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451 STEROL REGULATORY ELEMENT BINDING PROTEIN-1 PROTEIN EXPRESSION IN MONKEY MODELS OF INSULIN RESISTANCE

Purpose Increased lipid deposition in skeletal muscle is associated with insulin resistance (IR) and type 2 diabetes (T2DM), but the mechanism is unknown. Sterol regulatory element binding proteins (SREBP) are a family of transcription factors that regulate the biosynthesis of cholesterol and fatty acids. In skeletal muscle in vitro, expression of SREBP-1 is enhanced by insulin via the MAP-kinase pathway. Despite a decrease in skeletal muscle PI3-kinase signaling with IR, the MAP-kinase pathway remains intact. Therefore, we expect SREBP-1 to be increased in skeletal muscle in IR, as a consequence of the hyperinsulinemia. Herein, we examined basal and insulin-stimulated SREBP-1 expression in skeletal muscle of normal, obese, T2DM, and calorie restricted rhesus monkeys. Methods Biopsies of the vastus lateralis muscle were taken in a basal (overnight fasted) state, and after a 2-hour euglycemic-hyperinsulinemic clamp in 24 monkeys (6 per group). The status of their insulin sensitivity has been reported earlier. Muscle samples were rapidly frozen in liquid nitrogen. Protein was isolated, and expression of total cellular and nuclear SREBP-1 protein was determined by Western blot. Results At baseline, total cellular SREBP-1 was higher in obese vs normal (p=0.004), and higher yet in T2DM animals (p≤0.0001). Unexpectedly, we also found higher levels of SREBP-1 in skeletal muscle of calorie restricted, yet normally insulin sensitive monkeys (p≤0.0001). Insulin increased total cellular SREBP-1 in normal (p=0.04) and obese (p=0.01) animals. In contrast, no insulin response was seen in calorie restricted or T2DM animals. At baseline, nuclear SREBP-1 was increased in T2DM (p≤0.05) and calorie restricted (p=0.03) monkeys, but was similar to controls in obese animals. In response to insulin, nuclear SREBP-1 increased significantly in normal (p≤0.02) and calorie restricted (p≤0.05), with no insulin response in the obese and T2DM animals. Conclusions Baseline SREBP-1 protein rises with increasing IR, likely due to chronic insulin stimulation through the MAP-kinase pathway. The latter may also explain lack of insulin response in obesity and T2DM. Thus, in the state of IR (impaired PI3-K signaling), with compensatory hyperinsulinemia, the stimulatory effect of insulin may continue unabated in skeletal muscle, resulting in ectopic deposition of lipids. Further studies are needed to determine the mechanism of SREBP-1 increases in calorie restricted animals.