MUSCLE RAD EXPRESSION AND HUMAN METABOLISM - POTENTIAL ROLE OF THE NOVEL RAS-RELATED GTPASE IN ENERGY-EXPENDITURE AND BODY-COMPOSITION

Ras associated with diabetes (Rad), a new ras-related GTPase, was rece ntly identified by subtractive cloning as an mRNA in skeletal muscle t hat is overexpressed in NIDDM. To better understand its metabolic sign ificance, we measured skeletal muscle Rad expression in well-character ized insulin sensitive (IS) and insulin resistant (IR) subjects with n ormal glucose tolerance and in untreated NIDDM patients. We found no d ifferences in expression of Rad mRNA levels among IS, IR, and NIDDM gr oups using a ribonuclease protection assay (0.22 +/- 0.06, 0.13 +/- 0. 01, and 0.16 +/- 0.02 relative units, respectively; NS) and no differe nces in Rad protein expression using a specific anti-peptide Rad antib ody (1.05 +/- 0.18, 1.14 +/- 0.08, and 1.08 +/- 0.21 units/mg protein, respectively; NS). However, Rad protein levels were positively correl ated with BMI (r = 0.43, P = 0.03) and percentage body fat (r = 0.55, P < 0.005), two independent measures of obesity, and negatively correl ated with resting metabolic rate (r = 0.49, P = 0.01). In multiple reg ression analyses, percentage body fat and resting metabolic rate indep endently accounted for 30 and 10% of individual variability in muscle Rad protein expression. In conclusion, Rad expression in skeletal musc le is not altered as a function of insulin resistance or NIDDM in huma ns. However, these data, for the first time, implicate a role for Rad in regulating body composition and energy expenditure and provide a fr amework for studies designed to elucidate Rad's cellular functions.