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...

The adipocyte-derived hormone adiponectin seems to protect from insulin resistance, a key factor in the pathogenesis of type 2 diabetes. Genome-wide scans have mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome to chromosome 3q27, where the adiponectin gene is located. A common silent T-G exchange in nucleotide 94 (exon 2) of the adiponectin gene has been associated with increased circulating adiponectin levels. Metabolic abnormalities associated with the G allele have not been reported. We therefore assessed whether this polymorphism alters insulin sensitivity and/or measures of obesity using the Tü bingen Family Study database (prevalence of the G allele, 28%). In 371 nondiabetic individuals, we found a significantly greater BMI in GG ؉ GT (25.5 ؎ 0.7 kg/m 2 ) compared with TT (24.1 ؎ 0.3 kg/m 2 ; P ‫؍‬ 0.02). Insulin sensitivity (determined by euglycemic clamp, n ‫؍‬ 209) was significantly lower in GG ؉ GT (0.089 ؎ 0.007 units) compared with TT (0.112 ؎ 0.005 units; P ‫؍‬ 0.02). This difference disappeared completely on adjustment for BMI. Because our population contains a relatively high proportion of first-degree relatives of patients with type 2 diabetes, we stratified by family history (FHD). Much to our surprise, the genotype differences in BMI and insulin sensitivity in the whole population were attributable entirely to differences in the subgroup without FHD, whereas in the subgroup with FHD, the G allele had absolutely no effect. Moreover, individuals without FHD had a significantly lower BMI than individuals with FHD (25.2 ؎ 0.4 vs. 26.2 ؎ 0.5 kg/m 2 ; P ‫؍‬ 0.01), which was not the case for the GG ؉ GT subgroup without FHD (27.0 ؎ 0.9 kg/m 2 ; NS). This suggests that in individuals without familial predisposition for type 2 diabetes, the adiponectin polymorphism may mildly increase the obesity risk (and secondarily insulin resistance). In contrast, in individuals who are already burdened by other genetic factors, this small effect may be very hard to detect. Diabetes 51:37-41, 2002

Animal studies have shown that the brain is an insulin-responsive organ and that central nervous insulin resistance induces obesity and disturbances in glucose metabolism. In humans, insulin effects in the brain are poorly characterized. We used a magnetoencephalography approach during a two-step hyperinsulinemic euglycemic clamp to (i) assess cerebrocortical insulin effects in humans, (ii) compare these effects between 10 lean and 15 obese subjects, and (iii) test whether the insulin receptor substrate (IRS)-1 Gly972Arg polymorphism in the insulin-signaling cascade modifies these effects. Both spontaneous and stimulated (mismatch negativity) cortical activity were assessed. In lean humans, stimulated cortical activity (P ‫؍‬ 0.046) and the beta and theta band of spontaneous cortical activity (P ‫؍‬ 0.01 and 0.04) increased with insulin infusion relative to saline. In obese humans, these effects were suppressed. Moreover, the insulin effect on spontaneous cortical activity correlated negatively with body mass index and percent body fat (all r < ؊0.4; all P < 0.05) and positively with insulin sensitivity of glucose disposal (theta band, r ‫؍‬ 0.48, P ‫؍‬ 0.017). Furthermore, insulin increased spontaneous cortical activity (beta band) in carriers of wild-type IRS-1, whereas, in carriers of the 972Arg allele, this insulin effect was absent (P ‫؍‬ 0.01). We conclude that, in lean humans, insulin modulates cerebrocortical activity, and that these effects are diminished in obese individuals. Moreover, cerebrocortical insulin resistance is found in individuals with the Gly972Arg polymorphism in IRS-1, which is considered a type 2 diabetes risk gene.glucose metabolism ͉ insulin resistance ͉ magnetoencephalography ͉ mismatch negativity ͉ type 2 diabetes T he human brain has been traditionally regarded as an insulininsensitive organ. However, there is now growing evidence that insulin signaling might be an important modulator of several functions of the brain. The insulin receptor and other components of the insulin-signaling chain, such as the insulin receptor substrate (IRS)-1 are ubiquitously expressed throughout the brain in animals and humans with particularly high concentrations in the hypothalamus, the hippocampus, and the cerebral cortex (1-3). Early work in animals suggested that insulin acts in the CNS and controls food intake and body weight (4). Furthermore, it was clearly shown that insulin crosses the blood-brain barrier (5) and, when given directly to the brain, suppresses food intake (6, 7) and mediates peripheral metabolic effects (8). Most important for the understanding of central nervous insulin function was the observation that brainspecific deletion of the insulin receptor in mice resulted in hyperphagia, obesity, and metabolic insulin resistance (9).In mice, insulin effects have been intensively studied in the hypothalamus. However, it is noteworthy that insulin receptors are also abundant in the cerebral cortex (2). Furthermore, intracerebroventricular insulin administration was associated with imp...

Aims/hypothesis Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta cell dysfunction. We investigated whether these polymorphisms are also associated with impaired proinsulin to insulin conversion. Methods We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and 120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion. Results In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p<0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p<0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p>0.6). Conclusions/interpretation Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8.

The existence of metabolically relevant intramyocellular lipids (IMCL) as assessed by the noninvasive (1)H-magnetic resonance spectroscopy (MRS) has been established. In the present studies, we analyzed the relationships between IMCL in two muscle types [the predominantly nonoxidative tibialis muscle (tib) and the predominantly oxidative soleus muscle (sol)] and anthropometric data, aerobic capacity (VO(2)max, bicycle ergometry, n = 77) and insulin sensitivity (hyperinsulinemic euglycemic clamp, n = 105) using regression analysis. In univariate regression, IMCL (tib) was weakly but significantly correlated with percentage of body fat (r = 0.28, P = 0.01), whereas IMCL (sol) was better correlated with waist-to-hip ratio (r = 0.41, P < 0.0001). No significant univariate correlation with age or maximal aerobic power was observed. After adjusting for adiposity, IMCL (tib) was positively correlated with measures of aerobic fitness. A significant interaction term between VO(2)max and percentage of body fat on IMCL (tib) (P = 0.04) existed (whole model r(2) = 0.26, P = 0.001). In contrast, aerobic fitness did not influence IMCL (sol). No correlation between insulin sensitivity as such and IMCL (tib) (r = -0.13, P = 0.2) or IMCL (sol) (r = 0.03, P = 0.72) was observed. Nethertheless, a significant interaction term between VO(2)max and IMCL on insulin sensitivity existed [P = 0.04 (tib) and P = 0.02 (sol)]; [whole model (sol) r(2) = 0.61, P < 0.0001, (tib) r(2) = 0.60, P < 0.0001]. In conclusion, obesity and aerobic fitness are important determinants of IMCL. IMCL and insulin sensitivity are negatively correlated in untrained subjects. The correlation between the two parameters is modified by the extent of aerobic fitness and cannot be found in endurance trained subjects. Thus, measurements of aerobic fitness and body fat are indispensable for the interpretation of IMCL and its relationship with insulin sensitivity.

Aims/hypothesis: The adipokine adiponectin has insulin-sensitising, anti-atherogenic and anti-inflammatory properties. Recently, the genes for mouse and human adiponectin receptor-1 (ADIPOR1) and -2 (ADIPOR2) have been cloned. The aim of this study was to investigate whether genetic variants of the genes encoding ADIPOR1 and ADIPOR2 play a role in human metabolism. Materials and methods: We screened ADIPOR1 and ADIPOR2 for polymorphisms and determined their association with glucose metabolism, lipid metabolism, an atherogenic lipid profile and inflammatory markers in 502 non-diabetic subjects. A subgroup participated in a longitudinal study; these subjects received diet counselling and increased their physical activity. Results: We identified six variants of ADIPOR1 and seven variants of ADIPOR2. A single-nucleotide polymorphism (SNP) in the putative promoter region 8503 bp upstream of the translational start codon (−8503 G/A) of ADIPOR1 (frequency of allele A=0.31) was in almost complete linkage disequilibrium with another SNP (−1927 T/C) in intron 1. Subjects carrying the −8503 A and −1927 C alleles had lower insulin sensitivity, as estimated from a 75 g OGTT (p=0.04) and determined during a euglycaemic clamp (n=295, p=0.04); they also had higher HbA 1 c levels (p=0.02) and, although the difference was not statistically significant, higher liver fat (n=85, determined by proton magnetic resonance spectroscopy, p=0.056) (all p values are adjusted for age, sex and percentage of body fat). In the longitudinal study (n=45), the −8503 A and −1927 C alleles were associated with lower insulin sensitivity (p=0.03) and higher liver fat (p=0.02) at follow-up compared with the −8503 G and −1927 T alleles, independently of basal measurements, sex and baseline and follow-up percentage of body fat. Conclusions/interpretation: The present findings suggest that the −8503 G/A SNP in the promoter or the −1927 T/C SNP in intron 1 of ADIPOR1 may affect insulin sensitivity and liver fat in humans.

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...

STAIGER, HARALD, OTTO TSCHRITTER, JÜ RGEN MACHANN, CLAUS THAMER, ANDREAS FRITSCHE, ELKE MAERKER, FRITZ SCHICK, HANS-ULRICHHÄ RING, AND MICHAEL STUMVOLL. Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obes Res. 2003;11:368 -376. Objective: We investigated whether serum concentrations of adiponectin are determined by body fat distribution and compared the findings with leptin. Research Methods and Procedures: Serum concentrations of adiponectin and leptin were measured by radioimmunoassay (n ϭ 394) and analyzed for correlation with sex, age, and body fat distribution, i.e., waist-to-hip ratio, waist and hip circumference, and subcutaneous adipose tissue area of the lower leg as assessed by magnetic resonance imaging. Results: After adjusting for sex and percentage of body fat, adiponectin was negatively (r ϭ Ϫ0.17, p Ͻ 0.001) and leptin was positively (r ϭ 0.22, p Ͻ 0.001) correlated with waist-to-hip ratio. Leptin, but not adiponectin, correlated with both waist (r ϭ 0.49, p Ͻ 0.001) and hip circumference (r ϭ 0.46, p Ͻ 0.001). Furthermore, leptin, but not adiponectin, correlated with the proportion of subcutaneous fat of the lower leg cross-sectional area (r ϭ 0.37, p Ͻ 0.001). Discussion: These data suggest that both adipocytokines are associated with central body fat distribution, and serum adiponectin concentrations are determined predominantly by the visceral fat compartment.