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.

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

Short-term trials with the antioxidant thioctic acid (TA) appear to improve neuropathic symptoms in diabetic patients, but the long-term response remains to be established. Therefore, Type 1 and Type 2 diabetic patients with symptomatic polyneuropathy were randomly assigned to three treatment regimens: (1) 2 x 600(mg of TA (TA 1200), (2) 600)mg of TA plus placebo (PLA) (TA 600) or (3) placebo and placebo (PLA). A trometamol salt solution of TA of 1200 or 600 mg or PLA was intravenously administered once daily for five consecutive days before enrolling the patients in the oral treatment phase. The study was prospective, PLA-controlled, randomized, double-blind and conducted for two years. Severity of diabetic neuropathy was assessed by the Neuropathy Disability Score (NDS) and electrophysiological attributes of the sural (sensory nerve conduction velocity (SNCV), sensory nerve action potential (SNAP)) and the tibial (motor nerve conduction velocity (MNCV), motor nerve distal latency (MNDL)) nerve. Statistical analysis was performed after independent reviewers excluded all patients with highly variable data allowing a final analysis of 65 patients (TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At baseline no significant differences were noted between the groups regarding the demographic variables and peripheral nerve function parameters for these 65 patients. Statistically significant changes after 24 months between TA and PLA were observed (mean +/- SD) for sural SNCV: +3.8 +/- 4.2 m/s in TA 1200, +3.0+/-3.0m/s in TA 600, -0.1+/-4.8m/s in PLA (p < 0.05 for TA 1200 and TA 600 vs. PLA); sural SNAP: +0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in TA 600, -0.7 +/- 1.5 microV in PLA (p = 0.076 for TA 1200 vs. PLA and p < 0.05 for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8 m/s in TA 1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA (p < 0.05 for TA 1200 vs. PLA). No significant differences between the groups after 24 months were noted regarding the tibial MNDL and the NDS. We conclude that in a subgroup of patients after exclusion of patients with excessive test variability throughout the trial, TA appeared to have a beneficial effect on several attributes of nerve conduction.

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