incretins and Hyperlipidemias

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperlipidemias; Incretins; Lipid Metabolism; Postprandial Period; Randomized Controlled Trials as Topic; Risk Factors

To test whether liraglutide suppresses postprandial elevations in lipids and thus protects against high saturated fatty acid (SFA) diet-induced insulin resistance.. In a randomized placebo-controlled crossover study, 32 participants with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and after a 24-hour SFA-enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non-esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants underwent ex vivo measurements of insulin-mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle.. Liraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA diet (by 50%, 25% and 9%, respectively), and the SFA diet increased plasma glucose during the IST (by 36%; all P < .01 vs placebo). The SFA diet-induced impairment of vasodilation on placebo (-9.4% vs baseline; P < .01) was ameliorated by liraglutide (-4.8%; P = .1 vs baseline). In skeletal muscle, liraglutide abolished the SFA-induced increase in thioredoxin-interacting protein (TxNIP) expression (75% decrease; P < .01 vs placebo) and increased 5'AMP-activated protein kinase (AMPK) phosphorylation (50% vs -3%; P = .04 vs placebo).. Liraglutide blunted the SFA-enriched diet-induced peripheral insulin resistance. This effect may be related to improved microvascular function and modulation of TxNIP and AMPK pathways in skeletal muscle.

Topics: Adult; Aged; Body Mass Index; Cohort Studies; Cross-Over Studies; Diet, High-Fat; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hyperlipidemias; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Male; Microvessels; Middle Aged; Muscle, Skeletal; Overweight; Postprandial Period; Prediabetic State; Subcutaneous Fat, Abdominal; Vasodilation

Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified.. To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL) response to a fat-rich meal.. Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m(2)) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal.. Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins.. The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p<0.0001; r = 0.46, p<0.001 and r = 0.69, p<0.001, respectively). Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest.. In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor.

Topics: Adult; Aged; Apolipoprotein B-100; Apolipoprotein B-48; Area Under Curve; Blood Glucose; Chylomicrons; Dietary Fats; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Tolerance Test; Humans; Hyperlipidemias; Incretins; Lipid Metabolism; Male; Meals; Middle Aged; Obesity; Postprandial Period; Triglycerides

Subjects with type 2 diabetes (T2D) and their nondiabetic first-degree relatives (REL) have increased risk of cardiovascular disease (CVD). Postprandial triglyceridemia (PPL), influenced by diet, is an independent risk factor for CVD. Dietary fat elicits increased PPL in T2D compared with nondiabetic controls, but our knowledge of PPL responses to fat in REL is sparse. Our aim was to test the hypothesis that REL respond to a monounsaturated fatty acid (MUFA) challenge with a higher PPL response compared with controls who have no family history of T2D (CON) and that MUFAs exert a differential impact on incretin responses and on the expression of genes involved in carbohydrate and lipid metabolism in muscle and adipose tissues of REL and CON.. A total of 17 REL and 17 CON consumed a meal with 72 energy percent derived from MUFAs (macadamia nut oil). Plasma triglycerides, free fatty acids, insulin, glucose, glucagon-like peptide 1, glucose-dependent insulintropic peptide and ghrelin were measured at baseline and regular intervals until 4 h postprandially. Muscle and adipose tissue biopsies were collected at baseline and at 210 min after the meal.. The MUFA-rich meal did not elicit different responses (P>0.05) in PPL, insulin, glucose, incretins or ghrelin in REL and CON. Several genes were differentially regulated in muscle and adipose tissues of REL and CON.. A MUFA-rich meal elicits similar PPL, insulin and incretin responses in REL and CON. MUFAs have a differential impact on gene expression in muscle and adipose tissues in a pattern pointing toward early defects in lipid metabolism in REL.

Topics: Adipose Tissue; Adult; Diabetes Mellitus, Type 2; Family; Fatty Acids, Monounsaturated; Female; Gene Expression; Humans; Hyperlipidemias; Incretins; Insulin; Lipid Metabolism; Macadamia; Male; Meals; Middle Aged; Muscles; Postprandial Period; Triglycerides

Exaggerated and prolonged postprandial lipemia is potentially atherogenic and associated with type 2 diabetes. Limited data exist regarding the influence of dietary protein on postprandial lipemia in type 2 diabetes. We investigated, over 8-h, the acute effects of casein alone or in combination with carbohydrate on postprandial lipid and incretin responses to a fat-rich meal in type 2 diabetes.. Eleven type 2 diabetic subjects ingested four test meals in random order: an energy-free soup plus 80 g of fat (control-meal); control-meal plus 45 g carbohydrates (CHO-meal); control-meal plus 45 g of casein (PRO-meal); and PRO-meal plus 45 g carbohydrates (CHO+PRO-meal). Triglyceride and retinyl palmitate responses were measured in plasma and in a chylomicron-rich and chylomicron-poor fraction. We found no significant differences in triglyceride responses to PRO- and CHO+PRO-meal compared to the control-meal. However, the addition of casein to the CHO-meal reduced the raised triglyceride response in the chylomicron-rich fraction. Retinyl palmitate responses did not differ significantly between meals in the chylomicron-rich fraction, whereas the PRO-meal increased retinyl palmitate in the chylomicron-poor fraction. PRO- and PRO+CHO-meal increased insulin and glucagon compared to the control-meal. PRO+CHO-meal increased the glucose-dependent insulinotropic peptide response while no change in glucagon-like peptide-1 responses was detected.. The data presented suggest that casein per se did not modulate the postprandial triglyceride response in type 2 diabetes. When added to carbohydrate, casein suppressed the triglyceride response in the chylomicron-rich fraction, increased insulin and glucagon but did not affect the incretin responses.

Topics: Aged; Biomarkers; Blood Glucose; Caseins; Chylomicrons; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Diterpenes; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Postprandial Period; Retinyl Esters; Time Factors; Triglycerides; Vitamin A

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

Bariatric surgery (BS) is able to positively influence fasting lipid profile in obese type 2 diabetic patients (T2DM), but no data is available on the impact of BS on postprandial lipid metabolism neither on its relation with incretin hormones. We evaluated the short-term (2 weeks) effects of BS on fasting and postprandial lipid metabolism in obese T2DM patients and the contribution of changes in active GLP-1.. We studied 25 obese T2DM patients (age = 46 ± 8 years, BMI = 44 ± 7 kg/m2), of which 15 underwent sleeve gastrectomy and 10 underwent gastric bypass. Lipid and incretin hormone concentrations were evaluated for 3 h after ingestion of a liquid meal before and 2 weeks after BS.. After BS, there was a significant reduction in body weight (p < 0.001), fasting plasma glucose (p < 0.001), fasting plasma insulin (p < 0.05), HOMA-IR (p < 0.001), and fasting plasma lipids (p < 0.05). The meal response of plasma triglycerides, total cholesterol, and HDL cholesterol was significantly lower compared to pre-intervention (p < 0.05, p < 0.001). In particular, the incremental area under the curve (IAUC) of plasma triglycerides decreased by 60% (p < 0.005). The meal-stimulated response of active GLP-1 increased, reaching a statistical significance (p < 0.001).. BS leads to an early improvement of fasting and postprandial lipemia. The fall in fasting triglycerides is associated with an improvement of insulin resistance, while the reduction of postprandial lipemia is likely related to reduced intestinal lipid absorption consequent to bariatric surgery.

Topics: Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Homeostasis; Humans; Hyperlipidemias; Incretins; Insulin Resistance; Lipids; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Treatment Outcome; Triglycerides

Increased fat mass contributes to bone deterioration. Glucagon-like peptide 1 (GLP-1) and its related peptide exendin 1-39 amide (Ex-4), two lipid-lowering peptides, exert osteogenic effects in diabetic states. We examined the actions of 3-day administration of GLP-1 or Ex-4 on bone remodeling markers and on bone mass and structure in hyperlipidic (HL) and hypercaloric rats. Wistar rats on a hyperlipidemic diet for 35 days were subcutaneously administered GLP-1 (0.86  nmol/kg per h), Ex-4 (0.1  nmol/kg per h), or saline (control) by continuous infusion for 3 days. After killing, tibiae were removed for total RNA and protein isolation, as well as femurs and L1-L4 vertebrae for bone mass and quality assessment. Body weight and plasma insulin were unaltered in HL rats, which showed osteopenia (by dual-energy X-ray absorptiometry), associated with hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. GLP-1 or Ex-4 administration decreased the levels of glucose, triglycerides, and total cholesterol in plasma but increased osteocalcin (OC) gene expression and the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio - at the expense of an augmented OPG - above corresponding control values in the tibia. Each tested peptide similarly reversed the decreased femoral and vertebral bone mass in these rats, whereas the deteriorated trabecular structure in the vertebrae improved associated with normalization of bone remodeling. These findings demonstrate that GLP-1 and Ex-4 are similarly efficient in reversing the bone alterations in this HL rat model, which has proven to be useful for studying the fat-bone relationships.

Topics: Animals; Biomarkers; Bone Density; Bone Diseases, Metabolic; Dietary Fats; Drug Evaluation, Preclinical; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperlipidemias; Hypoglycemic Agents; Incretins; Lumbar Vertebrae; Osteogenesis; Peptides; Rats; Rats, Wistar; Venoms