Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization.

Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARgamma ligands. We characterized 72 human subjects by relating their clinical phenotypes with functional pathway alterations. We transcriptionally profiled 364 biopsies harvested before and after hyperinsulinemic-euglycemic clamp studies, at baseline and after 3-month TZD treatment. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness.

Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women.

Elevation of plasma nonesterified fatty acid (NEFA) levels has been shown in various studies to induce peripheral tissue insulin resistance and impair the suppression of endogenous glucose production (EGP). These studies have been conducted predominantly in men. We compared the effects of elevated plasma NEFA levels on basal and insulin-stimulated glucose metabolism in 8 normal women (age 42 +/- 8 years [mean +/- SD], BMI 25 +/- 3 kg/m(2)) and 10 normal men (35 +/- 6 years, 24 +/- 3 kg/m(2)). Each subject underwent two 5-h 80 mU. m(-2). min(-1) hyperinsulinemic-euglycemic clamps with measurement of glucose kinetics (intravenous [3-(3)H]glucose) and substrate oxidation. Plasma NEFA levels were elevated in one study for 3 h before and during the clamp ( approximately 1 mmol/l in both groups) by infusion of 20% Intralipid (60 ml/h) and heparin (900 U/h). In the control studies, the men and women had similar insulin-stimulated glucose disposal rates (R(d)) and substrate oxidation rates. In the men, elevated NEFA levels decreased insulin-stimulated glucose R(d) during the final 40 min of the clamp by 23% (P < 0.001). By contrast, no significant change in glucose R(d) was found in the women (control 10.4 +/- 1.1, lipid study 9.9 +/- 1.3 mg. kg(-1). min(-1)). Glucose R(d) was also unchanged in six women studied at a lower insulin dose (40 mU. m(-2). min(-1)). During the last 40 min of the high-insulin dose clamps with elevated NEFA, glucose oxidation was decreased by 33% in the men (P < 0.001) and by 23% in the women (P < 0.02). Nonoxidative glucose R(d) at this time was decreased by 15% in the men (P = 0.02) but was not significantly affected in women. Basal EGP was unaffected by elevation of plasma NEFA levels in both groups. Suppression of EGP during the glucose clamps, however, was impaired. At the insulin infusion rate used, the magnitude of this defect was comparable in men and women. In summary, our findings suggest that although the effects on EGP appear comparable, the inhibitory effects of NEFA on peripheral tissue insulin sensitivity are observed in men but cannot be demonstrated in women.