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Objective: Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2 diabetes., Research Design and Methods: Eighteen male type 2 diabetic and 20 healthy male control subjects of comparable body weight, BMI, age, and VO2max participated in a 12-week combined progressive training program (three times per week and 45 min per session). In vivo mitochondrial function (assessed via magnetic resonance spectroscopy), insulin sensitivity (clamp), metabolic flexibility (indirect calorimetry), and IMCL content (histochemically) were measured before and after training., Results: Mitochondrial function was lower in type 2 diabetic compared with control subjects (P = 0.03), improved by training in control subjects (28% increase; P = 0.02), and restored to control values in type 2 diabetic subjects (48% increase; P < 0.01). Insulin sensitivity tended to improve in control subjects (delta Rd 8% increase; P = 0.08) and improved significantly in type 2 diabetic subjects (delta Rd 63% increase; P < 0.01). Suppression of insulin-stimulated endogenous glucose production improved in both groups (-64%; P < 0.01 in control subjects and -52% in diabetic subjects; P < 0.01). After training, metabolic flexibility in type 2 diabetic subjects was restored (delta respiratory exchange ratio 63% increase; P = 0.01) but was unchanged in control subjects (delta respiratory exchange ratio 7% increase; P = 0.22). Starting with comparable pretraining IMCL levels, training tended to increase IMCL content in type 2 diabetic subjects (27% increase; P = 0.10), especially in type 2 muscle fibers., Conclusions: Exercise training restored in vivo mitochondrial function in type 2 diabetic subjects. Insulin-mediated glucose disposal and metabolic flexibility improved in type 2 diabetic subjects in the face of near-significantly increased IMCL content. This indicates that increased capacity to store IMCL and restoration of improved mitochondrial function contribute to improved muscle insulin sensitivity.

Objective: The physiologic role of circulating endogenous testosterone and estrogen concentrations in relation to lean body mass (LBM) and muscle strength is not as well documented in postmenopausal women as in elderly men., Design: Three hundred and twenty-nine healthy postmenopausal women were randomly selected from a general practice population-based sample aged between 55 and 85 years., Methods: Total testosterone and estrogen (TT and TE) and sex hormone-binding globulin (SHBG) were determined and estimates of bioavailable testosterone (free androgen index (TT/SHBG, FAI), calculated free testosterone (cFT), and estrogen (TE/SHBG, ESR) were calculated. Examinations included bone mineral density (BMD) of the spine and femoral neck (FN), LBM, maximum quadriceps extension strength (MES) and maximum handgrip strength (MGS), timed up-and-go test (TUGT), osteocalcin (OC), and urinary deoxy-pyridinoline/creatinine (DPyr). Correlations were assessed using Pearson's correlation coefficient (r)., Results: With advancing age, LBM, MES, MGS, BMD, and ESR significantly declined (range r: -0.356 to -0.141) and TUGT, and DPyr significantly increased (range r: 0.135 to 0.282 (P<0.05)). After age-adjustment, LBM, MES, and BMD in spine and FN were significantly related to bioavailable testosterone (range r: 0.146 to 0.193, for cFT, and 0.157 to 0.224, for FAI) and to ESR (range r: 0.162 to 0.273). OC and DPyr were significantly inversely related to ESR (r: -0.154 and -0.144 respectively)., Conclusions: Age-related loss of LBM, MES and BMD in postmenopausal women is partly dependent on the presence of endogenous bioavailable testosterone and estrogen.

Objective: A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type 2 diabetic patients. The nature of this reduction is unknown. Here, we tested the hypothesis that a lower intrinsic mitochondrial respiratory capacity may underlie lower in vivo mitochondrial function observed in diabetic patients., Research Design and Methods: Ten overweight diabetic patients, 12 first-degree relatives, and 16 control subjects, all men, matched for age and BMI, participated in this study. Insulin sensitivity was measured with a hyperinsulinemic-euglycemic clamp. Ex vivo intrinsic mitochondrial respiratory capacity was determined in permeabilized skinned muscle fibers using high-resolution respirometry and normalized for mitochondrial content. In vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time after exercise using (31)P-magnetic resonance spectroscopy., Results: Insulin-stimulated glucose disposal was lower in diabetic patients compared with control subjects (11.2 +/- 2.8 vs. 28.9 +/- 3.7 micromol x kg(-1) fat-free mass x min(-1), respectively; P = 0.003), with intermediate values for first-degree relatives (22.1 +/- 3.4 micromol x kg(-1) fat-free mass x min(-1)). In vivo mitochondrial function was 25% lower in diabetic patients (P = 0.034) and 23% lower in first-degree relatives, but the latter did not reach statistical significance (P = 0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in diabetic patients (P = 0.031), and fluoro-carbonyl cyanide phenylhydrazone-driven maximal mitochondrial respiratory capacity was 31% lower in diabetic patients (P = 0.05) compared with control subjects with intermediate values for first-degree relatives., Conclusions: A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity.

Aims: Our objective was to investigate whether improved in vivo mitochondrial function in skeletal muscle and intramyocellular lipids (IMCLs) contribute to the insulin-sensitizing effect of rosiglitazone., Methods: Eight overweight type 2 diabetic patients (body mass index = 29.3 +/- 1.1 kg/m(2)) were treated with rosiglitazone for 8 wk. Before and after treatment, insulin sensitivity was determined by a hyperinsulinemic euglycemic clamp. Muscular mitochondrial function (half-time of phosphocreatine recovery after exercise) and IMCL content were measured by magnetic resonance spectroscopy., Results: Insulin sensitivity improved after rosiglitazone (glucose infusion rate: 19.9 +/- 2.8 to 24.8 +/- 2.1 micromol/kg.min; P < 0.05). In vivo mitochondrial function (phosphocreatine recovery half-time: 23.8 +/- 3.5 to 20.0 +/- 1.7 sec; P = 0.23) and IMCL content (0.93 +/- 0.18% to 1.37 +/- 0.40%; P = 0.34) did not change. Interestingly, the changes in PCr half-time correlated/tended to correlate with changes in fasting insulin (R(2) = 0.50; P = 0.05) and glucose (R(2) = 0.43; P = 0.08) levels. Changes in PCr half-time did not correlate with changes in glucose infusion rate (R(2) = 0.08; P = 0.49)., Conclusion: The rosiglitazone-enhanced insulin sensitivity does not require improved muscular mitochondrial function.

Despite life-long galactose restriction, long-term complications generally occur in classical galactosemia. We report an adult male with classical galactosemia (Q188R homozygosity, severely reduced erythrocyte galactose-1-phosphate uridyltransferase activity) who has a surprisingly mild phenotype despite genotype and enzyme activity associated with severe phenotype. Moreover he has a normal galactose intake from the age of 3 years. This case is probably an example of the important role of yet unknown susceptibility and or modifier genes.

Context: The mitochondrial uncoupling protein-3 (UCP3) has been implicated in the protection of the mitochondrial matrix against lipid-induced mitochondrial damage. Recent evidence points toward mitochondrial aberrations as a major contributor to the development of insulin resistance and diabetes, and UCP3 is reduced in diabetes., Objective: We compared skeletal muscle UCP3 protein levels in prediabetic subjects [i.e. impaired glucose tolerance (IGT)], diabetic patients, and healthy controls and examined whether rosiglitazone treatment was able to restore UCP3. PATIENTS, DESIGN, INTERVENTION: Ten middle-aged obese men with type 2 diabetes mellitus [age, 61.4 +/- 3.1 yr; body mass index (BMI), 29.8 +/- 2.9 kg/m(2)], nine IGT subjects (age, 59.0 +/- 6.6 yr; BMI, 29.7 +/- 3.0 kg/m(2)), and 10 age- and BMI-matched healthy controls (age, 57.3 +/- 7.4 yr; BMI, 30.1 +/- 3.9 kg/m(2)) participated in this study. After baseline comparisons, diabetic patients received rosiglitazone (2 x 4 mg/d) for 8 wk., Main Outcome Measures: Muscle biopsies were sampled to determine UCP3 and mitochondrial protein (complex I-V) content., Results: UCP3 protein content was significantly lower in prediabetic IGT subjects and in diabetic patients compared with healthy controls (39.0 +/- 28.5, 47.2 +/- 24.7, and 72.0 +/- 23.7 arbitrary units, respectively; P < 0.05), whereas the levels of the mitochondrial protein complex I-V were similar between groups. Rosiglitazone treatment for 8 wk significantly increased insulin sensitivity and muscle UCP3 content (from 53.2 +/- 29.9 to 66.3 +/- 30.9 arbitrary units; P < 0.05)., Conclusion: We show that UCP3 protein content is reduced in prediabetic subjects and type 2 diabetic patients. Eight weeks of rosiglitazone treatment restores skeletal muscle UCP3 protein in diabetic patients.