The homeostatic model assessment (HOMA) has been used as a measure of insulin sensitivity and resistance. Insulin resistance has been associated with obesity. Higher protein diets and resistance-training have been reported to help maintain FFM and improve markers of insulin sensitivity. PURPOSE: This study examined whether sedentary women with elevated HOMA levels (> 3.5) experience greater benefits from an exercise and weight loss program. In addition, to determine whether macronutrient composition of isocaloric diets promote differential effects. METHODS: 181 sedentary women (44±12 yrs; 92±17 kg; 44±5 % fat) participated in an exercise program while maintaining a higher carbohydrate (HC, n=66) or higher protein (HP, n=115) diet. Diets consisted of 1,200 kcal/d for 1-wk and 1,600 kcal/d for 9 wks. Diets were 55% CHO, 15% P, and 30% F (HC) or 7-15% CHO, 55-63% P, and 30% F (HP). Exercise groups participated in a supervised fitness program (3-d/wk) that involved 30 min of circuit-style resistance training interspersed with callisthenic exercises. Fasting blood samples, body mass, and DEXA body composition measurements were obtained at 0 & 10 wks. Subjects were stratified into groups of less than (LH, n=163) and higher than (HH, n=55) 3.5 HOMA. Data were analyzed by MANOVA. RESULTS: HOMA levels in the LH group were significantly lower than the HM group (LH 0.6±0.8; HH 6.7±3.7, p=0.000). Diet and training significantly decreased (M±SEM) body weight (-3.6±0.4 kg, p=0.001), fat mass (-2.7±0.3 kg, p=0.001), body fat (-1.7±0.2 %, p=0.001, and glucose levels (-8.2±2.7 mg/dL, p=0.001), while not significantly affecting FFM (-0.38±0.23 kg, p=0.10), and HOMA (0.20±0.16, p=0.22). HOMA increased to a greater degree in the HP group (1.48±0.4) while glucose decreased to a greater degree in the HH group (-13.3±5 mg/dL). A significant diet × HOMA interaction (M±SD) was observed in glucose (HP/LH -0.9±15; HP/HH -27±60; HC/LH -2.3±10; HC/HH -3.1±21 mg/dL, p=0.02) with no differences observed among groups in changes in weight loss (HP/LH -4.3±3.7; HP/HH -3.9±2.2; HC/LH -2.8±3.1; HC/HH -3.1±2.2 kg, p=0.73); fat loss (HP/LH -3.3±2.7; HP/HH -3.0±2.2; HC/LH -2.1±2.1; HC/HH -2.3±1.8 kg, p=0.64); FFM (HP/LH -0.8±1.9; HP/HH -0.4±2.1; HC/LH -0.30±1.8; HC/HH 0.08±0.9 kg, p=0.98); or, HOMA (HP/LH 0.10±0.7; HP/HH 0.32±3.4; HC/LH 0.54±1.4; HC/HH -0.17±1.7, p=0.16). CONCLUSION: A HP diet during resistance training promotes more favorable changes in HOMA and individuals with higher HOMA values experience a greater reduction in fasting glucose levels. Supported by Curves International, Waco, TX