OBJECTIVE -Insulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, can not only predict type 2 diabetes development but also cardiovascular disease. Thus, precise insulin resistance measurement in individuals at risk for metabolic diseases would support clinical risk stratification. However, the gold standard for measuring insulin resistance, the hyperinsulinemic clamp test, is too labor intensive to be performed in large clinical studies/settings.RESEARCH DESIGN AND METHODS -Using plasma glucose and C-peptide concentrations from oral glucose tolerance tests (OGTTs), we developed the novel "clamp-like index" (CLIX) for insulin sensitivity calculation and compared CLIX to clamp glucose infusion rates (GIR) (100 -120 min). We evaluated CLIX in 89 nondiabetic subjects (58 female and 31 male, aged 45 Ϯ 1 years, BMI 27.5 Ϯ 0.8 kg/m 2 ) who underwent frequently sampled 3-h 75-g OGTTs and 2-h hyperinsulinemic-isoglycemic clamp (40 mU/min per m 2 ) tests.RESULTS -CLIX, calculated as serum creatinine (ϫ0.85 if male)/(mean AUC glucose ϫ mean AUC C-peptide ) ϫ 6,600, was highly correlated (r ϭ 0.670, P Ͻ 10 Ϫ12 ) with and comparable to clamp GIRs 100 -120 min . In subgroup analyses, GIRs 100 -120 min were lower (P Ͻ 0.005) in type 2 diabetic offspring (6.2 Ϯ 0.7 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ) than in sex-, age-, and BMI-matched subjects without a family history of type 2 diabetes (8.6 Ϯ 0.5 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ), which was also reflected by CLIX (insulin-resistant offspring 6.4 Ϯ 0.6 vs. those without a family history of type 2 diabetes 9.0 Ϯ 0.5; P Ͻ 0.002). When compared with normal-weight subjects (GIR 8.8 Ϯ 0.4 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; CLIX 9.0 Ϯ 0.5), both GIRs 100 -120 min and CLIX of obese (5.2 Ϯ 0.9 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; 5.7 Ϯ 0.9) and morbidly obese (2.4 Ϯ 0.4 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; 3.3 Ϯ 0.5) humans were lower (each P Ͻ 0.02).CONCLUSIONS -CLIX, a novel index obtained from plasma OGTT glucose and Cpeptide levels and serum creatinine, without inclusion of anthropometrical measures to calculate insulin sensitivity in nondiabetic humans, highly correlates with clamp GIRs and reveals even slight insulin sensitivity alterations over a broad BMI range and is as sensitive as the hyperinsulinemic clamp test. Diabetes Care 30:2374-2380, 2007I nsulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, is closely associated with common metabolic and inflammatory diseases, such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, and cardiovascular disease (1-3). The degree of insulin resistance in the insulinresistant offspring of parents with type 2 diabetes, but not in humans without a family history of type 2 diabetes, serves as a predictor for later onset of the disease (4 -6). Overweight or obesity also results in a tremendous fall in insulin sensitivity, combined with a markedly increased risk for type 2 diabetes and other disturbances (such as hyperlipidemia or arterial hypertension) (1,7).Insulin sensitivity can best be measured with the labor-intensive h...

Obestatin, a recently discovered 23-amino acid peptide, is involved in the regulation of appetite and body weight in antagonistic fashion to ghrelin, both deriving from a common precursor peptide. Ghrelin was shown to be associated with insulin resistance, which may also affect obestatin. We investigated the association between insulin resistance and plasma concentrations of obestatin and ghrelin in nondiabetic individuals with high (IS; n ϭ 18, 13 females and 5 males, age 47 Ϯ 2 yr, BMI ϭ 25.5 Ϯ 0.9 kg/m 2 ) and low (IR; n ϭ 18, 12 females and 6 males, age 45 Ϯ 2 yr, P ϭ 0.49, BMI ϭ 27.5 Ϯ 1.1 kg/m 2 , P ϭ 0.17) insulin-stimulated glucose disposal (M), measured by 2-h hyperinsulinemic (40 mU ⅐ min Ϫ1 ⅐ m Ϫ2 ) isoglycemic clamp tests. M100-120 min was higher in IS (10.7 Ϯ 0.7) than in IR (4.4 Ϯ 0.2 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 , P Ͻ 10 Ϫ9 ), whereas insulin-dependent suppression of free fatty acids (FFA) in plasma was reduced in IR (71 Ϯ 6% vs. IS: 82 Ϯ 5%, P Ͻ 0.02). In both groups, plasma ghrelin concentrations were comparable at fasting and similarly reduced by 24 -28% during insulin infusion. IR had lower fasting plasma obestatin levels (383 Ϯ 26 pg/ml vs. IS: 469 Ϯ 23 pg/ml, P Ͻ 0.02). Clamp insulin infusion reduced plasma obestatin to ϳ81% of basal values in IS (P Ͻ 0.00002), but not in IR. Fasting plasma obestatin was correlated positively with M (r ϭ 0.34, P ϭ 0.04), HDL cholesterol (r ϭ 0.45, P ϭ 0.01), and plasma ghrelin concentrations (r ϭ 0.80, P Ͻ 0.000001) and negatively with measures of adiposity, plasma FFA during clamp (r ϭ Ϫ0.42, P Ͻ 0.01), and systolic blood pressure (r ϭ Ϫ0.33, P Ͻ 0.05). In conclusion, fasting plasma concentrations of obestatin, but not of ghrelin, are reduced in insulin resistance and are positively associated with whole body insulin sensitivity in nondiabetic humans. Furthermore, plasma obestatin is reduced by insulin in insulin-sensitive but not in insulinresistant persons.ghrelin; hyperinsulinemic clamp test; free fatty acids; appetite regulation OBESTATIN, A RECENTLY DISCOVERED 23-amino acid peptide hormone, is derived by posttranslational cleavage of the same peptide precursor (preproghrelin) as ghrelin, which is a 28-amino acid peptide released from the stomach (34, 38). Obestatin appears to have actions opposite to ghrelin in the regulation of food intake, emptying of the stomach, and body weight in rodents and could be part of a dual system connecting the gut and the brain to regulate energy homeostasis (38). However, other recent studies (25, 32, 36) did not provide evidence for a crucial role of obestatin in regulating food intake. Intracerebroventricular and intravenous administration of obestatin in rats did not affect food intake and could not antagonize the ghrelin-stimulated increase in food intake.The administration of ghrelin increased the food intake and body weight in rodents and humans (23,34, 35) and accelerated gastric emptying (10). In the presence of a negative energy balance, such as starvation, cachexia, or anorexia nervosa, the secretion of ghrelin increa...

Background: Bilirubin has antioxidative and cytoprotective properties. Low plasma concentrations of bilirubin are reportedly associated with the development of coronary and cerebrovascular disease, and bilirubin concentrations are strongly correlated with the enzyme activity of the hepatic uridine diphosphate glucuronosyltransferase (UGT1A1). The activity of UGT1A1 is influenced by a TA-repeat polymorphism in the promoter of the UGT1A1 gene (UDP glucuronosyltransferase 1 family, polypeptide A1). In a case-control study, we investigated the association between the UGT1A1 polymorphism, bilirubin concentration, and intermittent claudication. Methods: We included 255 consecutive male patients presenting with intermittent claudication in the investigation and matched the patients by age and diabetes mellitus with 255 control individuals. Results: Plasma bilirubin concentrations were significantly lower in patients than in controls [mean (SD), 12.5 (5.3) μmol/L vs 15.4 (7.9) μmol/L; P < 0.001]. We found a clear association between the number of TA repeats and plasma bilirubin concentration. Considering the 6/6 TA-repeat genotype as the wild type, we observed a slight increase in bilirubin concentration individuals with the heterozygous 6/7 genotype and pronounced increases for those with the homozygous 7/7 genotype. This association occurred in both controls and patients; however, patients and controls were not significantly different with respect to UGT1A1 TA-repeat genotype frequencies. Conclusions: Our study of a well-phenotyped group of patients with intermittent claudication and control individuals revealed a clear association between low bilirubin concentrations and peripheral arterial disease but no association between the UGT1A1 polymorphism and the disease.

The data obtained show middle-aged T2DM-OFF with normal glucose tolerance displaying reduced total insulin sensitivity and impaired beta cell function, which relates to impaired insulin-dependent suppression of plasma FFA and increased ICA-IMT.