Effects of Moderate Weight Loss and Orlistat on Insulin Resistance, Regional Adiposity, and Fatty Acids in Type 2 Diabetes

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Abstract
OBJECTIVE—Moderate weight loss is recommended for overweight and obese patients with type 2 diabetes, and conjunctive use of weight loss medication has been advocated. The current study examined weight loss–dependent and –independent effects of the intestinal lipase inhibitor orlistat at 6 months of treatment, using behavioral intervention (Int) combined with randomized, double-blinded, placebo (P)-controlled treatment with orlistat (O). RESEARCH DESIGN AND METHODS—Metabolic control, insulin sensitivity (IS), regional fat distribution, and fat content in liver and muscle were measured in 39 volunteers with type 2 diabetes in whom all antidiabetic medication was withdrawn 1 month preceding randomization. Weight loss was equivalent in the Int+O and Int+P groups, respectively (−10.3 ± 1.3 vs. −8.9 ± 1.1%), and there were identical decreases in visceral adipose tissue (VAT), fat mass (FM), thigh adiposity, and hepatic steatosis. RESULTS—Weight loss resulted in substantial improvement (P < 0.001) in HbA1c (−1.6 ± 0.3 vs. −1.0 ± 0.4%; NS between groups). IS improved significantly more with orlistat (Δ2.2 ± 0.4 vs. Δ1.2 ± 0.4 mg · min−1 · kg−1 fat-free mass [FFM]; P < 0.05), and plasma free fatty acid (FFA) levels were strongly correlated with IS (r = 0.56; P < 0.001). Orlistat caused greater reductions in fasting plasma FFA (Δ–154 ± 22 vs. Δ–51 ± 33 μmol/l; P < 0.05), insulin-suppressed FFA (Δ–119 ± 23 vs. Δ–87 ± 34 μmol/l; P < 0.05), and fasting plasma glucose (FPG; −62 ± 9 vs. −32 ± 8 mg/dl; P = 0.02). Changes in HbA1c were correlated with ΔIS (r = −0.41; P < 0.01) but not with weight loss per se. CONCLUSIONS—At equivalent weight loss, conjunctive use of orlistat resulted in greater improvement in FFA levels and IS.