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Insulin resistance plays an important role in the pathogenesis of human type 2 diabetes. In humans, a negative correlation between insulin sensitivity and intramyocellular lipid (IMCL) content has been shown; thus, IMCL becomes a marker for insulin resistance. Recently, magnetic resonance spectroscopy (MRS) has been established as a dependable method for selective detection and quantification of IMCL in humans. To validate the interrelation between insulin sensitivity and IMCL in an animal model of type 2 diabetes, we established volume selective 1H-MRS at 7 Tesla to noninvasively assess IMCL in the rat. In male obese Zucker Diabetic Fatty rats and their lean littermates, IMCL levels were determined repeatedly over 4 months, and insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp method at 6-7 and at 22-24 weeks of age. A distinct relation between IMCL and insulin sensitivity was demonstrated as well as age dependence for both parameters. Rosiglitazone treatment caused a clear reduction of IMCL and hepatic fat despite increased body weight, and a marked improvement of insulin sensitivity. Thus, the insulin sensitizing properties of rosiglitazone were consistent with a redistribution of lipids from nonadipocytic (skeletal muscle, liver) back into fat tissue. Diabetes 52:138-144, 2003
Insulin resistance (IR) is a common feature of the metabolic syndrome and an important factor in the cause of type 2 diabetes. There is abundant evidence that increased levels of plasma lipids, predominantly free fatty acids (FFAs) and triglycerides, are causally involved in IR (1). In the 1960s, Randle et al. (2) introduced the idea that FFAs interfere with insulin action in peripheral tissues. His group suggested a substrate competition between plasma glucose and FFAs as fuel for energy production, the "glucose fatty-acid cycle." In humans, lipid infusion plus heparin, which acutely raises plasma FFA levels, inhibits insulin-stimulated glucose uptake in muscle, a finding consistent with increased peripheral IR. However, in a temporal sequence, this FFA-mediated impairment of insulin-stimulated glucose utilization developed with a delay of ~3 h after starting the lipid infusion (3,4) and was accompanied by a fall rather than a rise in the muscle glucose-6-phosphate concentration (5) as expected by the original Randle hypothesis (6,7). In animal models, an increased IR was also observed after lipid infusion or high-fat feeding (8,9), which was accompanied by a rise...