incretins and Dyslipidemias

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Clinical Studies as Topic; Diabetes Mellitus, Type 2; Disease Management; Disease Susceptibility; Drug Design; Drug Development; Drug Evaluation, Preclinical; Dyslipidemias; Humans; Incretins; Lipid Metabolism; Molecular Targeted Therapy; PCSK9 Inhibitors; Risk Assessment; Risk Factors

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

Metabolic disorders are common in patients with chronic hepatitis C virus (HCV) infection. Epidemiologic and clinical data indicate an overprevalence of lipids abnormalite, steatosis, insuline resistance (IR) and diabetes mellitus in HCV patients, suggesting that HCV itself may interact with glucido-lipidic metabolism. HCV interacts with the host lipid metabolism by several mechanisms leading to hepatic steatosis and hypolipidemia which are reversible after viral eradication. Liver and peripheral IR are HCV genotype/viral load dependent and improved after viral eradication. This article examines examine the relationship between HCV, lipid abnormalities, steatosis, IR, and diabetes and the pathogenic mechanisms accounting for these events in HCV-infected patients.

Topics: Animals; Cytokines; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Liver; Hepacivirus; Hepatitis C, Chronic; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Mice; Prevalence; Risk Factors; Signal Transduction

The metabolic syndrome (MetS) is associated with a higher risk for both, type 2 diabetes mellitus and cardiovascular disease. The cornerstone of treatment is lifestyle modification, encompassing weight reduction and physical exercise. However, pharmacotherapy is usually also required to achieve the recommended target values for the various components of the MetS, such as hypertension, dysglycemia and dyslipidemia. Regarding lipid treatment, statins are the main therapeutic agents while in blood pressure control a significant amount of pathophysiological and clinical evidence would suggest the use, as first line agents, of ACE inhibitors or angiotensin receptor blockers. Metformin seems to be the drug of choice for dysglycemia, specially since recent evidence questions the safety of thiazolidinediones. New drugs, targeting multiple components of the MetS, are under development but no data are currently available regarding their long-term efficacy and safety profile. In general, a multifactorial approach is recommended to decrease cardiovascular risk in patients with the MetS.

Topics: Acarbose; Cardiovascular Diseases; Drug Combinations; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Insulin; Metabolic Syndrome; Metformin; Risk Reduction Behavior; 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

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

It has been demonstrated that fatty acids (FAs) are physiological ligands of G-protein-coupled receptors (GPRs). Activation of the GPRs (40, 41, 43, 84, 119 and 120) by FAs or synthetic agonists modulates several responses. In this review, we discuss the current knowledge on the actions of FA-activated GPRs and their relevance in normal and pathological conditions.. Studies have shown that FA-activated GPRs modulate hormone secretion (incretin, insulin and glucagon), activation of leukocytes and several aspects of metabolism.. Understanding GPR actions and their involvement in the development of insulin-resistance, β-cell failure, dyslipidemia and inflammation associated with obesity, type 2 diabetes, metabolic syndrome and cardiovascular diseases is important for the comprehension of the mechanisms underlying these pathological conditions and for the establishment of new and effective interventions.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Acids; Feeding Behavior; Gastrointestinal Tract; Humans; Incretins; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leukocytes; Ligands; Obesity; Receptors, G-Protein-Coupled

In addition to progressive pancreatic β-cell failure resulting in impaired insulin secretion, and increased insulin resistance in muscle and liver, incretin hormone-related abnormalities have been identified as key underlying defects in patients with type 2 diabetes mellitus. Treatment goals for patients with type 2 diabetes should be aligned with the basic defects of the disease. Many of the available antidiabetes agents correct hyperglycemia but do not impact other cardiovascular risk factors, and may actually aggravate some. This paper reviews the role of defects in the incretin system in the pathophysiology of type 2 diabetes, and discusses recent advances in the use of incretinbased agents that target the fundamental disease mechanisms of type 2 diabetes. The incretinbased agents reduce hyperglycemia and provide beneficial effects on surrogate markers of cardiovascular risk, including weight gain, elevated blood pressure, and dyslipidemia.

Topics: Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins

Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes-associated metabolic disturbances (IR, subclinical inflammation, dyslipidemia, hyperglycemia, dysregulated production of adipokines, defective incretin and gut hormones production/action, and oxidative stress) and ED, focusing on oxidative stress and endothelial progenitor cells (EPCs). In addition, we re-emphasize that oxidative stress is the final common pathway that transduces signals from other conditions-either directly or indirectly-leading to ED and CVD.

Topics: Adipokines; Animals; Diabetes Mellitus; Dyslipidemias; Endothelial Progenitor Cells; Endothelium, Vascular; Ghrelin; Humans; Hyperglycemia; Incretins; Inflammation; Insulin Resistance; Oxidative Stress

Atherosclerosis and cardiovascular events are highly prevalent and represent the major cause of mortality in patients with type 2 diabetes. Therefore, there is significant interest in the non-glycemic properties of anti-diabetic agents, particularly on those that are effective on cardiovascular risk factors. Thiazolidinediones and incretin-based therapies (IBTs) represent some of the most recent treatment options approved for the management of type 2 diabetes; these agents have shown important glycemic effects, as well as a number of non-glycemic effects. The latter include those on body weight, inflammation, hypertension and dyslipidemia, thus impacting the different components of the metabolic syndrome. Pioglitazone has been shown to significantly reduce cardiovascular adverse outcomes, while preliminary data on IBTs are very encouraging as well. Although highlighting the non-glycemic effects of pioglitazone and incretin-based therapies is of potential significance, clinical practice and patient care must be based largely on evidence-based medicine. Therefore, definitive opinions will await additional data from ongoing studies evaluating the effects of both GLP-1 agonists and DPP-4 inhibitors on cardiovascular morbidity and mortality.

Topics: Body Weight; Cardiovascular Diseases; Dyslipidemias; Humans; Hypoglycemic Agents; Incretins; Pioglitazone; Thiazolidinediones

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incretins; Obesity; Postprandial Period; Prevalence