Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association With Severe Insulin Resistance
Open accessAbstract
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 with Northern European Americans that may render them more susceptible to diabetes. RESEARCH DESIGN AND METHODS— We studied 13 diabetic Indians, 13 nondiabetic Indians, and 13 nondiabetic Northern European Americans who were matched for age, BMI, 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 nondiabetic participants (P < 0.001), and they were lower in nondiabetic Indians than in nondiabetic Northern European 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, interleukin-6, and tumor necrosis factor-α concentrations were higher, whereas adiponectin concentrations were lower in diabetic Indians. CONCLUSIONS— Despite being more insulin resistant, diabetic Indians had similar muscle OXPHOS capacity as nondiabetic Indians, demonstrating that diabetes per se does not cause mitochondrial dysfunction. Indians irrespective of their diabetic status had higher OXPHOS capacity than Northern European Americans, although Indians were substantially more insulin resistant, indicating a dissociation between mitochondrial dysfunction and insulin resistance.
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An increasing body of work points to a dissociation between insulin sensitivity and mitochondrial oxidative capacity.
“However, growing evidence suggests a disassociation between insulin sensitivity and mitochondrial oxidative capacity (6–14).”
From Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training (2015) · cites this paper as [7]
Maximal mitochondrial oxidative capacity might not primarily determine insulin sensitivity in obesity or PCOS.
“The current study is consistent with emerging evidence from our laboratory and others that maximal mitochondrial oxidative capacity may not be a primary determinant of insulin sensitivity in obesity or PCOS (6,7,10,11,14,19).”
From Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training (2015) · cites this paper as [7]
Insulin resistance is closely associated with skeletal muscle mitochondrial dysfunction in some but not all conditions.
“Of interest, insulin resistance is closely associated with skeletal muscle mitochondrial dysfunction in some (3,5,13,14) but not in all conditions (15,16).”
From Age, Obesity, and Sex Effects on Insulin Sensitivity and Skeletal Muscle Mitochondrial Function (2010) · cites this paper as [16]
Insulin resistance is not always associated with reduced mitochondrial respiration, as reported in rodents on high-fat diet or in humans.
“Insulin resistance is not always associated with reduced mitochondrial respiration, as reported in rodents on a high-fat diet (HFD) (86-89) or in humans (90).”
From Altered mitochondrial function in insulin-deficient and insulin-resistant states (2018) · cites this paper as [90]
Nondiabetic Asian Indians were highly insulin resistant compared with appropriately matched northern Europeans even though their skeletal muscle demonstrated a greater capacity for oxidative phosphorylation.
“For example, a recent report showed that nondiabetic Asian Indians were highly insulin resistant when compared with appropriately matched northern Europeans, even though skeletal muscle from these subjects demonstrated a greater capacity for oxidative phosphorylation (76).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [76]
Enhanced mitochondrial function is prevalent among diabetic Asian Indians.
“and the prevalence of enhanced mitochondrial function in diabetic Asian Indians (34).”
From Physical activity is the key determinant of skeletal muscle mitochondrial function in type 2 diabetes (2012) · cites this paper as [34]
In Asian Indian subjects, there is no correlation between changes in OXPHOS gene expression and insulin resistance.
“Interestingly, a recent study of Asian Indian subjects found no correlation between changes in OXPHOS gene expression and insulin resistance (125).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [125]
In Asian Indian subjects, expression of OXPHOS and TCA cycle genes, mtDNA content, and ATP production rates were higher in both nondiabetic and diabetic individuals compared with Northern European controls, despite lower overall insulin sensitivity.
“In these individuals, expression of OXPHOS and TCA cycle genes, mtDNA content, and ATP production rates were actually higher in both nondiabetic and diabetic individuals compared with Northern European controls, despite lower overall insulin sensitivity.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [125]
Circulating triglycerides were significantly elevated in both nondiabetic and diabetic individuals of Asian Indian origin.
“However, circulating triglycerides were significantly elevated in both nondiabetic and diabetic individuals of Asian Indian origin (125).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [125]
Oxidative dysfunction is not observed in all insulin resistant individuals.
“First, oxidative dysfunction is not observed in all insulin resistant individuals (125).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [125]
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Cites
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769 · see citing works
Giancotti, F. G., & Ruoslahti, E. (1999) · Science · doi:10.1126/science.285.5430.1028 · Cited by 3,869 · see citing works
Etiology of Insulin Resistance
Petersen, K. F., & Shulman, G. I. (2006) · The American Journal of Medicine · doi:10.1016/j.amjmed.2006.01.009 · Cited by 825 · see citing works
Morino, K. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25151 · Cited by 811 · see citing works
Gene Expression Profile in Skeletal Muscle of Type 2 Diabetes and the Effect of Insulin Treatment
Sreekumar, R., Halvatsiotis, P., Schimke, J. C., & Nair, K. S. (2002) · Diabetes · doi:10.2337/diabetes.51.6.1913 · Cited by 257 · see citing works
Self-citationInsulin resistance and body fat distribution in South Asian men compared to Caucasian men
Chandalia, M., Lin, P., Seenivasan, T., Livingston, E. H., Snell, P. G., Grundy, S. M., & Abate, N. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000812 · Cited by 253 · see citing works
Asmann, Y. W., Stump, C. S., Short, K. R., Coenen-Schimke, J. M., Guo, Z., Bigelow, M. L., & Nair, K. S. (2006) · Diabetes · doi:10.2337/db05-1230 · Cited by 207 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Insulin sensitivity: Modulation by nutrients and inflammation
Schenk, S., Saberi, M., & Olefsky, J. M. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34260 · Cited by 1,191 · see citing works
The Critical Role of Metabolic Pathways in Aging
Barzilai, N., Huffman, D. M., Muzumdar, R. H., & Bartke, A. (2012) · Diabetes · doi:10.2337/db11-1300 · Cited by 803 · see citing works
Ramachandran, A., Wan Ma, R. C., & Snehalatha, C. (2010) · The Lancet · doi:10.1016/s0140-6736(09)60937-5 · Cited by 782 · see citing works
Mechanisms of insulin resistance in obesity
Ye, J. (2013) · Frontiers of Medicine · doi:10.1007/s11684-013-0262-6 · Cited by 699 · see citing works
The role of mitochondria in insulin resistance and type 2 diabetes mellitus
Szendroedi, J., Phielix, E., & Roden, M. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.138 · Cited by 600 · see citing works
Endurance Exercise as a Countermeasure for Aging
Lanza, I. R., Short, D. K., Short, K. R., Raghavakaimal, S., Basu, R., Joyner, M. J., McConnell, J. P., & Nair, K. S. (2008) · Diabetes · doi:10.2337/db08-0349 · Cited by 582 · see citing works
Self-citationThe role of mitochondria in the pathogenesis of type 2 diabetes
Patti, M.-E., & Corvera, S. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0027 · Cited by 551 · see citing works
Age, Obesity, and Sex Effects on Insulin Sensitivity and Skeletal Muscle Mitochondrial Function
Karakelides, H., Irving, B. A., Short, K. R., O'Brien, P., & Nair, K. S. (2010) · Diabetes · doi:10.2337/db09-0591 · Cited by 293 · see citing works
Self-citationRole of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes
Zorzano, A., Liesa, M., & Palacín, M. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.02.004 · Cited by 209 · see citing works
Altered mitochondrial function in insulin-deficient and insulin-resistant states
Ruegsegger, G. N., Creo, A. L., Cortes, T. M., Dasari, S., & Nair, K. S. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120843 · Cited by 202 · see citing works
Self-citationMitochondrial dysfunction and complications associated with diabetes
Blake, R., & Trounce, I. A. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.11.007 · Cited by 190 · see citing works
Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance
Holloszy, J. O. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26717c · Cited by 175 · see citing works
The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance
Pagel-Langenickel, I., Bao, J., Pang, L., & Sack, M. N. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0003 · Cited by 154 · see citing works
Holmström, M. H., Iglesias-Gutierrez, E., Zierath, J. R., & Garcia-Roves, P. M. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00159.2011 · Cited by 137 · see citing works
van Tienen, F. H. J., Praet, S. F. E., de Feyter, H. M., van den Broek, N. M., Lindsey, P. J., Schoonderwoerd, K. G. C., de Coo, I. F. M., Nicolay, K., Prompers, J. J., Smeets, H. J. M., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3454 · Cited by 111 · see citing works
Konopka, A. R., Asante, A., Lanza, I. R., Robinson, M. M., Johnson, M. L., Dalla Man, C., Cobelli, C., Amols, M. H., Irving, B. A., & Nair, K. S. (2015) · Diabetes · doi:10.2337/db14-1701 · Cited by 112 · see citing works
“Obese women (BMI 28–40 kg/m2) were diagnosed with PCOS using the Rotterdam criteria (i.e., two of three criteria: excess androgens, ovulatory dysfunction, and polycystic ovaries).”
ResultInfluentialSelf-citation“Deficiency” of Mitochondria in Muscle Does Not Cause Insulin Resistance
Holloszy, J. O. (2013) · Diabetes · doi:10.2337/db12-1107 · Cited by 111 · see citing works
Hall, L. M. L., Moran, C. N., Milne, G. R., Wilson, J., MacFarlane, N. G., Forouhi, N. G., Hariharan, N., Salt, I. P., Sattar, N., & Gill, J. M. R. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014197 · Cited by 106 · see citing works
Ramachandran, A., Snehalatha, C., Mary, S., Selvam, S., Kumar, C. K. S., Seeli, A. C., & Shetty, A. S. (2009) · Diabetologia · doi:10.1007/s00125-009-1315-x · Cited by 105 · see citing works
The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases
Yi, H.-S., Chang, J. Y., & Shong, M. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-18-0005 · Cited by 99 · see citing works
Muscle mitochondria and insulin resistance: a human perspective
Hoeks, J., & Schrauwen, P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.05.007 · Cited by 94 · see citing works
Skeletal muscle mitochondrial capacity and insulin resistance in type 2 diabetes.
Bajpeyi, S., Pasarica, M., Moro, C., Conley, K., Jubrias, S., Sereda, O., Burk, D. H., Zhang, Z., Gupta, A., Kjems, L., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1621 · Cited by 84 · see citing works
Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans
Fisher-Wellman, K. H., Weber, T. M., Cathey, B. L., Brophy, P. M., Gilliam, L. A. A., Kane, C. L., Maples, J. M., Gavin, T. P., Houmard, J. A., & Neufer, P. D. (2014) · Diabetes · doi:10.2337/db13-0940 · Cited by 82 · see citing works
Regulation of skeletal muscle mitochondrial function: genes to proteins
Lanza, I. R., & Sreekumaran Nair, K. (2010) · Acta Physiologica · doi:10.1111/j.1748-1716.2010.02124.x · Cited by 83 · see citing works
Bhopal, R. S. (2013) · Diabetic Medicine · doi:10.1111/dme.12016 · Cited by 77 · see citing works
Bakker, L. E. H., van Schinkel, L. D., Guigas, B., Streefland, T. C. M., Jonker, J. T., van Klinken, J. B., van der Zon, G. C. M., Lamb, H. J., Smit, J. W. A., Pijl, H., et al. (2014) · Diabetes · doi:10.2337/db13-0696 · Cited by 77 · see citing works
Deficiency of the Mitochondrial Electron Transport Chain in Muscle Does Not Cause Insulin Resistance
Han, D.-H., Hancock, C. R., Jung, S. R., Higashida, K., Kim, S. H., & Holloszy, J. O. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019739 · Cited by 71 · see citing works
Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction
Kraegen, E. W., Cooney, G. J., & Turner, N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803901105 · Cited by 62 · see citing works
Hansen, M., Lund, M. T., Gregers, E., Kraunsøe, R., Van Hall, G., Helge, J. W., & Dela, F. (2015) · Obesity · doi:10.1002/oby.21223 · Cited by 57 · see citing works
Frederiksen, C. M., Højlund, K., Hansen, L., Oakeley, E. J., Hemmings, B., Abdallah, B. M., Brusgaard, K., Beck-Nielsen, H., & Gaster, M. (2008) · Diabetologia · doi:10.1007/s00125-008-1122-9 · Cited by 57 · see citing works
Bhopal, R. S., & Rafnsson, S. B. (2009) · International Journal of Epidemiology · doi:10.1093/ije/dyp202 · Cited by 53 · see citing works
Are Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance?
Genders, A. J., Holloway, G. P., & Bishop, D. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186948 · Cited by 51 · see citing works
Mitochondrial Inhibitor as a New Class of Insulin Sensitizer
Zhang, Y., & Ye, J. (2012) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2012.06.010 · Cited by 47 · see citing works
Irving, B. A., Short, K. R., Nair, K. S., & Stump, C. S. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2863 · Cited by 42 · see citing works
Self-citationFranko, A., von Kleist-Retzow, J. C., Böse, M., Sanchez-Lasheras, C., Brodesser, S., Krut, O., Kunz, W. S., Wiedermann, D., Hoehn, M., Stöhr, O., et al. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0887-y · Cited by 39 · see citing works
- Authors
- Nair, K. S., Bigelow, M. L., Asmann, Y. W., Chow, L. S., Coenen-Schimke, J. M., Klaus, K. A., Guo, Z.-K., Sreekumar, R., & Irving, B. A.
- Affiliations
- Mayo Clinic (US)
- From the Division of Endocrinology, Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-05-01
- Volume
- 57
- Issue
- 5
- Pages
- 1166-1175
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC7812549
- OpenAlex
- W2142730929
- Cited by
- 187
- References
- 7
- Citations by year
- 2026: 3 · 2025: 4 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 7 · 2017: 7 · 2016: 7 · 2015: 9 · 2014: 7 · 2013: 18 · 2012: 23
- FWCI
- 15.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- Mayo Clinic
- Georgia Clinical and Translational Science Alliance
- Centers for Disease Control and Prevention
- Center for Clinical and Translational Research
- National Institute of Diabetes and Digestive and Kidney Diseases (T32-DK-07352-28, R01DK041973, T32DK007352)
- National Center for Research Resources (UL1RR024150)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- Asian Indians, type 2 diabetes, insulin resistance, skeletal muscle mitochondria, oxidative phosphorylation, mitochondrial DNA copy number, citrate synthase, intramuscular triglycerides, adiponectin, inflammatory cytokines, C-reactive protein
- MeSH terms
- Adenosine Triphosphate, Adult, Blood Glucose, Diabetes Mellitus, Female, Humans, India, Insulin Resistance, Male, Middle Aged, Mitochondria, Muscle, North America, Oxidative Phosphorylation, Reference Values, Glucose Clamp Technique, Body Mass Index, Muscle, Skeletal, White People
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