A Single Nucleotide Polymorphism Associates With the Response of Muscle ATP Synthesis to Long-Term Exercise Training in Relatives of Type 2 Diabetic Humans

Abstract

OBJECTIVEMyocellular ATP synthesis (fATP) associates with insulin sensitivity in first-degree relatives of subjects with type 2 diabetes. Short-term endurance training can modify their fATP and insulin sensitivity. This study examines the effects of moderate long-term exercise using endurance or resistance training in this cohort.RESEARCH DESIGN AND METHODSA randomized, parallel-group trial tested 16 glucose-tolerant nonobese relatives (8 subjects in the endurance training group and 8 subjects in the resistance training group) before and after 26 weeks of endurance or resistance training. Exercise performance was assessed from power output and oxygen uptake (Vo2) during incremental tests and from maximal torque of knee flexors (MaxTflex) and extensors (MaxText) using isokinetic dynamometry. fATP and ectopic lipids were measured with 1H/31P magnetic resonance spectroscopy.RESULTSEndurance training increased power output and Vo2 by 44 and 30%, respectively (both P < 0.001), whereas resistance training increased MaxText and MaxTflex by 23 and 40%, respectively (both P < 0.001). Across all groups, insulin sensitivity (382 ± 90 vs. 389 ± 40 mL ⋅ min−1 ⋅ m−2) and ectopic lipid contents were comparable after exercise training. However, 8 of 16 relatives had 26% greater fATP, increasing from 9.5 ± 2.3 to 11.9 ± 2.4 μmol ⋅ mL−1 ⋅ m−1 (P < 0.05). Six of eight responders were carriers of the G/G single nucleotide polymorphism rs540467 of the NDUFB6 gene (P = 0.019), which encodes a subunit of mitochondrial complex I.CONCLUSIONSModerate exercise training for 6 months does not necessarily improve insulin sensitivity but may increase ATP synthase flux. Genetic predisposition can modify the individual response of the ATP synthase flux independently of insulin sensitivity.

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).…”

Ectopic lipid storage in non-alcoholic fatty liver disease is not mediated by impaired mitochondrial oxidative capacity in skeletal muscle

“…We found no difference in PCr rate constant between those with or without the metabolic syndrome nor did we observe any relationship between the number of components and the PCr rate constant. A recent paper [30] has addressed the issue of a connection (possibly causal) between muscle energy metabolism, liver steatosis and insulin resistance by reanalysing data collected together from 6 previously-published studies [8, [31][32][33][34][35] of the research group. The total study population comprised 113 (52 male and 61 female) participants of whom 87 had normal glucose tolerance, 16 had impaired fasting glucose and/or glucose intolerance, and 10 had frank type 2 diabetes.…”

Mitochondrial Plasticity in Obesity and Diabetes Mellitus

“…This suggests that reduced P i supply, possibly due to decreased phosphate transport, accounts for the compromised mitochondrial plasticity in insulin-resistant FDR. We further studied mitochondrial plasticity in a cohort of FDR with low degree of insulin resistance employing short-and long-term exercise training (29,30). In vivo flux through ATP synthase increased with both training interventions, while insulin sensitivity improved only upon short-term exercise training.…”