Mitochondrial DNA copy number associates with insulin sensitivity and aerobic capacity, and differs between sedentary, overweight middle-aged males with and without type 2 diabetes.

Dumitru Constantin-Teodosiu,Luc Van Loon,Paul L Greenhaff,Lex B Verdijk,Maurice M Pelsers,Despina Constantin

doi:10.1038/s41366-019-0473-2

Abstract

Increased risk of type 2 diabetes mellitus (T2DM) is linked to impaired muscle mitochondrial function and reduced mitochondrial DNA copy number (mtDNAnum). However, studies have failed to control for habitual physical activity levels, which directly influences both mtDNA copy number and insulin sensitivity. We, therefore, examined whether physical conditioning status (maximal oxygen uptake, V̇O2max) was associated with skeletal muscle mitochondrial volume and mtDNAnum, and was predictive of T2DM in overweight, middle-aged men. Whole-body physiological (ISI-insulin sensitivity index, HOMA-IR, V̇O2max) and muscle biochemical/molecular (vastus lateralis; mtDNAnum, mitochondrial and glycolytic enzymes activity, lipid content and markers of lipid peroxidation) measurements were performed in three groups of overweight, middle-aged male volunteers (n = 10 per group): sedentary T2DM (ST2DM); sedentary control (SC) and non-sedentary control (NSC), who differed in aerobic capacity (ST2DM < SC < NSC). mtDNAnum was greater in NSC versus SC and ST2DM (P < 0.001; P < 0.001), and less in ST2DM versus SC (P < 0.01). Across all groups, mtDNAnum positively correlated with ISI (P < 0.001; r = 0.688) and V̇O2max (normalised to free fat mass; r = 0.684, P < 0.001), and negatively correlated to HOMA-IR (r = -0.544, P < 0.01). The activity of mitochondrial enzymes (GluDH, CS and β-HAD) was greater in NSC than ST2DM (P < 0.01, P < 0.001 and P < 0.05) and SC (P < 0.05, P < 0.01 and P < 0.05), but similar between ST2DM and SC. Intramuscular-free fatty acids, triglycerides and malondialdehyde contents were similar between ST2DM and SC. Body composition and indices of muscle mitochondrial volume/function were similar between SC and ST2DM. However, mtDNAnum differed and was positively associated with ISI, HOMA-IR and V̇O2max across all groups. Collectively, the findings support the contention that habitual physical activity is a key component of T2DM development, possibly by influencing mtDNAnum.

Highlights

Excess caloric intake and lack of physical activity are primary causes of increasing obesity prevalence worldwide
MtDNAnum positively correlated with insulin sensitivity (ISI) (P
Body composition and indices of muscle mitochondrial volume/function were similar between sedentary control (SC) and sedentary T2DM (ST2DM)

Summary

Introduction

Excess caloric intake and lack of physical activity are primary causes of increasing obesity prevalence worldwide. Being overweight or obese is commonly associated with elevated circulating free fatty acid concentrations and increased risk of metabolic inflexibility (defined as the inability of skeletal muscle to switch from fat to carbohydrate oxidation in response to increased circulating glucose and insulin concentrations), a central feature of insulin resistance (IR) and type 2 diabetes (T2DM). Not all obese people develop T2DM, and not all. Increased risk of T2DM development has been linked to reduced muscle mitochondrial function (defects in intrinsic mitochondrial ATP production) and reduced mitochondrial DNA copy number (mtDNAnum) have not been consistent across studies, and some would argue that declines in mitochondrial function are normalised when differences in physical activity levels (VO2), mitochondrial content and insulin action are considered 6-8. Whether reduced intrinsic mitochondrial function is causative in the induction of insulin resistance/T2DM, or contributes to increased susceptibility to T2DM, or arises as a consequence of existing insulin resistance remains an openly debated topic

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