Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance

Abstract

Objective: Type 2 diabetes has become a global epidemic, and Asian Indians have a higher susceptibility to diabetes than Europeans. We investigated whether Indians had any metabolic differences compared with Northern European Americans that may render them more susceptible to diabetes.

Research design and methods: We studied 13 diabetic Indians, 13 nondiabetic Indians, and 13 nondiabetic Northern European Americans who were matched for age, BMI, and sex. The primary comparisons were insulin sensitivity by hyperinsulinemic-euglycemic clamp and skeletal muscle mitochondrial capacity for oxidative phosphorylation (OXPHOS) by measuring mitochondrial DNA copy number (mtDNA), OXPHOS gene transcripts, citrate synthase activity, and maximal mitochondrial ATP production rate (MAPR). Other factors that may cause insulin resistance were also measured.

Results: The glucose infusion rates required to maintain identical glucose levels during the similar insulin infusion rates were substantially lower in diabetic Indians than in the nondiabetic participants (P < 0.001), and they were lower in nondiabetic Indians than in nondiabetic Northern European Americans (P < 0.002). mtDNA (P < 0.02), OXPHOS gene transcripts (P < 0.01), citrate synthase, and MAPR (P < 0.03) were higher in Indians irrespective of their diabetic status. Intramuscular triglyceride, C-reactive protein, interleukin-6, and tumor necrosis factor-alpha concentrations were higher, whereas adiponectin concentrations were lower in diabetic Indians.

Conclusions: Despite being more insulin resistant, diabetic Indians had similar muscle OXPHOS capacity as nondiabetic Indians, demonstrating that diabetes per se does not cause mitochondrial dysfunction. Indians irrespective of their diabetic status had higher OXPHOS capacity than Northern European Americans, although Indians were substantially more insulin resistant, indicating a dissociation between mitochondrial dysfunction and insulin resistance.

FIG. 1.

Plasma concentrations of inflammatory factors and adiponectin. Asian Indian diabetic patients have significantly higher hsCRP, IL, and TNF-α but lower total and high molecular weight adiponectin levels. Nondiabetic Indians also have lower total and high molecular weight adiponectin levels and higher IL-6 than the Northern European Americans.

FIG. 2.

Glucose infusion rate (A) and insulin concentrations (B) during an 8-h euglycemic-hyperinsulinemic clamp in 13 each of nondiabetic European Americans, nondiabetic Asian Indians, and diabetic Asian Indians matched for sex. Data are presented as means ± SE. Mixed-effects ANCOVA models were used to test the main effect of group adjusted for age, sex, and percent fat. ANCOVA revealed a significant group × time interaction (P < 0.001) for the glucose infusion rate. Glucose area-under-the-curve values were significant different among the all three groups (P < 0.001; data not shown). ANCOVA did not reveal a significant group × time interaction (P > 0.05) for the insulin concentrations. Post hoc analyses were conducted using the Fisher’s least significant differences criterion.

FIG. 3.

Baseline MAPRs (A) and the insulin-induced changes in MAPRs (B) obtained from 13 nondiabetic Northern European Americans, 13 nondiabetic Asian Indians, and 13 diabetic Asian Indians matched for sex. ATP production rate measurements were made in the presence of six different substrate combinations: succinate plus rotenone (SR), pyruvate plus malate (PM), glutamate plus malate (GM), palmitoyl-l-carnitine plus α-ketoglutarate plus malate (PPKM), α-ketoglutarate, and palmitoyl-l-carnitine plus malate (PCM). C: Baseline mitochondrial citrate synthase activity. D and E: mtDNA copy numbers assessed using primers and probes directed to mitochondrial-encoded genes NADH dehyrogenase 1 (D) and Cytochrome B (E) normalized to 28 s. ANCOVA was used to test the main effect of group adjusted for age, sex, and percent fat. Post hoc analyses were conducted using the Fisher’s least significant differences criterion when the main effect for group was significant at P < 0.05. The data were log normalized for analysis.

FIG. 4.

Skeletal muscle gene transcript profiles measured using Affymetrix HG-U133 plus 2.0 GeneChip arrays in nondiabetic Asian Indians and Northern European Americans. A volcano plot of 1,222 differentially expressed gene transcripts is shown. The altered canonical pathways based on IPA are shown with the pathways associated with higher expression of gene transcripts in Asian Indians on the right panel and the pathways associated with lowered expressed transcripts on the left panel. The OXPHOS (shown in red, P = 0.013) and citrate cycle (blue, P = 0.015) involving mitochondrial function gene transcripts are expressed at higher levels in Asian Indians. The list of other pathways significantly different between nondiabetic Asian Indians and Northern European Americans are given in Tables 2 and 3.