Lipids; Lipogenesis; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Probiotics; Transcriptome

Obesity is a major health threat that affects men and women equally. Despite this fact, weight-loss potential of pharmacotherapies is typically first evaluated in male mouse models of diet-induced obesity (DIO). To address this disparity we herein determined whether a monomeric peptide with agonism at the receptors for glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon is equally efficient in correcting DIO, dyslipidemia, and glucose metabolism in DIO female mice as it has been previously established for DIO male mice.. Female C57BL/6J mice and a cohort of fatmass-matched C57BL/6J male mice were treated for 27 days via subcutaneous injections with either the GLP-1/GIP/glucagon triagonist or PBS. A second cohort of C57BL/6J male mice was included to match the females in the duration of the high-fat, high-sugar diet (HFD) exposure.. Our results show that GLP-1/GIP/glucagon triple agonism inhibits food intake and decreases body weight and body fat mass with comparable potency in male and female mice that have been matched for body fat mass. Treatment improved dyslipidemia in both sexes and reversed diet-induced steatohepatitis to a larger extent in female mice compared to male mice.. We herein show that a recently developed unimolecular peptide triagonist is equally efficient in both sexes, suggesting that this polypharmaceutical strategy might be a relevant alternative to bariatric surgery for the treatment of obesity and related metabolic disorders.

Topics: Adiposity; Animals; Diet, High-Fat; Dyslipidemias; Eating; Fatty Liver; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Male; Mice; Mice, Inbred C57BL; Obesity; Sex Factors

Quantification of changes in glucose and lipid concentrations in women with intrahepatic cholestasis of pregnancy (ICP) and uncomplicated pregnancy and study of their influence on fetal growth.. A prospective study comparing metabolic outcomes in cholestastic and uncomplicated singleton pregnancies was undertaken at two university hospitals in the U.K. and U.S. from 2011-2014. A total of 26 women with ICP and 27 control pregnancies with no prior history of gestational diabetes mellitus were recruited from outpatient antenatal services and followed until delivery. Alterations in glucose, incretins, cholesterol, and triglycerides were studied using a continuous glucose monitoring (CGM) system and/or a standard glucose tolerance test (GTT) in conjunction with GLP-1 and a fasting lipid profile. Fetal growth was quantified using adjusted birth centiles.. Maternal blood glucose concentrations were significantly increased in ICP during ambulatory CGM (P < 0.005) and following a GTT (P < 0.005). ICP is characterized by increased fasting triglycerides (P < 0.005) and reduced HDL cholesterol (P < 0.005), similar to changes observed in metabolic syndrome. The offspring of mothers with ICP had significantly larger customized birth weight centiles, adjusted for ethnicity, sex, and gestational age (P < 0.005).. ICP is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. These findings may have implications regarding the future health of affected offspring.

Topics: Adult; Birth Weight; Blood Glucose; Cholestasis, Intrahepatic; Cholesterol; Diabetes, Gestational; Dyslipidemias; Female; Fetal Development; Fetal Macrosomia; Gestational Age; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Lipids; Male; Metabolic Syndrome; Metabolome; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Triglycerides

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

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

Topics: Aged; Body Mass Index; Dyslipidemias; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Insulin; Middle Aged; Obesity, Morbid; Sleep Apnea, Obstructive; Treatment Outcome; Weight Loss

Obesity and dyslipidemia often coexist in patients with type 2 diabetes and contribute to increase the risk of cardiovascular events. Pharmacological treatments of diabetes often result in weight gain, an undesirable event associated with a worse cardiovascular risk profile and decreased adherence to therapy. Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs have been shown to improve glycemic control without promoting weight gain and to exert beneficial effects on lipid profile by reducing total and LDL cholesterol, triglycerides, and free fatty acid levels. DPP-4 inhibitors have demonstrated to be weight neutral whereas treatment with GLP-1 analogs is associated with a significant weight loss. DPP-4 and GLP-1 analogs represent a new therapeutic option for type 2 diabetes, which offers the advantage of combining glycemic control with beneficial effects on body weight and lipid profile, thus providing greater cardiovascular protection.

Topics: Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Therapy, Combination; Dyslipidemias; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Metformin; Obesity; Risk Factors; Thiazolidinediones

Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.

Topics: Adrenocorticotropic Hormone; Animals; Body Weight; Diabetes Mellitus, Type 2; Dyslipidemias; Eating; Fatty Acids; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Muscle, Skeletal; Physical Conditioning, Animal; Rats; Rats, Zucker

In addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism.. The GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined.. CNTO3649 and exendin-4 reduced fasting plasma glucose (up to -30% and -28% respectively) and insulin (-43% and -65% respectively). In addition, these agents reduced VLDL-TG production (-36% and -54% respectively) and VLDL-apoB production (-36% and -43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (-39% and -55% respectively), cholesterol (-30% and -55% respectively), and phospholipids (-23% and -36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob).. GLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus.

Topics: Animals; Apolipoprotein E3; Apolipoproteins B; Blood Glucose; Diabetes Mellitus, Type 2; Dyslipidemias; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin; Lipogenesis; Liver; Male; Mice; Mice, Transgenic; Peptides; Receptors, Glucagon; Venoms

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