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Skeletal Muscle Mitochondrial Functions, Mitochondrial DNA Copy Numbers, and Gene Transcript Profiles in Type 2 Diabetic and Nondiabetic Subjects at Equal Levels of Low or High Insulin and Euglycemia

¹ Endocrinology Division, Mayo Clinic School of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota
² Research Computing Facility, Mayo Clinic School of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota

Address correspondence and reprint requests to K. Sreekumaran Nair, Endocrinology Research Unit, Mayo Clinic, 200 First St. SW, Joseph 5-194, Rochester, MN 55905. E-mail: nair.sree{at}mayo.edu

Abbreviations: COX, cytochrome c oxidase; ETC, electron transport chain; FFM, fat-free mass; GCRC, General Clinical Research Center; MAPR, mitochondrial ATP production rate; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; ND, NADH dehydrogenase; PGC-1, peroxisome proliferator–activated receptor- coactivator-1; PPIase, peptidyl-prolyl cis-trans isomerase; S6K, p70 S6 kinase

We investigated whether previously reported muscle mitochondrial dysfunction and altered gene transcript levels in type 2 diabetes might be secondary to abnormal blood glucose and insulin levels rather than an intrinsic defect of type 2 diabetes. A total of 13 type 2 diabetic and 17 nondiabetic subjects were studied on two separate occasions while maintaining similar insulin and glucose levels in both groups by 7-h infusions of somatostatin, low- or high-dose insulin (0.25 and 1.5 mU/kg of fat-free mass per min, respectively), and glucose. Muscle mitochondrial DNA abundance was not different between type 2 diabetic and nondiabetic subjects at both insulin levels, but the majority of transcripts in muscle that are involved mitochondrial functions were expressed at lower levels in type 2 diabetes at low levels of insulin. However, several gene transcripts that are specifically involved in the electron transport chain were expressed at higher levels in type 2 diabetic patients. After the low-dose insulin infusion, which achieved postabsorptive insulin levels, the muscle mitochondrial ATP production rate (MAPR) was not different between type 2 diabetic and nondiabetic subjects. However, increasing insulin to postprandial levels increased the MAPR in nondiabetic subjects but not in type 2 diabetic patients. The lack of MAPR increment in response to high-dose insulin in type 2 diabetic patients occurred in association with reduced glucose disposal and expression of peroxisome proliferator–activated receptor- coactivator 1, citrate synthase, and cytochrome c oxidase I. In conclusion, the current data supports that muscle mitochondrial dysfunction in type 2 diabetes is not an intrinsic defect, but instead a functional defect related to impaired response to insulin.

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