incretins and Metabolic-Diseases

This review aimed to describe the potential mechanisms by which incretin hormones could mediate the relationship between glycemic index and cardiometabolic diseases. A body of evidence from many studies suggests that low glycemic index (GI) diets reduces the risk for type 2 diabetes and coronary heart disease. In fact, despite the extensive literature on this topic, the mechanisms underlying unfavorable effects of high GI foods on health remain not well defined. The postprandial and hormonal milieu could play a key role in the relationship between GI and cardiovascular risk. Incretin hormones, glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important regulators of postprandial homeostasis by amplifying insulin secretory responses. Response of GIP and GLP-1 to GI have been studied more in depth, also by several studies on isomaltulose, which have been taken as an ideal model to investigate the kinetics of incretin secretion in response to foods' GI. In addition, extrapancreatic effects of these incretin hormones were also recently observed. Emerging from this have been exciting effects on several targets, such as body weight regulation, lipid metabolism, white adipose tissue, cardiovascular system, kidney, and liver, which may importantly affect the health status.

Topics: Animals; Blood Glucose; Dietary Carbohydrates; Energy Metabolism; Glycemic Index; Heart Diseases; Humans; Incretins; Metabolic Diseases; Nutritional Status

Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA.

Topics: Bariatric Surgery; Bile Acids and Salts; Constipation; Diabetes Mellitus; Energy Metabolism; Gastrointestinal Microbiome; Glucose; Homeostasis; Humans; Incretins; Lipid Metabolism; Metabolic Diseases; Metabolism; Obesity; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Thyroid Gland

Bariatric surgery is currently the most efficacious treatment for obesity and its associated metabolic co-morbidities, such as diabetes. The metabolic improvements occur through both weight-dependent and weight-independent mechanisms. Bile acids (BAs) have emerged as key signalling molecules that have a central role in modulating many of the physiological effects seen after bariatric surgery. This systematic review assesses the evidence from both human and animal studies for the role of BAs in reducing the metabolic complications of obesity following bariatric surgery.. We conducted a systematic search of Medline and Embase databases to identify all articles investigating the role of BAs in mediating the metabolic changes observed following bariatric surgery in both animal and human studies. Boolean logic was used with relevant search terms, including the following MeSH terms: 'bile acids and salts', 'bariatric surgery', 'metabolic surgery', 'gastrointestinal tract/surgery' and 'obesity/surgery'.. Following database searches (n=1197), inclusion from bibliography searches (n=2) and de-duplication (n=197), 1002 search results were returned. Of these, 132 articles were selected for full-text review, of which 38 articles were deemed relevant and included in the review. The findings support the effects of BAs on satiety, lipid and cholesterol metabolism, incretins and glucose homoeostasis, energy metabolism, gut microbiota and endoplasmic reticulum stress following bariatric surgery. Many of these metabolic effects are modulated through the BA receptors FXR and TGR5. We also explore a possible link between BAs and carcinogenesis following bariatric surgery.. Overall there is good evidence to support the role of BAs in the metabolic effects of bariatric surgery through the above mechanisms. BAs could serve as a novel therapeutic pharmacological target for the treatment of obesity and its associated co-morbidities.

Topics: Bariatric Surgery; Bile Acids and Salts; Endoplasmic Reticulum; Energy Metabolism; Gastrointestinal Microbiome; Glucose; Homeostasis; Humans; Incretins; Lipid Metabolism; Metabolic Diseases; Obesity, Morbid; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Treatment Outcome; Weight Loss

GPR120 receptor functions as a receptor for ω-3 fatty acid, involving regulating the secretion of gastrointestinal peptide hormone, adipogenesis, adipogenic differentiation and anti-inflammatory process and the like in the aspect of biological functions. In view that the dysfunction of GPR120 receptor is closely correlated with metabolic disorders, GPR120 may act as a novel potential therapeutic target for the treatment of obesity, insulin resistance, Type 2 diabetes and so on. Therefore, mounting scientists devote themselves to probing the molecular mechanism of the biological function of GPR120 receptor and their ligands for the treatment of impaired metabolic health. Herein, we summarize the mechanisms of signal transduction through GPR120 receptor, and discovery and development of GPR120 agonists thereof.

Topics: Amino Acid Sequence; Animals; Appetite Regulation; Diabetes Mellitus, Type 2; Drug Discovery; Fatty Acids, Omega-3; Humans; Incretins; Insulin Resistance; Metabolic Diseases; Molecular Sequence Data; Obesity; Receptors, G-Protein-Coupled; Sequence Alignment

Dipeptidylpeptidase-4 (DPP-4) is a ubiquitously expressed transmembrane protein that removes NH2-terminal dipeptides from various substrate hormones, chemokines, neuropeptides, and growth factors. Two known substrates of DPP-4 include the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide, which are secreted by enteroendocrine cells in response to postprandial hyperglycemia and account for 60–70% of postprandial insulin secretion. DPP-4 inhibitors (DPP-4i) block degradation of GLP-1 and gastric inhibitory peptide, extend their insulinotropic effect, and improve glycemia. Since 2006, several DPP-4i have become available for treatment of type 2 diabetes mellitus. Clinical trials confirm that DPP-4i raises GLP-1 levels in plasma and improves glycemia with very low risk for hypoglycemia and other side effects. Recent studies also suggest that DPP-4i confers cardiovascular and kidney protection, beyond glycemic control, which may reduce the risk for further development of the multiple comorbidities associated with obesity/type 2 diabetes mellitus, including hypertension and cardiovascular disease (CVD) and kidney disease. The notion that DPP-4i may improve CVD outcomes by mechanisms beyond glycemic control is due to both GLP-1-dependent and GLP-1-independent effects. The CVD protective effects by DPP-4i result from multiple factors including insulin resistance, oxidative stress, dyslipidemia, adipose tissue dysfunction, dysfunctional immunity, and antiapoptotic properties of these agents in the heart and vasculature. This review focuses on cellular and molecular mechanisms mediating the CVD protective effects of DPP-4i beyond favorable effects on glycemic control.

Topics: Animals; Cardiovascular Diseases; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Incretins; Metabolic Diseases

Dual activation of the glucagon-like peptide 1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor has potential as a novel strategy for treatment of diabesity. Here, we created a hybrid peptide which we named 19W, and show that it is more stable in presence of murine plasma than exendin-4 is. In vitro studies were performed to reveal that 19W could stimulate insulin secretion from INS-1 cells in a dose-dependent manner, just like the native peptide GIP and exendin-4 do. 19W effectively evoked dose-dependent cAMP production in cells targeting both GLP-1R and GIPR. In healthy C57BL/6J mice, the single administration of 19W significantly improved glucose tolerance. When administered in combination with sodium deoxycholate (SDC), its oral hypoglycemic activity was enhanced. Pharmacokinetics studies in Wistar rats revealed that 19W was absorbed following oral uptake, while SDC increased its bioavailability. A long-term (28 days) exposure study of twice-daily oral administration to high fat-fed (HFF) mice showed that 19W significantly reduced animal food intake, body weight, fasting blood glucose, total serum cholesterol (T-CHO), non-esterified free fatty acids (NEFA), and low-density lipoprotein cholesterol (LDL-C) levels. It also significantly improved glucose tolerance and the pancreatic β/α cell ratio, and decreased the area of liver fibrosis. These results clearly demonstrate the beneficial action of this novel oral GLP-1/GIP dual receptor agonist to reduce adiposity and hyperglycemia in diabetic mice and to ameliorate liver fibrosis associated with obesity. This dual-acting peptide can be considered a good candidate for novel oral therapy to treat obesity and diabetes.

Topics: Animals; Cyclic AMP; Diabetes Mellitus, Experimental; Eating; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Metabolic Diseases; Mice; Obesity; Rats; Receptors, Gastrointestinal Hormone

Recent studies show that incretin hormone analogues effectively control blood glucose while producing major weight losses and reducing the risk of all-cause mortality, myocardial infarction, stroke and kidney function impairment. Furthermore, the risk of dementia and cognitive impairment is reduced. A monomolecular coagonist (tirzepatide) of receptors for both incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) produced HbA1c values below 5.7% in 50% of the treated patients and weight losses exceeding 20% in obese individuals. These new agents will radically change our approach to the treatment of T2DM and obesity alike.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Metabolic Diseases; Obesity; Weight Loss

Gallstone disease is associated with insulin resistance, type 2 diabetes mellitus, and increased risk of incident ischemic heart disease. It is known that the profile of branched‑chain amino acids (BCAAs) is altered in cardiac diseases as well as metabolic diseases, such as diabetes and obesity. The role of BCAAs in gallstone disease is still not known.. The aim of this study was to evaluate the concentration of essential amino acids and incretin hormones in patients with cholecystolithiasis.. The study included 31 patients with cholecystolithiasis and 25 gallstone‑free controls. The levels of free exogenous and endogenous amino acids, bile acids, glucagon‑like peptide 1, glucose‑dependent insulinotropic polypeptide, ghrelin, C-peptide, and insulin were measured in the fasting state and 1 hour after consumption of a 300‑kcal mixed meal.. The mean fasting and postprandial levels of valine, isoleucine, leucine, and lysine were higher in the study group than in controls (all P.

Topics: Adult; Aged; Cholecystolithiasis; Diabetes Mellitus, Type 2; Female; Humans; Incretins; Isoleucine; Leucine; Lysine; Male; Metabolic Diseases; Middle Aged; Pilot Projects; Valine

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Metabolic Diseases

We previously showed that parenteral nutrition (PN) compared with formula feeding results in hepatic insulin resistance and steatosis in neonatal pigs. The current aim was to test whether the route of feeding (intravenous [IV] vs enteral) rather than other feeding modalities (diet, pattern) had contributed to the outcome.. Neonatal pigs were fed enterally or parenterally for 14 days with 1 of 4 feeding modalities as follows: (1) enteral polymeric formula intermittently (FORM), (2) enteral elemental diet (ED) intermittently (IEN), (3) enteral ED continuously (CEN), and (4) parenteral ED continuously (PN). Subgroups of pigs underwent IV glucose tolerance tests (IVGTT) and hyperinsulinemic-euglycemic clamps (CLAMP). Following CLAMP, pigs were euthanized and tissues collected for further analysis.. Insulin secretion during IVGTT was significantly higher and glucose infusion rates during CLAMP were lower in CEN and PN than in FORM and IEN. Endogenous glucose production rate was suppressed to zero in all groups during CLAMP. In the fed state, plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2 were different between feeding modalities. Insulin receptor phosphorylation in liver and muscle was decreased in IEN, CEN, and PN compared with FORM. Liver weight was highest in PN. Steatosis and myeloperoxidase (MPO) activity tended to be highest in PN and CEN. Enterally fed groups had higher plasma GLP-2 and jejunum weight compared with PN.. PN and enteral nutrition (EN) when given continuously as an elemental diet reduces insulin sensitivity and the secretion of key gut incretins. The intermittent vs continuous pattern of EN produced the optimal effect on metabolic function.

Topics: Administration, Intravenous; Animals; Animals, Newborn; Blood Glucose; Endpoint Determination; Enteral Nutrition; Fatty Liver; Female; Food, Formulated; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Incretins; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Intestine, Small; Liver; Metabolic Diseases; Nonlinear Dynamics; Organ Size; Parenteral Nutrition; Swine