Short-Term Exercise Training Does Not Stimulate Skeletal Muscle ATP Synthesis in Relatives of Humans With Type 2 Diabetes

Abstract

OBJECTIVE-We tested the hypothesis that short-term exercise training improves hereditary insulin resistance by stimulating ATP synthesis and investigated associations with gene polymorphisms. RESEARCH DESIGN AND METHODS-We studied 24 nonobese first-degree relatives of type 2 diabetic patients and 12 control subjects at rest and 48 h after three bouts of exercise. In addition to measurements of oxygen uptake and insulin sensitivity (oral glucose tolerance test), ectopic lipids and mitochondrial ATP synthesis were assessed using 1 H and 31 P magnetic resonance spectroscopy, respectively. They were genotyped for polymorphisms in genes regulating mitochondrial function, PPARGC1A (rs8192678) and NDUFB6 (rs540467).RESULTS-Relatives had slightly lower (P ϭ 0.012) insulin sensitivity than control subjects. In control subjects, ATP synthase flux rose by 18% (P ϭ 0.0001), being 23% higher (P ϭ 0.002) than that in relatives after exercise training. Relatives responding to exercise training with increased ATP synthesis (ϩ19%, P ϭ 0.009) showed improved insulin sensitivity (P ϭ 0.009) compared with those whose insulin sensitivity did not improve. A polymorphism in the NDUFB6 gene from respiratory chain complex I related to ATP synthesis (P ϭ 0.02) and insulin sensitivity response to exercise training (P ϭ 0.05). ATP synthase flux correlated with O 2 uptake and insulin sensitivity.CONCLUSIONS-The ability of short-term exercise to stimulate ATP production distinguished individuals with improved insulin sensitivity from those whose insulin sensitivity did not improve. In addition, the NDUFB6 gene polymorphism appeared to modulate this adaptation. This finding suggests that genes involved in mitochondrial function contribute to the response of ATP synthesis to exercise training. Diabetes 58:1333-1341, 2009

Comparison of measuring energy metabolism by different 31P‐magnetic resonance spectroscopy techniques in resting, ischemic, and exercising muscle

“…Furthermore, fATP has been repeatedly shown to be responsive to insulin stimulation, a condition known to increase energy expenditure. The insulin-induced increase in fATP is pronounced in insulin sensitive, but poor or absent insulin resistant states (5,30), again paralleling the response in energy expenditure. This again argues for fATP measurements as markers of oxidative activity.…”

Mitochondrial Plasticity in Obesity and Diabetes Mellitus

“…Of note, ex vivo mitochondrial respiration negatively correlates with fasting plasma glucose levels and near-normalization of glycemia by insulin improved respiration in T2DM patients with severe hyperglycemia ( > 15 mmol/l) (61). Recently, we showed that even near-normoglycemic patients with longstanding T1DM show substantial insulin resistance with impaired insulinstimulated myocellular G6P concentrations, as well as compromised mitochondrial plasticity (28) (Fig. 5A and 5B).…”

“…In Non-DM, stimulation by insulin markedly increases myocellular concentrations of substrates for oxidation such as glucose-6-phosphate (G6P) and thereby rates of ATP synthesis (mitochondrial plasticity). In T1DM, both G6P and ATP synthesis do not adequately rise during insulin stimulation (28) . FIG.…”

Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes

“…Finally, a variant in the NDUFB6 gene, encoding a subunit of complex I of the respiratory chain, associates with increased type 2 diabetes risk, relates to insulin resistance (48), and predicts the response of muscle energy metabolism to exercise training (16,17). However, no difference in hepatic phosphorous metabolites and HCL between carriers of the A allele in NDUFB6 polymorphism rs540467 and noncarriers was found (Table 3).…”

“…Genetic variants in regulators of oxidative phosphorylation like peroxisome proliferator-activated receptor-g and Δ (genes PPARG and PPARD), PPARG coactivator-1a (gene PPARGC1A), respiratory chain complex 1 (gene NDUFB6), and fat mass-and obesityassociated gene (gene FTO) also modulate glucose and lipid metabolism (14)(15)(16)(17)(18). Several cytokines, such as adiponectin, fetuin A, and fibroblast growth factor 21 (FGF21), can be altered in insulin-resistant states, but also in human (19)(20)(21) and rodent type 1 diabetes (11).…”