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Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association with Severe Insulin-Resistance

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Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association with Severe Insulin-Resistance Diabetes Publish Ahead of Print, published online March 26, 2008 Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association with Severe Insulin-Resistance K. Sreekumaran Nair, Maureen L. Bigelow, Yan W. Asmann, Lisa S. Chow, Jill M. Coenen-Schimke, Katherine A. Klaus, Zeng-Kui Guo, Raghavakaimal Sreekumar, Brian A. Irving Division of Endocrinology, Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, MN Running Title: Muscle mitochondrial function and insulin sensitivity in Indians Corresponding Author: Dr. K. Sreekumaran Nair Mayo Clinic 200 First Street SW, Joseph 5-194 Rochester, MN 55905 [email protected] Received for publication 1 November 2007 and accepted in revised form 30 January 2008. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. Copyright American Diabetes Association, Inc., 2008 Muscle mitochondrial function and insulin sensitivity in Indians ABSTRACT Objective: Type 2 diabetes has become a global epidemic; and Asian Indians have a higher susceptibility to diabetes than Europeans. We investigated whether Indians had any metabolic differences compared to Northern European (NE) Americans that may render them more susceptible to diabetes. Research Design and Methods: We studied thirteen diabetic Indians, thirteen non-diabetic Indians, and thirteen non-diabetic NE Americans who were matched for age, body mass index, and sex. The primary comparisons were insulin sensitivity by hyperinsulinemic-euglycemic clamp and skeletal muscle mitochondrial capacity for oxidative phosphorylation (OXPHOS) by measuring mitochondrial DNA copy number (mtDNA), OXPHOS gene transcripts, citrate synthase activity and maximal mitochondrial ATP production rate (MAPR). Other factors that may cause insulin-resistance were also measured. Results: The glucose infusion rates required to maintain identical glucose levels during the similar insulin infusion rates were substantially lower in diabetic Indians than in the non-diabetic participants (p<0.001); and were lower in non-diabetic Indians than in non-diabetic NE Americans (p<0.002). mtDNA (P<0.02), OXPHOS gene transcripts (P<0.01), citrate synthase and MAPR (P<0.03) were higher in Indians irrespective of their diabetic status. Intramuscular triglyceride, C-reactive protein, IL-6 and TNF-α concentrations were higher, whereas, adiponectin concentrations were lower in diabetic Indians. Conclusion: Despite being more insulin-resistant diabetic Indians had similar muscle OXPHOS capacity as non-diabetic Indians, demonstrating that diabetes per se does not cause mitochondrial dysfunction. Indians irrespective of their diabetic status had higher OXPHOS capacity than NE Americans, although Indians were substantially more insulin-resistant, indicating a dissociation between mitochondrial dysfunction and insulin-resistance. 2 Muscle mitochondrial function and insulin sensitivity in Indians here is a global epidemic of type 2 Europeans. The emigration to Europe diabetes (1); and while mortality from occurred approximately 40,000 years ago T other leading causes of death, when the European continent had sparse including coronary artery disease, stroke and vegetation for many months due to long cancer is declining, deaths attributed to type 2 winters (8,9), and the diet therefore consisted diabetes are escalating (2). It is estimated that predominantly of energy dense meat products. Asian Indians have the highest world-wide It has also been proposed that obesity (and prevalence of diabetes (~32 million), and it is type 2 diabetes) stemmed from a natural conservatively predicted that the number of selection of our ancestors favoring a “thrifty affected individuals will double in the next 30 genotype” that enabled highly efficient years (3). Population growth, urbanization, storage of energy during periods of food aging, obesity and physical inactivity are well abundance (10). Similarly, a relationship recognized contributing factors for the between low birth weight and type 2 diabetes increase in type 2 diabetes (3). In addition, has been observed, epigenetically suggesting Indians show several unique features, that type 2 diabetes may be attributed to a including a younger age of onset of type 2 “thrifty phenotype” (11). A corollary of the diabetes, relatively lower body mass index above two hypotheses is that prolonged (BMI) compared to Northern European (NE) periods of low energy availability induced descendants at the onset of type 2 diabetes adaptive changes in genes and/or phenotypes and lower thresholds for the other risk factors that may become disadvantageous when food associated with type 2 diabetes (4,5). is plentiful and energy expenditure is Recently an increased prevalence of non- minimized. Since the mitochondria is the alcoholic fatty liver disease in association primary organelle involved in fuel with insulin-resistance has also been reported metabolism, we sought to determine whether among Indians (6). Body fat distribution that differences in mitochondrial function may causes insulin-resistance is also reported to be occur in the Indian population with high different among South Asian Indians (7) and susceptibility to develop diabetes. they show a higher body fat percentage for a A hallmark metabolic defect of type 2 given BMI in comparison to Caucasians. The diabetes is insulin-resistance, especially in underlying cause of the unusual susceptibility skeletal muscle which is the predominant of Indians to type 2 diabetes remains to be organ involved in glucose disposal following determined. a meal (12). Recent studies (13-17) have We investigated whether Indians have shown an association between insulin- underlying differences in energy metabolism resistance and mitochondrial dysfunction. that may render them to be more insulin- We therefore, sought to determine whether resistant and contribute to their greater diabetic and non-diabetic Indians were more susceptibility to type 2 diabetes. There were insulin-resistant than non-diabetic NE several reasons to consider the involvement of Americans who are reported to have a lesser energy metabolism and mitochondrial susceptibility to type 2 diabetes than Indians function in potentially contributing to insulin- (3). In addition, we determined whether the resistance and type 2 diabetes. First, Indians theory that insulin-resistance may result from lived for centuries as an agrarian society with mitochondrial dysfunction is supported by a predominantly vegetarian diet, which studies in Indians and NE Americans. provided lower energy density in comparison to the predominantly meat diet of Northern 3 Muscle mitochondrial function and insulin sensitivity in Indians RESEARCH DESIGN AND METHODS FFM with CHO:Fat:Protein 55:30:15) at 6 Subjects. Thirteen diabetic Indians, thirteen PM followed by insertion of a retrograde hand non-diabetic Indians, and thirteen non- vein catheter for blood collections. A second diabetic NE Americans who were matched for catheter in the contralateral arm was used for sex (8 male and 5 female per group), age and infusion of insulin. Plasma glucose levels BMI (Table 1) were recruited. Type 2 were maintained in type 2 diabetic diabetic participants were selected based on a participants between 5.0-6.7 mmol/L (90-120 known diagnosis and matched to non-diabetic mg/dl) using a standardized insulin infusion control participants who had no first-degree protocol starting at 6 PM. At bedtime, a relatives with type 2 diabetes and a fasting snack (5.5 kcal/kg FFM) was provided to all plasma glucose concentration below 100 subjects to avoid long-term fasting. At 7 AM, mg/dl. Participants were excluded following in both diabetic and non-diabetic participants, history and physical examination if there was we collected a baseline blood sample and then evidence of clinically important co-existing started an infusion of insulin at a rate of 1.5 illnesses or conditions that could have an mU/kgFFM/min, plasma glucose was effect on the outcome measures. Participants monitored every 10 min and a variable 40% with serum creatinine concentrations greater dextrose infusion was adjusted to maintain than 1.5 mg/dl, taking medications that may glucose between 4.7-5.0 mmol/L (85-90 have an impact on energy metabolism, liver mg/dl) as previously described (13,18). Two function abnormalities or active coronary vastus lateralis muscle percutaneous needle artery disease were excluded. All attempts biopsies were performed in two different legs were made to match participants for their under local anesthesia as previously described activity levels. Except for one non-diabetic (19) before and 8 h through the glucose Indian and one non-diabetic NE American clamp. Arterialized (20) blood samples were who were matched for their exercise collected every two hours for measurements programs, no other participants were involved of hormones and substrates. in any regular exercise programs. Participants on thiazolidinediones (two of ANALYSIS thirteen diabetic Indians) were required to Muscle Mitochondrial Studies. Fresh muscle stop these medications for 3 weeks prior to needle biopsy samples (≈50-mg) (see above) the study. Of the other eleven, one was on were kept on ice in a saline-soaked gauze for metformin alone, two were on sulfonylurea immediate measurement of maximal alone, six were on combination of mitochondrial ATP production rates (MAPR). sulfonylurea and metformin and two Mitochondrial separation procedures and participants were
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