Insulin resistance plays an important role in the pathogenesis of type 2 diabetes; however, the multiple mechanisms causing insulin resistance are not yet fully understood. The aim of this study was to explore the possible contribution of intramyocellular lipid content in the pathogenesis of skeletal muscle insulin resistance. We compared insulin-resistant and insulin-sensitive subjects. To meet stringent matching criteria for other known confounders of insulin resistance, these individuals were selected from an extensively metabolically characterized group of 280 first-degree relatives of type 2 diabetic subjects. Some 13 lean insulin-resistant and 13 lean insulin-sensitive subjects were matched for sex, age, BMI, percent body fat, physical fitness, and waist-to-hip ratio. Insulin sensitivity was determined by the hyperinsulinemic-euglycemic clamp method (for insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77+/-0.28 ml x kg(-1) x min(-1) [mean +/- SE]; for insulin-sensitive subjects, MCR was 10.15+/-0.7 ml x kg(-1) x min(-1); P<0.002). Proton magnetic resonance spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in both groups. MRS studies demonstrated that in soleus muscle, IMCL was increased by 84% (11.8+/-1.6 vs. 6.4+/-0.59 arbitrary units; P = 0.008 ), and in tibialis anterior muscle, IMCL was increased by 57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary units; P = 0.017) in the insulin-resistant offspring, whereas the extramyocellular lipid content and total muscle lipid content were not statistically different between the two groups. These data demonstrate that in these well-matched groups of lean subjects, IMCL is increased in insulin-resistant offspring of type 2 diabetic subjects when compared with an insulin-sensitive group matched for age, BMI, body fat distribution, percent body fat, and degree of physical fitness. These results indicate that increased IMCL represents an early abnormality in the pathogenesis of insulin resistance and suggest that increased IMCL may contribute to the defective glucose uptake in skeletal muscle in insulin-resistant subjects.

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...

Background--Endothelial dysfunction (ED) is regarded as an early step in the development of atherosclerosis. Among the pathogenetic factors leading to atherosclerosis, the role of insulin resistance and hyperinsulinemia as independent risk factors is still under debate. In this study, we examined the association between ED and insulin resistance in normotensive and normoglycemic first-degree relatives (FDRs) of patients with type 2 diabetes mellitus (DM). Methods and Results--Endothelium-dependent and -independent vasodilation of the brachial artery was measured with high-resolution ultrasound (13 MHz) in 53 normotensive FDRs (21 men, 32 women; mean age, 35 years) with normal oral glucose tolerance, 10 age-and sex-matched normal control subjects, and 25 DM patients (mean age, 57 years). According to the tertiles of the clamp-derived glucose metabolic clearance rate (MCR), the FDRs were further classified as insulin resistant with an MCR Յ5.8 mL ⅐ kg Ϫ1 ⅐ min

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.

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