Metabolic Flexibility in Response to Glucose is not Impaired in People with Type 2 Diabetes after Controlling for Glucose Disposal Rate

Abstract

Introduction: Type 2 diabetic compared to non-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 non-diabetic versus type 2 diabetic subjects, and in the latter group after 1-year lifestyle intervention (Look AHEAD).

Research Design and Methods: Macronutrient oxidation rates under fasting and hyperinsulinemic conditions (clamp at 80 mU/m²/min), body composition (DXA, CT) and relevant hormonal/metabolic blood variables were assessed in 59 type 2 diabetic and 42 non-diabetic 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; ΔRQ) 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 vs. non-diabetic subjects (ΔRQ: 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.

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