Relationships Between Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes Mellitus

PLoS One. 2013;8(2):e51648. doi: 10.1371/journal.pone.0051648. Epub 2013 Feb 13.

Abstract

Introduction: 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.

Methods: 49 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.

Results: Fasting 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) (R(2) = 0.18, p<0.05); whereas WGD predicted both insulin-stimulated RER (R(2) = 0.29, p<0.001) and metabolic flexibility (R(2) = 0.40, p<0.001).

Conclusions: These 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Fatty Acids, Nonesterified / metabolism*
  • Glucose Clamp Technique
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / physiology
  • Lipid Metabolism / physiology*
  • Male
  • Middle Aged
  • Mitochondria / metabolism*
  • Muscle, Skeletal / metabolism*
  • Obesity / metabolism

Substances

  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin

Grant support

This work was supported by the Center for Translational Molecular Medicine and the Netherlands Heart Foundation, Dutch Diabetes Research Foundation and Dutch Kidney Foundation (PREDICCt); see URL:http://www.ctmm.nl/pro1/general/home.asp. Also V.S. is supported by a VENI grant (Grant 916.11.136) and P.S. is supported by a VICI grant (Grant 918.96.618)from the Netherlands Organization for Scientific Research (NWO); also see URL: http://www.nwo.nl/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.