incretins and Hypercholesterolemia

Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose-lowering effect in patients with type 2 diabetes remain unclear. This article offers a review of the mechanisms behind the glucose-lowering effect of BASs, and the efficacy of BASs in the treatment of type 2 diabetes.

Topics: Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Epichlorohydrin; Female; Gastric Emptying; Glycated Hemoglobin; Humans; Hypercholesterolemia; Hypoglycemic Agents; Imidazoles; Incretins; Lipid Metabolism; Male; Resins, Synthetic; Signal Transduction; Treatment Outcome

The dialogue between gut hormone, bile acids, and the brain plays an important role in energy homeostasis and the onset of Type 2 diabetes mellitus (T2DM). The present review focuses on: (i) bile acid metabolism and the role of bile acids in the regulation of both glucose homeostasis and the control of hypercholesterolemia; (ii) the role of gut hormones in energy homeostasis; and (iii) translation of the pathophysiology of bile acids and gut hormones into clinical practice. Although definitive mechanisms of action of gut hormones and bile acids have not been elucidated completely, these concepts allow us to understand several pharmacological interventions in the treatment of T2DM. Results from further clinical studies with related therapies will help us determine the role of these treatments in the management of energy homeostasis.

Topics: Bile Acids and Salts; Brain; Gastrointestinal Hormones; Ghrelin; Glucose; Homeostasis; Humans; Hypercholesterolemia; Incretins; Leptin; Receptors, Cytoplasmic and Nuclear; Satiety Response

Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin enhancer that improves glucose tolerance by inhibiting dipeptidyl peptidase-4, but it also has reported anti-inflammatory effects. The current study was thus undertaken to examine the interactions of dietary Cholesterol (Cho) and sitagliptin on markers of inflammation.. Male Sprague-Dawley rats were provided diets high in Cho and gavaged with vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day) from day 10 through day 35. Molecular methods were used to analyze the lipid profile and inflammatory markers in liver and serum samples. H&E-stained liver sections were used for histopathological evaluation. Hepatic influx of mononuclear cells and necrosis were assessed by immunohistochemistry.. Sitagliptin reduced triglyceride and Cho levels in serum of rats on the control diet but these effects were abrogated in rats on the high-Cho diet. Sitagliptin produced a significant increase in the expression of hepatic inflammatory markers (Tnfa, Il1b, and Mcp1) and a corresponding increase in serum TNFα and IL-1β in rats on the high-Cho diet, but it had no effect on rats on the control diet. Additionally, sitagliptin had no effect on liver morphology in rats on the control diet, but it produced hepatic histopathological changes indicative of necrosis and mononuclear cell infiltration in rats on the high-Cho diet. These mononuclear cells were identified as macrophages and T cells.. When provided in the context of a high-Cho diet, these findings reveal previously unrecognized hepato-inflammatory effects of sitagliptin that are accompanied by evidence of hepatic necrosis and mononuclear cell infiltration.

Topics: Animals; Cholesterol, Dietary; Cytokines; Hypercholesterolemia; Incretins; Liver; Male; Rats, Sprague-Dawley; Sitagliptin Phosphate

Glipitins are widely used for the treatment of type 2 diabetic patients. In addition to their improvement of glycemic control, animal studies have suggested an independent anti-atherosclerotic effect of gliptins. Nevertheless, recent clinical trials regarding long-term effects of gliptin therapy on vascular events have been disappointing. This discrepancy led us to better dissect the functional role of SDF-1/CXCR4 signaling as a potential mechanism underlying gliptin action. The study should give improved understanding of the potential of gliptin therapy in the prevention and treatment of atherosclerosis.. In an ApoE-/- mouse model on high cholesterol diet, long-term treatment with the DPP-4 inhibitor Sitagliptin significantly reduced atherosclerosic plaque load in the aorta. Flow cytometry analyses showed an enrichment of M2 macrophages in the aortic wall under gliptin therapy. Importantly, the number of recruited CD206+ macrophages was inversely correlated with total plaque area while no correlation was found for the overall macrophage population or M1 macrophages. Blockade of CXCR4/SDF-1 signaling by AMD3100 inhibited aortic M2 accumulation and the therapeutic effect of Sitagliptin. Correspondingly, Sitagliptin shifted the polarization profile of macrophages towards a M2-like phenotype.. Sitagliptin-mediated inhibition of early atherosclerosis is based on M2-polarization during monocyte differentiation via the SDF-1/CXCR4 signaling. In contrast to earlier assumptions gliptin treatment might be especially effective in prevention of atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Chemokine CXCL12; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Flow Cytometry; Hypercholesterolemia; Incretins; Insulin Resistance; Macrophages; Male; Mice; Monocytes; Plaque, Atherosclerotic; Receptors, CXCR4; Repetition Priming; Sitagliptin Phosphate

Obesity has reached epidemic proportions in the USA with a nearly fourfold rise in the prevalence of childhood obesity. There are many possible etiologies of obesity as the adipose tissue plays a significant, complex role in the physiology of fuel metabolism and hormone regulation. The development of obesity represents a pathophysiologic increase in fat mass in which multiple metabolic pathways are deranged. The consequences of these metabolic derangements, including insulin resistance and inflammation, are reflected in obesity-related comorbidities and can be seen in the setting of pediatric obesity. Obese adolescents demonstrate increased rates of early maturation, orthopedic growth abnormalities, diabetes mellitus, obstructive sleep apnea, hypertension, steatosis, and polycystic ovarian syndrome, placing this group of children at risk for long-term health problems and reduced quality of life. Given the negative short- and long-term impact of obesity on children, careful attention should be paid to the unique health issues of this "at-risk" population with both prevention and early intervention strategies.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Animals; Body Mass Index; Diabetes Mellitus; Evidence-Based Medicine; Female; Humans; Hypercholesterolemia; Hypertension; Incretins; Metabolic Syndrome; Obesity; Ohio; Polycystic Ovary Syndrome; Prevalence; Quality of Life; Risk Factors; Sleep Apnea, Obstructive