We determined the effects of acute and chronic calorie restriction with either a low-fat, high-carbohydrate (HC) diet or a low-carbohydrate (LC) diet on hepatic and skeletal muscle insulin sensitivity.

Twenty-two obese subjects (body mass index, 36.5 ± 0.8 kg/m²) were randomized to an HC (>180 g/day) or LC (<50 g/day) energy-deficit diet. A euglycemic-hyperinsulinemic clamp, muscle biopsy specimens, and magnetic resonance spectroscopy were used to determine insulin action, cellular insulin signaling, and intrahepatic triglyceride (IHTG) content before, after 48 hours, and after ∼11 weeks (7% weight loss) of diet therapy.

At 48 hours, IHTG content decreased more in the LC than the HC diet group (29.6% ± 4.8% vs 8.9% ± 1.4%; P < .05) but was similar in both groups after 7% weight loss (LC diet, 38.0% ± 4.5%; HC diet, 44.5% ± 13.5%). Basal glucose production rate decreased more in the LC than the HC diet group at 48 hours (23.4% ± 2.2% vs 7.2% ± 1.4%; P < .05) and after 7% weight loss (20.0% ± 2.4% vs 7.9% ± 1.2%; P < .05). Insulin-mediated glucose uptake did not change at 48 hours but increased similarly in both groups after 7% weight loss (48.4% ± 14.3%; P < .05). In both groups, insulin-stimulated phosphorylation of c-Jun-N-terminal kinase decreased by 29% ± 13% and phosphorylation of Akt and insulin receptor substrate 1 increased by 35% ± 9% and 36% ± 9%, respectively, after 7% weight loss (all P < .05).

Moderate calorie restriction causes temporal changes in liver and skeletal muscle metabolism; 48 hours of calorie restriction affects the liver (IHTG content, hepatic insulin sensitivity, and glucose production), whereas moderate weight loss affects muscle (insulin-mediated glucose uptake and insulin signaling).