glucagon-like-peptide-1 and Hypercholesterolemia

Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obesity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3 Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral β-amyloidogenesis in murine model of AD, accompanied by a significant elevation in APP (Amyloid Precursor Protein) and BACE1 (β-site APP Cleaving Enzime 1). Similarly, deposits of Aβ produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway. Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat together AD and DM. The aim of the present review is to better understand the strengths and drawbacks of these therapies.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypoglycemic Agents; Incidence; Liraglutide; Male; Metformin; Receptor, Insulin; Risk Factors; tau Proteins

Aim    To study the adipokine profile in young people with hypercholesterolemia and low-density lipoproteins (LDL) and to evaluate the relationship between concentrations of LDL cholesterol (LDL-C) and metabolic hormones in men and women younger than 45 years. Material and methods    This study included 304 subjects (group 1, 56 men with LDL-C concentration <2.1 mmol/l; group 2, 87 men with LDL-C concentration ≥4.2 mmol/l; group 3, 90 women with LDL-C concentration <2.1 mmol/l; and group 4, 71 women with LDL-C concentration ≥4.2 mmol/l). Serum concentrations of total cholesterol (C), triglycerides (TG), high-density lipoprotein C, and glucose were measured by an enzymatic assay with ThermoFisher Scientific kits and a KonelabPrime 30i biochemical analyzer. LDL-C was calculated using the Friedewald's formula. Concentrations of amylin, C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 (GLP-1), glucagon, interleukin 6, insulin, leptin, monocyte chemotactic protein 1 (MCP-1), pancreatic polypeptide (PP), peptide YY (PYY), tumor necrosis factor alpha (TNF-α), adiponectin, adipsin, lipocalin-2, plasminogen activator inhibitor 1 (PAI-1), and resistin were measured by multiplex analysis (Human Metabolic Hormone V3 and Human Adipokine Panel 1 panels).Results    The groups differed in traditional cardiometabolic risk factors. In the male and female patient groups with LDL-C ≥4.2 mmol/l, the prevalence of impaired fasting glucose, incidence of insulin resistance, TG, and TC were higher than in subjects with LDL-C <2.1 mmol/l. The odds for the presence of LDL hypercholesterolemia (LDL-C ≥4.2 mmol/l) were significantly associated with increased concentrations of C-peptide and lipocalin-2 in men and with increased concentrations of lipocalin-2 and decreased concentrations of GLP-1 in women (р<0.05).Conclusion    Increased concentrations of LDL-C in young people were associated with changes in the adipokine profile and with the presence of metabolic syndrome components. These results were confirmed by changes in blood concentrations of metabolic markers that characterize disorders of metabolic processes.

Topics: Adipokines; Adolescent; C-Peptide; Cholesterol, LDL; Female; Glucagon-Like Peptide 1; Glucose; Humans; Hypercholesterolemia; Hyperlipidemias; Lipocalin-2; Male; Triglycerides

The incretin hormone Glucagon-like peptide 1(GLP-1) plays a pivotal role in maintaining glucose homeostasis with effects also on the cardiovascular system. GLP-1 influences platelet functions by increasing the inhibitory action of nitric oxide (NO) and reducing oxidative stress. To date, the role of hypercholesterolemia (HyC) on platelet GLP-1 effects needs to be elucidated.. Forty-five subjects with primary HyC and twenty normocholesterolemic controls (NoC) were enrolled. In platelets from all subjects, the native GLP-1 (7-36), the truncated GLP-1 (9-36) and the GLP-1 analogue Liraglutide were evaluated in their ability to interfere with the activation of NO/PKG/VASP, PI-3K/Akt e MAPK/ERK-1/2 pathways and oxidative stress. Furthermore, in HyC subjects the role of a lipid-lowering therapy with statin on GLP-1 related peptide effects on platelet function was evaluated.. Unlike in NoC, in platelets from HyC subjects the GLP-1 related peptides GLP-1 (7-36), GLP-1 (9-36) and Liraglutide all failed to: i) increase the antiaggregating effects of NO and the NO-induced VASP-ser239 phosphorylation, ii) decrease phosphorylation levels of Akt and ERK-2 and iii) reduce reactive oxygen species (ROS) generation. The treatment with simvastatin (40 mg/die) in HyC (n = 18) significantly reduced total and LDL cholesterol levels, platelet aggregability/activation, ROS production and NO action but did not modify platelet sensitivity to the GLP-1 effects.. Collectively, these results indicate that hypercholesterolemia per se is characterized by a resistance to GLP-1 effects on platelets and this impairment is not corrected by treatment with simvastatin.

Topics: Adult; Blood Platelets; Female; Glucagon-Like Peptide 1; Humans; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Phosphorylation; Platelet Aggregation; Reactive Oxygen Species; Simvastatin

Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight.. C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46±2% and 60±2% greater body weight relative to regular chow diet-fed mice at 16 and 32 weeks, respectively (both P<0.0001), manifesting impaired glucose tolerance, insulin resistance, and cardiac ceramide accumulation by 16 weeks. One-week treatment with liraglutide (30 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase-dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-α-activated human endothelial cells in vitro.. Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity.

Topics: Animals; Blood Glucose; Cardiotonic Agents; Cell Line; Connexin 43; Coronary Vessels; Disease Models, Animal; Endoplasmic Reticulum Stress; Endothelial Cells; Gene Expression; Glucagon-Like Peptide 1; Heart Diseases; Humans; Hypercholesterolemia; Insulin Resistance; Liraglutide; Mice; Mice, Inbred C57BL; Monocytes; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Obesity; Risk Factors; Signal Transduction; Tumor Necrosis Factor-alpha

Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes complicated by hypercholesterolemia.. To examine the mechanism by which colestimide decreases plasma glucose levels in the above patients.. A total of 16 inpatients with type 2 diabetes complicated by hypercholesterolemia received colestimide for 1 week after their plasma glucose levels stabilized. We measured plasma glucose, serum immunoreactive insulin (IRI), serum lipid, plasma glucagon, and plasma glucagon-like peptide-1 (GLP-1) levels. These variables at baseline and 1 week of colestimide administration were compared.. Preprandial plasma glucose levels (baseline: 132 +/- 33 mg/dL vs. completion: 118 +/- 43 mg/dL, P=0.073) tended to decrease after colestimide administration, while 1-hr postprandial plasma glucose levels (baseline: 208 +/- 49 mg/dL vs. completion: 166 +/- 30 mg/dL, P<0.001) and 2-hr postprandial plasma glucose levels (baseline: 209 +/- 56 mg/dL vs. completion: 178 +/- 39 mg/dL, P=0.015) decreased significantly at 1 week of colestimide administration. The 2-hr postprandial plasma GLP-1 level was significantly (P=0.015) higher at 1 week of colestimide administration as compared with the baseline level, while there were no significant changes in preprandial and 1-hr postprandial plasma GLP-1 levels.. The GLP-1-increasing activity of colestimide may explain, at least in part, the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes complicated by hypercholesterolemia.

Topics: Anion Exchange Resins; Blood Glucose; Diabetes Mellitus, Type 2; Epichlorohydrin; Female; Glucagon-Like Peptide 1; Humans; Hypercholesterolemia; Imidazoles; Lipids; Male; Middle Aged; Resins, Synthetic