Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients

Abstract

Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type 2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes. To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using (13)C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive control subjects underwent (13)C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of (13)C label into C(4) glutamate during a [2-(13)C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by 30% in lean, insulin-resistant offspring (59.8 +/- 5.1 nmol x g(-1) x min(-1), P = 0.02) compared with insulin-sensitive control subjects (96.1 +/- 16.3 nmol x g(-1) x min(-1)). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial oxidative phosphorylation.

FIG. 1

Schematic of the TCA cycle, demonstrating incorporation of ¹³C label from plasma [2-¹³C]acetate into the muscle [4-¹³C]glutamate pool. *The carbon position labeled with ¹³C. Pyr, pyruvate; FFA, free fatty acids; AcCoA, acetyl-CoA; αKG, α-ketoglutarate. A single turn of the TCA cycle is shown; a second turn of the cycle forms [2-¹³C]glutamate and [3-¹³C]glutamate.

FIG. 2

Time course of enrichment (averaged data) of the muscle [4-¹³C]glutamate pool, measured by ¹³C MRS, during an infusion of [2-¹³C]acetate in insulin-resistant offspring of type 2 diabetic patients (◆, n = 12) and insulin-sensitive control subjects (□, n = 7). The curves of incorporation for each individual were computer modeled using CWave software to generate an estimate of TCA cycle flux using a nonlinear least-squares fitting algorithm. A CWave fit of the averaged data for each group is shown and yielded identical TCA cycle fluxes as the data for each individual.

FIG. 3

TCA cycle flux (nmol · g⁻¹ muscle · min⁻¹) calculated on an individual-by-individual basis in insulin-resistant offspring of type 2 diabetic patients (◆, n = 12) and insulin-sensitive control subjects (□, n = 7). The average rate of TCA cycle flux for each group is shown by the black bar.

FIG. 4

Schematic depicting the central role of the mitochondria and impaired lipid oxidation in causing insulin resistance in offspring of type 2 diabetic patients (IR offspring) and the elderly.