In animals, the adipocyte-derived hormone adiponectin has been shown to improve insulin sensitivity, a key factor in the pathogenesis of type 2 diabetes. In Pima Indians, high plasma adiponectin levels are associated with increased insulin sensitivity and reduced risk of type 2 diabetes. It is unclear whether this is also the case in white individuals and whether an additional beneficial effect on lipid metabolism exists. We therefore analyzed in nondiabetic individuals the associations between plasma adiponectin concentrations and insulin sensitivity measured by a euglycemic-hyperinsulinemic clamp (n ؍ 262) and estimated by an oral glucose tolerance test (OGTT; n ؍ 636) and serum lipid parameters using correlational analysis. Plasma adiponectin concentrations were positively correlated with insulin sensitivity, both measured with the clamp (r ؍ 0.28, P ؍ 0.0015 in women; r ؍ 0.42, P < 0.0001 in men) and estimated from the OGTT (r ؍ 0.37, P < 0.0001 in women; r ؍ 0.41, P < 0.0001 in men) before and after adjusting for sex and percentage of body fat (all P < 0.001). Fasting triglycerides and the free fatty acid (FFA) concentrations during the OGTT (area under the curve) and at 120 min were negatively correlated in both women and men, whereas HDL was positively correlated with plasma adiponectin concentrations (all P < 0.004). Most notable, these relationships remained significant after adjusting for insulin sensitivity of glucose disposal in addition to sex and percentage of body fat (all P < 0.05). In conclusion, high adiponectin predicts increased insulin sensitivity. This relationship is independent of low body fat mass and affects not only insulin-stimulated glucose disposal but also lipoprotein metabolism and insulin-mediated suppression of postprandial FFA release. This suggests pleiotropic insulin sensitizing effects of adiponectin in humans. Diabetes 52:239 -243, 2003 A number of hormone-like peptides released from the adipocyte, so-called adipocytokines, have been identified. For some, such as leptin, tumor necrosis factor-␣, resistin, and adiponectin, a number of metabolic effects have been demonstrated, making these molecules candidate links between obesity and insulin resistance (1,2). Adiponectin, however, unlike other adipocytokines, is decreased in adiposity (3,4) and increases after weight reduction (5). In a nested case-control study in Pima Indians, high plasma adiponectin concentrations strongly predicted a lower incidence rate of type 2 diabetes independent of obesity (6). This seemed to be secondary to the association with increased insulin sensitivity in this population (3,7).Despite the strong statistical correlation between circulating adiponectin and measures of adiposity, a high interindividual variability remains. In other words, for a given degree of fatness, adiponectin concentrations can vary considerably among individuals. It remains to be shown whether this remaining (or residual) variability in adiponectin concentrations is an independent predictor of insulin sensiti...
OBJECTIVE -The oral glucose tolerance test (OGTT) is used to define the status of glucose tolerance based on the plasma glucose level at 120 min. The purpose of the present study was to identify parameters that determine the shape of the plasma glucose course measured at 0, 30, 60, 90, and 120 min during an OGTT.RESEARCH DESIGN AND METHODS -OGTT data from 551 subjects (485 with normal glucose tolerance [NGT] and 66 with impaired glucose tolerance [IGT]) were analyzed. We distinguished between "monophasic," "biphasic," and unclassified glucose shapes. A "shape" index based on the extent and the direction of the plasma glucose change in the second hour allowed us to treat shape as a continuous variable.RESULTS -In the biphasic group, the NGT-to-IGT ratio was slightly higher (173/20 vs. 209/40, P ϭ 0.08) and the male-to-female ratio was lower (60/133 vs. 120/129, P ϭ 0.0003). Subjects with a biphasic shape had significantly lower age, BMI, waist-to-hip ratio (WHR), HbA 1c , plasma glucose, and area under the insulin curve (insulin AUC ) and a better estimated insulin sensitivity and secretion (using validated indexes) than monophasic subjects (all P Ͻ 0.05). By adjusting this shape index for glucose AUC (as continuous measure of glucose tolerance), correlations with age, BMI, WHR, HbA 1c , and insulin AUC were completely abolished. The adjusted shape index was still higher in female than in male subjects but lower in IGT than in NGT subjects (both P ϭ 0.0003). Finally, we tested common polymorphisms in insulin receptor substrate (IRS)-1, IRS-2, calpain-10, hepatic lipase, and peroxisome proliferator-activated receptor-␥ for association with the shape index.CONCLUSIONS -We conclude that the plasma glucose shape during an OGTT depends on glucose tolerance and sex. In addition, genetic factors seem to play a role. The shape index may be a useful metabolic screening parameter in epidemiological and genetic association studies. Diabetes Care 26:1026 -1033, 2003T he oral glucose tolerance test (OGTT) has traditionally been used to classify the status of glucose tolerance for diagnostic purposes: normal glucose tolerance (NGT) versus impaired glucose tolerance (IGT) versus diabetes (1). More recently, however, some authors have attempted to exploit the information contained in a 2-h OGTT to estimate insulin sensitivity (2-4) and -cell function (5). While the derived indexes are less accurate than the respective gold-standard methods, they can be obtained more easily and used in large epidemiological or genetic association studies.These indexes take advantage of glucose and insulin concentrations at specific time points during the OGTT. To the best of our knowledge, with one exception, nobody has tried to answer the question of whether the shape of the glucose curve over time during the OGTT has any relevance. The one study addressing this issue that we found in the literature is a paper written in Japanese (with an abstract in English), where the authors classified the glucose curve during the OGTT as "biphasic," "domed...
Elevated serum gamma-glutamyltransferase (GGT) concentrations have been related to features of the metabolic syndrome as well as increased risk of cardiovascular and liver disease. More recently, elevated GGT levels were shown to predict development of type 2 diabetes in a longitudinal study from Korea. The aim of the present study was to test the hypothesis that serum GGT is associated with glucose tolerance, insulin sensitivity and beta-cell function in a healthy, non-diabetic Caucasian population from the Tübingen family study. Insulin sensitivity was estimated by oGTT (n = 850) or measured by hyperinsulinemic euglycemic clamp (n = 245), respectively. A subgroup (n = 70) underwent additional determination of intrahepatic lipid content using 1H magnetic resonance spectroscopy. Serum GGT was positively correlated with two-hour glucose during oGTT (r = 0.15, p < 0.0001) and negatively correlated with insulin sensitivity from oGTT (r = -0.31, p < 0.0001) and clamp (r = -0.27, p < 0.0001). The relationship between GGT and insulin sensitivity remained significant after adjusting for sex, age, BMI, and AST using multivariate regression analysis. Inclusion of serum triglyceride levels as a parameter of lipid metabolism kept the relationship significant in the oGTT group (p < 0.0001), but not in the smaller clamp group (p = 0.11). Additionally, serum GGT was positively correlated with hepatic lipid content (r = 0.49, p < 0.001) independent of sex, age, BMI, AST or serum triglycerides. There was no significant correlation between GGT and the index for beta-cell function after adjusting for age, sex, BMI and insulin sensitivity (p = 0.74). In conclusion, elevated serum GGT levels predict glucose intolerance probably via insulin resistance rather than beta-cell dysfunction. This may be primarily related to hepatic insulin resistance and increased intrahepatic lipids. The association observed between elevated hepatic lipids and reduced insulin sensitivity might explain the increased diabetes risk observed in subjects with elevated serum GGT concentrations. In the absence of overt liver disease, elevated serum GGT concentrations may point the clinician to incipient disturbances in the glucose metabolism.
OBJECTIVE -Studies on insulin sensitivity and insulin secretion in subjects with a familial predisposition for type 2 diabetes mellitus (T2DM) traditionally produce inconsistent results. This may be due to small sample size, subject selection, matching procedures, and perhaps lack of a measure of physical fitness. RESEARCH DESIGN AND METHODS -In the present study, we specifically tested the hypothesis that a family history of T2DM is associated with reduced VO 2max , measured by incremental bicycle ergometry, independent of insulin sensitivity estimated from an oral glucose tolerance test (OGTT; n ϭ 424) and measured by a euglycemic-hyperinsulinemic clamp (n ϭ 185). Subjects included in the study were young (34 Ϯ 10 years), healthy, and normal glucose tolerant with either a first-degree relative (FDR) with T2DM (n ϭ 183), a second-degree relative with T2DM (n ϭ 94), or no family history of T2DM (control subjects, n ϭ 147). BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO 2max than control subjects: 40.5 Ϯ 0.6 vs. 45.2 Ϯ 0.9 ml O 2 /kg lean body mass, P ϭ 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp).RESULTS -BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO 2max than control subjects: 40.5 Ϯ 0.6 vs. 45.2 Ϯ 0.9 ml O 2 /kg lean body mass, P ϭ 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). Insulin sensitivity per se was not affected by family history of T2DM after adjusting for age, sex, BMI, and percent body fat (P ϭ 0.76). The appropriateness of -cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter [OGTT] and sensitivity [clamp]) was significantly lower in FDRs (87 Ϯ 4 units) versus control subjects (104 Ϯ 6 units, P ϭ 0.02 after adjusting for sex, age, and BMI). Analyses of the larger OGTT group produced essentially the same results.CONCLUSIONS -In conclusion, these data are compatible with the hypothesis that familial predisposition for T2DM impairs maximal oxygen consumption in skeletal muscle. Because habitual physical activity was not different, genetic factors may be involved. Conceivably, reduced VO 2max precedes skeletal muscle insulin resistance, providing a partial explanation for discrepancies in the literature. Diabetes Care 26:2126 -2132, 2003F amilial predisposition is an important risk factor for type 2 diabetes mellitus (T2DM). Studies performed to identify the underlying mechanisms have produced conflicting results. Whereas some primarily demonstrated impaired insulin secretion in subjects with a family history of T2DM, others reported reduced insulin sensitivity as the main finding. To date, no consensus has been reached (1,2). Issues such as differences in experimental techn...
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