Juraj Koska

Exenatide suppresses postprandial elevations in lipids and lipoproteins in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus

OBJECTIVE Chronic exenatide treatment in type 2 diabetes is associated with improved glucose control and fasting lipid levels, as well as weight loss. Less established is whether exenatide directly reduces postprandial lipid and lipoprotein levels without the reduction in body weight or fasting glucose and triglycerides levels that frequently occur with prolonged therapy. Therefore, the effect of a single injection of exenatide on postprandial lipids, remnant lipoproteins, and apolipoproteins was studied. METHODS A double-blinded, randomized, placebo-controlled, crossover study was conducted in 35 subjects (31 men and 4 women) with impaired glucose tolerance (n=20) or recent onset type 2 diabetes (n=15). A single subcutaneous injection of exenatide (10 microg) or normal saline was administered just prior to a high-calorie, fat-enriched breakfast meal. Concentrations of triglycerides (TG), apolipoproteins B-48 and CIII, non-esterified fatty acids (NEFA), and remnant lipoprotein (RLP) cholesterol and TG in serum or plasma were measured prior to the injection and for up to 8 h postprandially. RESULTS Exenatide markedly reduced postprandial elevation of TG, apolipoproteins B-48 and CIII, RLP-cholesterol and RLP-triglyceride (all p<0.001). Postprandial declines in NEFA were less pronounced but persisted longer with exenatide compared to placebo (p<0.05). These effects of exenatide were not affected either by glucose tolerance status or by treatment with statins. CONCLUSION These results demonstrate that exenatide acutely and profoundly inhibits postprandial excursions of proatherogenic lipids and lipoproteins and may offer additional cardiovascular risk reduction (NCT00974272).

Improvement of Postprandial Endothelial Function After a Single Dose of Exenatide in Individuals With Impaired Glucose Tolerance and Recent-Onset Type 2 Diabetes

OBJECTIVE Endothelial dysfunction is frequently present in individuals with insulin resistance or type 2 diabetes and can be induced by high-fat or high-carbohydrate meals. Because exenatide reduces postprandial glucose and lipid excursions, we hypothesized that it may also improve postprandial endothelial function. RESEARCH DESIGN AND METHODS In a double-blinded randomized crossover design, postprandial endothelial function was examined in 28 individuals with impaired glucose tolerance or recent-onset type 2 diabetes after a single injection of exenatide or placebo given just before a high-fat meal. Endothelial function was determined with peripheral arterial tonometry pre- and postprandially. RESULTS Postprandial endothelial function was higher after exenatide compared with placebo (P = 0.0002). In the placebo phase, postprandial change in endothelial function was inversely associated with mean postprandial concentrations of triglycerides (r = −0.62, P = 0.0004). Changes in postprandial triglyceride concentrations explained 64% of exenatides effect on postprandial endothelial function. CONCLUSIONS Exenatide ameliorates postprandial endothelial dysfunction after a high-fat meal.

Physiological Evidence for the Involvement of Peptide YY in the Regulation of Energy Homeostasis in Humans

Objective: To explore the potential role of the endogenous peptide YY (PYY) in the long‐term regulation of body weight and energy homeostasis.

Macrophage content in subcutaneous adipose tissue: associations with adiposity, age, inflammatory markers, and whole-body insulin action in healthy Pima Indians.

OBJECTIVE— In severely obese individuals and patients with diabetes, accumulation and activation of macrophages in adipose tissue has been implicated in the development of obesity-associated complications, including insulin resistance. We sought to determine whether in a healthy population, adiposity, sex, age, or insulin action is associated with adipose tissue macrophage content (ATMc) and/or markers of macrophage activation. RESEARCH DESIGN AND METHODS— Subcutaneous ATMc from young adult Pima Indians with a wide range of adiposity (13–46% body fat, by whole-body dual-energy X-ray absorptiometry) and insulin action (glucose disposal rate 1.6–9 mg/kg estimated metabolic body size/min, by glucose clamp) were measured. We also measured expression in adipose tissue of factors implicated in macrophage recruitment and activation to determine any association with ATMc and insulin action. RESULTS— ATMc, as assessed by immunohistochemistry (Mphi) and by macrophage-specific gene expression (CD68, CD11b, and CSF1R), were correlated with percent body fat, age, and female sex. Gene expression of CD68, CD11b, and CSF1R but not Mphi was correlated negatively with glucose disposal rate but not after adjustment for percent body fat, age, and sex. However, adipose tissue expression of plasminogen activator inhibitor type-1 (PAI-1) and CD11 antigen-like family member C (CD11c), markers produced by macrophages, were negatively correlated with adjusted glucose disposal rate (r = −0.28, P = 0.05 and r = −0.31, P = 0.03). CONCLUSIONS— ATMc is correlated with age and adiposity but not with insulin action independent of adiposity in healthy human subjects. However, PAI-1 and CD11c expression are independent predictors of insulin action, indicating a possible role for adipose tissue macrophage activation.

Adipogenic Human Adenovirus Ad-36 Induces Commitment, Differentiation, and Lipid Accumulation in Human Adipose-Derived Stem Cells

Human adenovirus Ad‐36 is causatively and correlatively linked with animal and human obesity, respectively. Ad‐36 enhances differentiation of rodent preadipocytes, but its effect on adipogenesis in humans is unknown. To indirectly assess the role of Ad‐36‐induced adipogenesis in human obesity, the effect of the virus on commitment, differentiation, and lipid accumulation was investigated in vitro in primary human adipose‐derived stem/stromal cells (hASC). Ad‐36 infected hASC in a time‐ and dose‐dependent manner. Even in the presence of osteogenic media, Ad‐36‐infected hASC showed significantly greater lipid accumulation, suggestive of their commitment to the adipocyte lineage. Even in the absence of adipogenic inducers, Ad‐36 significantly increased hASC differentiation, as indicated by a time‐dependent expression of genes within the adipogenic cascade—CCAAT/Enhancer binding protein‐β, peroxisome proliferator‐activated receptor‐γ, and fatty acid‐binding protein—and consequentially increased lipid accumulation in a time‐ and viral dose‐dependent manner. Induction of hASC to the adipocyte state by Ad‐36 was further supported by increased expression of lipoprotein lipase and the accumulation of its extracellular fraction. hASC from subjects harboring Ad‐36 DNA in their adipose tissue due to natural infection had significantly greater ability to differentiate compared with Ad‐36 DNA‐negative counterparts, which offers a proof of concept. Thus, Ad‐36 has the potential to induce adipogenesis in hASC, which may contribute to adiposity induced by the virus.

Interaction Between an 11βHSD1 Gene Variant and Birth Era Modifies the Risk of Hypertension in Pima Indians

11&bgr;-Hydroxysteroid dehydrogenase type 1 (11&bgr;HSD1) is a candidate gene for hypertension, diabetes, and obesity through altered glucocorticoid production. This study explored the association of 11&bgr;HSD1 gene variants with diabetes, hypertension, and obesity in a longitudinal population study of American Indians (N=918; exams=5508). In multivariate mixed models assuming an additive effect of genotype, a 5′ upstream variant (rs846910) was associated with blood pressure (diastolic blood pressure &bgr;=1.58 mm Hg per copy of the A allele, P=0.0008; systolic blood pressure &bgr;=2.28 mm Hg per copy of the A allele, P=0.004; mean arterial blood pressure &bgr;=1.83 mm Hg per copy of the A allele, P=0.0006) and hypertension (odds ratio=1.27 per copy of the A allele, P=0.02). However, birth date modified these associations (test for interaction: diastolic blood pressure P=0.16; systolic blood pressure P=0.007; mean arterial blood pressure P=0.01), such that the magnitude and direction of association between genotype and blood pressure changed with time. Finally, in models controlling for potential confounding by population stratification, we observed evidence of within-family effects for blood pressure (diastolic blood pressure &bgr;=1.77 mm Hg per copy of the A allele, P=0.004; systolic blood pressure &bgr;=2.04 mm Hg per copy of the A allele, P=0.07; mean arterial blood pressure &bgr;=1.85 mm Hg per copy of the A allele, P=0.01) and for hypertension (odds ratio=1.26 per copy of the A allele; P=0.08). No association was observed for obesity. Associations with diabetes were similar in magnitude as reported previously but were not statistically significant. These data demonstrate association between genetic variability at 11&bgr;HSD1 with hypertension, but these effects are modified by environmental factors.

Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins

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.

Exenatide Protects against Glucose and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans

GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist–mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation.

mRNA concentrations of MIF in subcutaneous abdominal adipose cells are associated with adipocyte size and insulin action

Objective:To determine whether the mRNA concentrations of inflammation response genes in isolated adipocytes and in cultured preadipocytes are related to adipocyte size and in vivo insulin action in obese individuals.Design:Cross-sectional inpatient study.Subjects:Obese Pima Indians with normal glucose tolerance.Measurements:Adipocyte diameter (by microscope technique; n=29), expression of candidate genes (by quantitative real-time PCR) in freshly isolated adipocytes (monocyte chemoattractant protein (MCP) 1 and MCP2, macrophage inflammatory protein (MIP) 1α, MIP1β and MIP2, macrophage migration inhibitory factor (MIF), tumor necrosis factor α, interleukin (IL) 6 and IL8; n=22) and cultured preadipocytes (MCP1, MIP1α, MIF, IL6 and matrix metalloproteinase 2; n=33) from subcutaneous abdominal adipose tissue (by aspiration biopsy, n=34), body fat by dual-energy X-ray absorptiometry, glucose tolerance by 75 g oral glucose tolerance test and insulin action by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU m−2 min−1) (all n=34).Results:MIF was the only gene whose expression in both freshly isolated adipocytes and cultured preadipocytes was positively associated with adipocytes diameter and negatively associated with peripheral and hepatic insulin action (all P<0.05). In multivariate analysis, the association between adipocyte MIF mRNA concentrations and adipocytes diameter was independent of the percentage of body fat (P=0.03), whereas adipocyte MIF mRNA concentrations, but not adipocyte diameter, independently predicted peripheral insulin action. The mRNA expression concentrations of the MIF gene in adipocytes were not associated with plasma concentrations of MIF, but were negatively associated with plasma adiponectin concentrations (P=0.004). In multivariate analysis, adipocyte MIF RNA concentrations (P=0.03) but not plasma adiponectin concentrations (P=0.4) remained a significant predictor of insulin action.Conclusions:Increased expression of MIF gene in adipose cells may be an important link between obesity characterized by enlarged adipocytes and insulin resistance in normal glucose tolerant people.

Dietary models of insulin resistance

Insulin resistance is a significant factor in the development of type 2 diabetes mellitus, however the connection between the Western diet and the development of insulin resistance has not been fully explained. Dietary macronutrient composition has been examined in a number of articles, and diets enriched in saturated fatty acids, and possibly in fructose, appear to be most consistently associated with the development of insulin resistance. However, mechanistic insights into the metabolic effects of such diets are lacking, and merit further study.