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...

Roux‐en‐Y‐Gastric‐Bypass (RYGB) reduces overall and diabetes‐specific mortality by 40% and over 90%. This study aims to gain insight into the underlying mechanisms of this effect. We evaluated time‐courses of glucose, insulin, C‐peptide, and the incretin glucagon like peptide‐1 (GLP‐1) following an oral glucose load. Insulin‐sensitivity was measured by a hyperinsulinemic‐isoglycemic‐clamp‐test; glucose‐turnover was determined using d‐[6,6‐2H2] glucose. Examinations were performed in six nondiabetic patients with excess weight before (PRE: BMI: 49.3 ± 3.2 kg/m2) and 7 months after RYGB (POST: BMI: 36.7 ± 2.9 kg/m2), in a lean (CON: BMI: 22.6 ± 0.6 kg/m2) and an obese control group (CONob) without history of gastrointestinal surgery (BMI: 34.7 ± 1.2 kg/m2). RYGB reduced fasting plasma concentrations of insulin and C‐peptide (P < 0.01, respectively) whereas fasting glucose concentrations remained unchanged. After RYGB increase of C‐peptide concentration following glucose ingestion was significantly higher compared to all other groups (dynamic‐area under the curve (Dyn‐AUC): 0–90 min: POST: 984 ± 115 ng·min/ml, PRE: 590 ± 67 ng·min/ml, CONob: 440 ± 44 ng·min/ml, CON: 279 ± 22 ng·min/ml, P < 0.01 respectively). Early postprandial increase of glucose concentration was however not affected. GLP‐1 concentrations following glucose ingestion were sixfold higher after RYBG than before (P = 0.01). Insulin‐stimulated glucose uptake tended to increase postoperatively (M‐value: PRE: 1.8 ± 0.5, POST: 3.0 ± 0.3, not significant (n.s.)). Endogenous glucose production (EGP) was unaffected by RYGB. Hepatic insulin resistance index improved after RYGB and was then comparable to both control groups (PRE: 29.2 ± 4.3, POST: 12.6 ± 1.1, P < 0.01). RYGB results in hyper‐secretion of insulin and C‐peptide, whereas improvements of insulin resistance are minor and seem to occur rather in the liver and the adipose tissue than in the skeletal muscle.

OBJECTIVESo far it is unclear whether chronic peripheral hyperinsulinemia per se might contribute to ectopic lipid accumulation and consequently insulin resistance. We investigated the effects of systemic instead of portal insulin release in type 1 diabetic patients after successful pancreas-kidney transplantation (PKT) with systemic venous drainage on the intracellular lipid content in liver and soleus muscle, endogenous glucose production (EGP), and insulin sensitivity.RESEARCH DESIGN AND METHODSIn nine PKT patients and nine matching nondiabetic control subjects, intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) were measured using 1H nuclear magnetic resonance spectroscopy. Fasting EGP was measured using d-[6,6-2H2]glucose tracer dilution. A 3-h 75-g oral glucose tolerance test (OGTT) allowed us to assess kinetics of glucose, free fatty acids, insulin, and C-peptide concentrations in plasma and to calculate the clamp-like index (CLIX) for insulin sensitivity and the hepatic insulin resistance (HIR) index.RESULTSThe PKT patients displayed approximately twofold increased fasting insulin (20 ± 6 vs. 9 ± 3 μU/ml; P < 0.0002) compared with that in nondiabetic control subjects and ∼10% increased fasting glucose (P < 0.02) concentrations, but during the OGTT areas under the concentration curves of C-peptide and insulin were similar. IHCL (PKT, 2.9 ± 2.5%; nondiabetic control subjects, 4.4 ± 6.6%), IMCL (PKT, 1.0 ± 0.4%; nondiabetic control subjects, 1.0 ± 0.5%), CLIX (PKT, 8 ± 2; nondiabetic control subjects, 7 ± 3), HIR (PKT, 25.6 ± 13.2; nondiabetic control subjects, 35.6 ± 20 [mg · min−1 · kg−1] × [μU/ml]), and EGP (PKT, 1.6 ± 0.2; nondiabetic control subjects, 1.7 ± 0.2 mg · min−1 · kg−1) were comparable between PKT patients and nondiabetic control subjects. IHCL was negatively correlated with CLIX in all participants (r = −0.55; P < 0.04).CONCLUSIONSDespite fasting peripheral hyperinsulinemia because of systemic venous drainage, type 1 diabetic patients after PKT show similar IHCL, IMCL, insulin sensitivity, and fasting EGP in comparison with nondiabetic control subjects. These results suggest that systemic hyperinsulinemia per se does not cause ectopic lipid accumulation in liver and skeletal muscle.

Weghuber D, Mandl M, Krššák M, Roden M, Nowotny P, Brehm A, Krebs M, Widhalm K, Bischof MG. Characterization of hepatic and brain metabolism in young adults with glycogen storage disease type 1: a magnetic resonance spectroscopy study. Am J Physiol Endocrinol Metab 293: E1378-E1384, 2007. First published September 4, 2007; doi:10.1152/ajpendo.00658.2006.-In glycogen storage disease type 1 (GSD1), children present with severe hypoglycemia, whereas the propensity for hypoglycemia may decrease with age in these patients. It was the aim of this study to elucidate the mechanisms for milder hypoglycemia symptoms in young adult GSD1 patients. Four patients with GSD1 [body mass index (BMI) 23.2 Ϯ 6.3 kg/m, age 21.3 Ϯ 2.9 yr] and four healthy controls matched for BMI (23.1 Ϯ 3.0 kg/m) and age (24.0 Ϯ 3.1 yr) were studied. Combined 1 H/ 31 P nuclear magnetic resonance spectroscopy (NMRS) was used to assess brain metabolism. Before and after administration of 1 mg glucagon, endogenous glucose production (EGP) was measured with D-[6,6-2 H2]glucose and hepatic glucose metabolism was examined by 1 H/ 13 C/ 31 P NMRS. At baseline, GSD1 patients exhibited significantly lower rates of EGP (0.53 Ϯ 0.04 vs. 1.74 Ϯ 0.03 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; P Ͻ 0.01) but an increased intrahepatic glycogen (502 Ϯ 89 vs. 236 Ϯ 11 mmol/l; P ϭ 0.05) and lipid content (16.3 Ϯ 1.1 vs. 1.4 Ϯ 0.4%; P Ͻ 0.001). After glucagon challenge, EGP did not change in GSD1 patients (0.53 Ϯ 0.04 vs. 0.59 Ϯ 0.24 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; P ϭ not significant) but increased in healthy controls (1.74 Ϯ 0.03 vs. 3.95 Ϯ 1.34; P Ͻ 0.0001). In GSD1 patients, we found an exaggerated increase of intrahepatic phosphomonoesters (0.23 Ϯ 0.08 vs. 0.86 Ϯ 0.19 arbitrary units; P Ͻ 0.001), whereas inorganic phosphate decreased (0.36 Ϯ 0.08 vs. Ϫ0.43 Ϯ 0.17 arbitrary units; P Ͻ 0.01). Intracerebral ratios of glucose and lactate to creatine were higher in GSD1 patients (P Ͻ 0.05 vs. control). Therefore, hepatic defects of glucose metabolism persist in young adult GSD1 patients. Upregulation of the glucose and lactate transport at the blood-brain barrier could be responsible for the amelioration of hypoglycemic symptoms. endogenous glucose production; glucose-6-phospate; intrahepatocellular lipid content; hypoglycemia GLYCOGEN STORAGE DISEASE (GSD) type 1 is an inherited defect of endogenous glucose production (EGP) occurring approximately once in every 100,000 live births (44). Two forms of GSD1 are known at present: GSD1a, caused by a defect of the glucose-6-phosphatase hydrolase, and GSD1b, caused by nonfunctioning mutations of the glucose-6-phosphatase translocase. Both known defects of GSD1 inactivate the multienzyme complex of glucose-6-phosphatase, which is necessary for the terminal step of gluconeogenesis, the conversion of glucose-6-phosphate (G6P) to glucose. Thus G6P is trapped inside the cell and cannot be released into the circulation, resulting in susceptibility to hypoglycemia during periods of fasting. Mutation search in liver biopsies is the gold standard for diagnosis of ...