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Metabolic Flexibility in Response to Glucose Is Not Impaired in People With Type 2 Diabetes After Controlling for Glucose Disposal Rate

¹ Pennington Biomedical Research Center, Baton Rouge, Louisiana
² Garvan Institute of Medical Research, New South Wales, Australia
³ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
⁴ New York Obesity Research Center, St. Luke's Roosevelt Hospital Center, New York, New York

Address correspondence and reprint requests to Eric Ravussin, PhD, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808. E-mail: eric.ravussin{at}pbrc.edu

Abbreviations: FFA, free fatty acid; FM, fat mass; FFM, fat-free mass; RQ, respiratory quotient

OBJECTIVE—Compared with nondiabetic subjects, type 2 diabetic subjects are metabolically inflexible with impaired fasting fat oxidation and impaired carbohydrate oxidation during a hyperinsulinemic clamp. We hypothesized that impaired insulin-stimulated glucose oxidation is a consequence of the lower cellular glucose uptake rate in type 2 diabetes. Therefore, we compared metabolic flexibility to glucose adjusted for glucose disposal rate in nondiabetic versus type 2 diabetic subjects and in the latter group after 1 year of lifestyle intervention (the Look AHEAD [Action For Health in Diabetes] trial).

RESEARCH DESIGN AND METHODS—Macronutrient oxidation rates under fasting and hyperinsulinemic conditions (clamp at 80 mU/m² per min), body composition (dual-energy X-ray absorptiometry), and relevant hormonal/metabolic blood variables were assessed in 59 type 2 diabetic and 42 nondiabetic individuals matched for obesity, sex, and race. Measures were repeated in diabetic participants after weight loss.

RESULTS—Metabolic flexibility to glucose (change in respiratory quotient [RQ]) was mainly related to insulin-stimulated glucose disposal rate (R² = 0.46, P < 0.0001) with an additional 3% of variance accounted for by plasma free fatty acid concentration at the end of the clamp (P = 0.03). The impaired metabolic flexibility to glucose observed in type 2 diabetic versus nondiabetic subjects (RQ 0.06 ± 0.01 vs. 0.10 ± 0.01, respectively, P < 0.0001) was no longer observed after adjusting for glucose disposal rate (P = 0.19). Additionally, the increase in metabolic flexibility to glucose after weight loss was accounted for by the concomitant increase in insulin-stimulated glucose disposal rate.

CONCLUSIONS—This study suggests that metabolic inflexibility to glucose in type 2 diabetic subjects is mostly related to defective glucose transport.

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