Abstract
IntroductionMitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects.Methods49 non-insulin dependent male T2D patients and 54 male control subjects were enrolled, and a hyperinsulinemic-euglycemic clamp and indirect calorimetry were performed. A muscle biopsy was taken and intramyocellular lipid (IMCL) was measured. In vivo mitochondrial function was measured by PCr recovery in 30 T2D patients and 31 control subjects.ResultsFasting NEFA levels were significantly elevated in T2D patients compared with controls, but IMCL was not different. Mitochondrial function in T2D patients was compromised by 12.5% (p<0.01). Whole body glucose disposal (WGD) was higher at baseline and lower after insulin stimulation. Metabolic flexibility (ΔRER) was lower in the type 2 diabetic patients (0.050±0.033 vs. 0.093±0.050, p<0.01). Mitochondrial function was the sole predictor of basal respiratory exchange ratio (RER) (R2 = 0.18, p<0.05); whereas WGD predicted both insulin-stimulated RER (R2 = 0.29, p<0.001) and metabolic flexibility (R2 = 0.40, p<0.001).ConclusionsThese results indicate that defects in skeletal muscle in vivo mitochondrial function in type 2 diabetic patients are only reflected in basal substrate oxidation and highlight the importance of glucose disposal rate as a determinant of substrate utilization in response to insulin.
Highlights
Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative
Multiple mechanisms have recently emerged as potential contributors to insulin resistance and type 2 diabetes progression, among them metabolic inflexibility, impaired mitochondrial function and intramyocellular lipid accumulation
By definition, fasting plasma glucose levels were significantly higher in T2D patients compared with control subjects (9.462.0 vs. 5.960.8 mmol/L, p,0.01); fasting plasma insulin levels were not different between groups
Summary
Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects. Type 2 diabetes is characterized by both diminished rates of fatty acid oxidation in the fasting state and the inability to efficiently switch to glucose oxidation in the post-prandial state [1]. This phenomenon has been termed metabolic inflexibility [2,3]. Both of these processes are aberrantly affected in type 2 diabetes [5,6]
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