Weight Loss-Induced Plasticity of Glucose Transport and Phosphorylation in the Insulin Resistance of Obesity and Type 2 Diabetes

Abstract

We tested the hypothesis that weight loss alleviates insulin resistance in skeletal muscle within the proximal steps of glucose metabolism, namely substrate delivery, glucose transport, and glucose phosphorylation. In obese subjects with and without type 2 diabetes, in vivo skeletal muscle assessments were obtained with dynamic positron emission tomography (PET) imaging performed during euglycemic clamps at moderate hyperinsulinemia (40 mU · min⁻¹ · m⁻²), using [¹⁵O]H₂O and [¹⁸F]fluoro-deoxyglucose ([¹⁸F]FDG) to quantify tissue perfusion and glucose metabolism. Dynamic [¹⁸F]FDG PET data were analyzed using both a novel muscle-specific compartmental model and a compartmental model originally developed for the brain and often used for [¹⁸F]FDG muscle image quantification. Weight loss in obese subjects with (n = 9) and without (n = 9) type 2 diabetes over a 4-month intervention was substantial (14 ± 2 kg, P < 0.05). Muscle insulin resistance, assessed by insulin-stimulated [¹⁸F]FDG uptake, decreased threefold in diabetic subjects and twofold in nondiabetic subjects (P < 0.001). Kinetic parameters for [¹⁸F]FDG transport and phosphorylation improved substantially in both groups, whereas tissue blood flow did not change. In particular, clinically significant weight loss fully corrected insulin resistance in type 2 diabetes at the step of glucose phosphorylation and largely, but incompletely, corrected insulin resistance at the glucose transport step.