Aims/hypothesis Mitochondrial dysfunction and increased intramyocellular lipid (IMCL) content have both been implicated in the development of insulin resistance and type 2 diabetes mellitus, but the relative contributions of these two factors in the aetiology of diabetes are unknown. As obesity is an independent determinant of IMCL content, we examined mitochondrial function and IMCL content in overweight type 2 diabetes patients and BMI-matched normoglycaemic controls. Methods In 12 overweight type 2 diabetes patients and nine controls with similar BMI (29.4±1 and 29.3±0.9 kg/m 2 respectively) in vivo mitochondrial function was determined by measuring phosphocreatine recovery halftime (PCr half-time) immediately after exercise, using phosphorus-31 magnetic resonance spectroscopy. IMCL content was determined by proton magnetic resonance spectroscopic imaging and insulin sensitivity was measured with a hyperinsulinaemic-euglycaemic clamp. Results The PCr half-time was 45% longer in diabetic patients compared with controls (27.3±3.5 vs 18.7±0.9 s, p<0.05), whereas IMCL content was similar (1.37±0.30 vs 1.25±0.22% of the water resonance), and insulin sensitivity was reduced in type 2 diabetes patients (26.0±2.2 vs 18.9± 2.3 μmol min −1 kg −1 , p<0.05 [all mean±SEM]). PCr halftime correlated positively with fasting plasma glucose (r 2 =0.42, p < 0.01) and HbA 1c (r 2 = 0.48, p <0.05) in diabetic patients. Conclusions/interpretation The finding that in vivo mitochondrial function is decreased in type 2 diabetes patients compared with controls whereas IMCL content is similar suggests that low mitochondrial function is more strongly associated with insulin resistance and type 2 diabetes than a high IMCL content per se. Whether low mitochondrial function is a cause or consequence of the disease remains to be investigated.

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Cardiac lipid accumulation is associated with decreased cardiac function and energy status (PCr/ATP). It has been suggested that elevated plasma fatty acid (FA) concentrations are responsible for the cardiac lipid accumulation. Therefore, the aim of the present study was to investigate if elevating plasma FA concentrations by exercise results in an increased cardiac lipid content, and if this influences cardiac function and energy status. Eleven male subjects (age 25.4 ± 1.1 years, BMI 23.6 ± 0.8 kg/m2) performed a 2-h cycling protocol, once while staying fasted and once while ingesting glucose, to create a state of high versus low plasma FA concentrations, respectively. Cardiac lipid content was measured by proton magnetic resonance spectroscopy (1H-MRS) at baseline, directly after exercise and again 4 h post-exercise, together with systolic function (by multi-slice cine-MRI) and cardiac energy status (by 31P-MRS). Plasma FA concentrations were increased threefold during exercise and ninefold during recovery in the fasted state compared with the glucose-fed state (p < 0.01). Cardiac lipid content was elevated at the end of the fasted test day (from 0.26 ± 0.04 to 0.44 ± 0.04%, p = 0.003), while it did not change with glucose supplementation (from 0.32 ± 0.03 to 0.26 ± 0.05%, p = 0.272). Furthermore, PCr/ATP was decreased by 32% in the high plasma FA state compared with the low FA state (n = 6, p = 0.014). However, in the high FA state, the ejection fraction 4 h post-exercise was higher compared with the low FA state (63 ± 2 vs. 59 ± 2%, p = 0.018). Elevated plasma FA concentrations, induced by exercise in the fasted state, lead to increased cardiac lipid content, but do not acutely hamper systolic function. Although the lower cardiac energy status is in line with a lipotoxic action of cardiac lipid content, a causal relationship cannot be proven.

Muscular mitochondrial aberrations in type 2 diabetes mellitus can be detected, but it is so far unclear if these aberrations are causally related to the development of the disease. Alternatively, mitochondrial dysfunction may simply be the consequence of elevated plasma fatty acids or glucose levels.

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Recently, we showed that short-term training induced a rapid increase in IMCL whilst insulin sensitivity tended to improve. Here we investigate molecular adaptations accompanying this physiological training-induced accumulation of IMCL. Nine untrained men (age: 23.3 +/- 3.2 y; maximal power output: 3.8 +/- 0.6 W/kg body weight) trained for two weeks. Before and after training, subjects cycled for three hours and biopsies were taken before and after exercise. mRNA concentrations of ACC2, HSL, LPL, Glut4 and HKII were quantified by RT-PCR and association of Glut4 with the membrane was quantified by immunohistochemical method. Endurance training resulted in a decrease of 29.1 % in ACC2 mRNA (p = 0.02). After training, ACC2 mRNA tended to decrease with acute exercise (- 24.4 % [p = 0.06]). HSL mRNA decreased with acute exercise after training (- 37.3 % [p = 0.002]). LPL mRNA concentrations increased with acute exercise before training (+ 42.4 % [p = 0.05]) and HKII mRNA increased with acute exercise before (+ 72.5 % [p = 0.025]) and after training (+ 99.3 % [p = 0.05]). After acute exercise, more Glut4 was associated with the membrane than before exercise, but it was not affected by training. We conclude that the training-induced increase in IMCL was accompanied by molecular adaptations in muscle to improve fat oxidative capacity, while markers of glucose metabolism were not yet changed. The present data are in line with the hypothesis that the fat oxidative capacity might be more important than the IMCL content in determining insulin sensitivity.