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

Objective. In type 2 diabetic patients and their firstdegree relatives, insulin resistance (IR) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate (g6p) and unidirectional flux through ATP synthase (fATP), suggesting the presence of inherited abnormal mitochondrial oxidative fitness. We hypothesized that patients with longstanding type 1 diabetes may also exhibit insulin resistance as well as lower fATP.Design. This single-centre trial was registered at ClinicalTrials.gov (NCT00481598).Subjects. We included eight nonobese type 1 diabetic patients (mean diabetes duration: 17 years) with near-target glycaemic control [haemoglobin A1c Results. Fasting fATP, g6p and IMCL did not differ between groups. During stimulation by insulin, type 1 diabetic patients exhibited $50% (P < 0.001) lower whole-body glucose disposal along with $42% (P = 0.003) lower intramyocellular g6p and $25% (P = 0.024) lower fATP. Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity (R = 0.706, P = 0.002) and negatively with HbA1c (R = )0.675, P = 0.004).Conclusions. Despite documented near-target glycaemic control for 1 year, nonobese patients with longstanding type 1 diabetes can exhibit insulin resistance. This associates with lower insulin-stimulated flux through muscular ATP synthase which could result from glucose toxicity.

OBJECTIVE -Impaired muscular mitochondrial function is related to common insulin resistance in type 2 diabetes. Mitochondrial diseases frequently lead to diabetes, which is mostly attributed to defective ␤-cell mitochondria and secretion.RESEARCH DESIGN AND METHODS -We assessed muscular mitochondrial function and lipid deposition in liver (hepatocellular lipids [HCLs]) and muscle (intramyocellular lipids [IMCLs]) using 31 P/ 1 H magnetic resonance spectroscopy and insulin sensitivity and endogenous glucose production (EGP) using hyperinsulinemic-euglycemic clamps combined with isotopic tracer dilution in one female patient suffering from MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome and in six control subjects.RESULTS -The MELAS patient showed impaired insulin sensitivity (4.3 vs. 8.6 Ϯ 0.5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and suppression of EGP (69 vs. 94 Ϯ 1%), and her baseline and insulin-stimulated ATP synthesis were reduced (7.3 and 8.9 vs. 10.6 Ϯ 1.0 and 12.8 Ϯ 1.3 mol ⅐ l Ϫ1 ⅐ min Ϫ1 ) compared with those of the control subjects. HCLs and IMCLs were comparable between the MELAS patient and control subjects.CONCLUSIONS -Impairment of muscle mitochondrial fitness promotes insulin resistance and could thereby contribute to the development of diabetes in some patients with the MELAS syndrome. Diabetes Care 32:677-679, 2009T he MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome is caused by a maternally inherited mtDNA mutation, resulting in defective cellular respiration. MELAS-associated diabetes has been primarily attributed to insufficient insulin secretion due to mitochondrial dysfunction of pancreatic ␤-cells. Insulinresistant populations show reduced mitochondrial function and increased soleus muscle lipids (intramyocellular lipids [IMCLs]) and liver lipids (hepatocellular lipids [HCLs]) (1). The sequence of events, particularly the possibility of muscle mitochondria leading to insulin resistance, is unclear.RESEARCH DESIGN AND METHODS -One female patient (age 37 years, BMI 24 kg/m 2 , A1C 7.4%) suffering from MELAS (mtDNA mutation A3243G, ϳ60% heteroplasmy in leukocytes, confirmed by PCR amplification) was compared with six nondiabetic female control subjects (age 45 Ϯ 4 years, BMI 24 Ϯ 1 kg/m 2 , A1C 5.2 Ϯ 0.1%). The protocol was approved by an institutional ethics board, and written informed consent was obtained. The patient developed bilateral labyrinthine hypacusis and insulin-dependent diabetes at 26 years of age, underwent surgery for ptosis, and showed vascular lesions in her periventricular white matter.Whole-body insulin sensitivity (insulin-mediated glucose disposal, M) and endogenous glucose production (EGP) were assessed during a normoglycemichyperinsulinemic clamp with infusion of insulin (40 mU ⅐ m body surface area Ϫ1 ⅐ min Ϫ1

Aims/hypothesis Women are at higher risk of diabetesrelated cardiovascular complications than men. We tested the hypothesis that there are sex-specific differences in glucometabolic control, and in social and psychological factors. We also examined the influence of these factors on glucometabolic control. Methods We examined 257 (126 men/131 women) consecutive patients (64±9 years, means±SD) of a metropolitan diabetes outpatient service employing clinical testing and standardised psychological questionnaires. Results Mean HbA 1c (7.6±1.2%) was not different between women and men. Women patients on oral hypoglycaemic agents were better informed about diabetes (p=0.012). They employed more strategies for coping with diabetes, including religion (p=0.0001), active coping (p=0.048) and distraction (p=0.007). Women reported lower satisfaction with social support (p=0.034), but not more depression than men. Although no differences were observed in compliance, insulin-treated patients were more satisfied with their therapy (p=0.007). Variables predicting poor metabolic control were different in men (R 2 =0.737, p=0.012) and women (R 2 =0.597, p=0.019). Major predictors of high HbA 1c included depressive coping, lower sexual desire, quality of life and internal locus of control, but high external doctor-related locus of control in women and frequent emotional experiences of hyperglycaemia in men. Conclusions/interpretation Lower quality of life, internal control and socioeconomic status, and higher prevalence of negative emotions probably prevented woman patients from achieving improved glucose control despite their better knowledge of and greater efforts to cope with diabetes. We suggest that women patients would benefit from individualised diabetes care offering social support, whereas men would benefit from knowledge-based diabetes management giving them more informational and instrumental support.