Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes.

Abstract.  Kacerovsky M, Brehm A, Chmelik M, Schmid AI, Szendroedi J, Kacerovsky-Bielesz G, Nowotny P, Lettner A, Wolzt M, Jones JG, Roden M (Karl-Landsteiner Institute for Endocrinology and Metabolism, Vienna; 1st Medical Department, Hanusch Hospital, Vienna; MR Center of Excellence, Medical University of Vienna, Vienna, Austria; Institute for Clinical Diabetology, German Diabetes Center (Leibniz Center for Diabetes Research), Dusseldorf; Heinrich-Heine University Dusseldorf, Dusseldorf, Germany; Medical University of Vienna, Vienna, Austria; and University of Coimbra, Coimbra, Portugal). Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes. J Intern Med 2011; 269: 189–199. Objective.  In type 2 diabetic patients and their first-degree 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 long-standing 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 (HbA1c): 6.8 ± 0.4%] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers (HbA1c: 5.4 ± 0.2%) of comparable age, body mass and level of physical activity. Outcome measures.  Myocellular fATP, g6p and intramyocellular lipid content (IMCL) were measured with 1H/31P magnetic resonance spectroscopy during fasting and hyperinsulinaemic–euglycaemic clamp tests. 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 long-standing type 1 diabetes can exhibit insulin resistance. This associates with lower insulin-stimulated flux through muscular ATP synthase which could result from glucose toxicity.