title: 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 x min(-1) x m(-2)), using [(15)O]H(2)O and [(18)F]fluoro-deoxyglucose ([(18)F]FDG) to quantify tissue perfusion and glucose metabolism. Dynamic [(18)F]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 [(18)F]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 [(18)F]FDG uptake, decreased threefold in diabetic subjects and twofold in nondiabetic subjects (P < 0.001). Kinetic parameters for [(18)F]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.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Montefiore University Hospital, Pennsylvania 15213, USA. williamsk@msx.dept-med.pitt.edu
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Williams
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bertoldo
authors.forename: Paul
authors.initials: P
authors.lastname: Kinahan
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.forename: David E
authors.initials: DE
authors.lastname: Kelley
mesh_terms: D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D001835:Body Weight; D003920:Diabetes Mellitus / Q000097:blood / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000503:physiopathology; D010766:Phosphorylation; D019275:Radiopharmaceuticals; D012016:Reference Values; D014055:Tomography, Emission-Computed; D015431:Weight Loss / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D005947:Glucose