Correspondence
Impaired Mitochondrial Activity and Insulin-Resistant Offspring of Patients with Type 2 Diabetes
N Engl J Med 2004; 350:2419-2421June 3, 2004
- Article
To the Editor:
Petersen et al. (Feb. 12 issue)1 provide further evidence that insulin resistance is associated with a reduction in mitochondrial function in muscle2 and an increase in lipid content.3 They propose that mitochondrial dysfunction causes lipid accumulation and insulin resistance, but the relation among these variables is probably more complex. For example, insulin can increase mitochondrial transcript levels, protein synthesis, and ATP production in healthy people but not in people with type 2 diabetes.4,5 Thus, one could argue that insulin signaling is required for maintenance of muscle mitochondria and that insulin resistance results in mitochondrial dysfunction, rather than the reverse.
Furthermore, there is growing evidence that links among mitochondria, lipids, and insulin resistance are indirect. First, increasing mitochondrial capacity by aerobic exercise is not sufficient to improve insulin sensitivity6; second, endurance-trained athletes have elevated muscle lipids (and mitochondria) yet excellent insulin sensitivity3; and third, in mice, an increase in muscle lipids is not sufficient to lower insulin-stimulated glucose uptake. Thus, although many interesting associations have been revealed, there remains much to learn about the causes and effects of insulin resistance.
6 ReferencesKevin R. Short, Ph.D.
K. Sreekumaran Nair, M.D., Ph.D.
Mayo Clinic School of Medicine, Rochester, MN 55905
short.kevin@mayo. edu Craig S. Stump, M.D., Ph.D.
University of Missouri–Columbia, Columbia, MO 652111
Petersen KF ,Dufour S ,Befroy D ,Garcia R ,Shulman GI . Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004;350:664-671
Full Text | Web of Science | Medline2
Kelley DE ,He J ,Menshikova EV ,Ritov VB . Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002;51:2944-2950
CrossRef | Web of Science | Medline3
Goodpaster BH ,He J ,Watkins S ,Kelley DE . Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 2001;86:5755-5761
CrossRef | Web of Science | Medline4
Stump CS ,Short KR ,Bigelow ML ,Schimke JM ,Nair KS . Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci U S A 2003;100:7996-8001
CrossRef | Web of Science | Medline5
Halvatsiotis P ,Short KP ,Bigelow M ,Nair KS . Synthesis rates of muscle proteins, muscle functions, and amino acid kinetics in type 2 diabetes. Diabetes 2002;51:2395-2404
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Short KR ,Vittone JL ,Bigelow ML , et al. Impact of aerobic training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 2003;52:1888-1896
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To the Editor:
Petersen et al. demonstrate that offspring of persons with type 2 diabetes have impaired mitochondrial activity. In the light of the possibility that decreased AMP kinase activity, brought about by decreased adiponectin signaling, is a likely explanation for these findings, it is surprising that in this study plasma adiponectin concentrations did not differ between offspring and controls. We and our colleagues1 and others2 have shown that plasma adiponectin levels in insulin-resistant offspring of persons with type 2 diabetes are lower than those in control subjects. Furthermore, the expression of both isoforms of the adiponectin receptor (AdipoR1 and AdipoR2) is decreased in the skeletal muscle of these offspring.1 We proposed that an impairment in the expression of the adiponectin receptors in combination with reduced concentrations of plasma adiponectin may reduce AMP kinase activation by adiponectin,3 thereby reducing fat oxidation within the skeletal muscle of these offspring. Although Petersen et al. studied persons who were leaner than those we examined (a factor that may have had some effect on their adiponectin concentrations), it is important to know whether these offspring had reduced expression of adiponectin receptors.
3 ReferencesMandeep Bajaj, M.D.
Lawrence J. Mandarino, Ph.D.
University of Texas Health Science Center, San Antonio, TX 78229
mandeepbajaj@hotmail.com 1
Civitarese AE, Jenkinson CP, Richardson D, et al. Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes. Diabetologia (in press).
2
Pellme F ,Smith U ,Funahashi T , et al. Circulating adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients. Diabetes 2003;52:1182-1186
CrossRef | Web of Science | Medline3
Yamauchi T ,Kamon J ,Minokoshi Y , et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002;8:1288-1295
CrossRef | Web of Science | Medline
To the Editor:
Petersen et al. suggest that a reduction in fatty acid oxidation in muscle that leads to intramyocellular lipid accumulation is a primary, inherited cause of insulin resistance, and they speculate about the role of peroxisome-proliferator–activated receptor γ coactivator 1 (PGC1). However, a cause-and-effect relation has not been demonstrated; only an association between insulin resistance (and hyperinsulinemia) and a reduction in mitochondrial function has been observed. No study has shown that such abnormalities precede the development of insulin resistance; in fact, Jove et al.1 have suggested that an improvement in insulin resistance with a reduction in hyperinsulinemia restores the reduced PGC1 transcript levels seen in Zucker diabetic fatty rats, suggesting that the process is a secondary one. Similarly, ectopic fat accumulation in liver and muscle may be a secondary process resulting from an increase in de novo lipogenesis. Hyperinsulinemia leads to up-regulation of sterol regulatory element–binding protein 1c (SREBP1c), a critical transcription factor that regulates the lipogenic genes. Knockout of SREBP1c in ob/ob mice ameliorates hepatic fat accumulation but does not alter insulin sensitivity.2 Changes in mitochondrial function may be important in the progression of disease but it has yet to be shown that they are a primary insult.
2 ReferencesPeter J. Raubenheimer, M.B., B.Ch.
University of Edinburgh, Edinburgh EH9 1AT, United Kingdom
p.raubenheimer@ed. ac. uk 1
Jove M ,Salla J ,Planavila A , et al. Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle of ZDF rats: restoration by troglitazone. J Lipid Res 2004;45:113-123
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Yahagi N ,Shimano H ,Hasty AH , et al. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)Lep(ob) mice. J Biol Chem 2002;277:19353-19357
CrossRef | Web of Science | Medline
To the Editor:
Petersen et al. conclude that impairment of mitochondrial metabolism precedes type 2 diabetes. This observation suggests that diseases with defined alterations of mitochondrial metabolism must cause diabetes as well. Friedreich's ataxia is an autosomal recessive disorder that results in impaired oxidative phosphorylation in skeletal muscle1 similar to that observed by Petersen et al. in diabetic persons. Friedreich's ataxia occurs as a result of reduced expression of a mitochondrial protein called frataxin, which has been functionally linked to cellular respiration and ATP replenishment.2 Diabetes frequently develops in patients with Friedreich's ataxia,3 and even heterozygous (i.e., unaffected) carriers of mutations causing Friedreich's ataxia have insulin resistance.4 Furthermore, such mutations have been found in association with type 2 diabetes.3 Finally, genetic studies indicate that type 2 diabetes is linked to chromosome 9q13, the location of the frataxin gene.3 Hence, the interesting findings of Petersen et al. regarding a mitochondrial pathogenesis of type 2 diabetes are strongly supported by metabolic and genetic data from studies of a primarily neurodegenerative disease — Friedreich's ataxia.
4 ReferencesMatthias Möhlig, M.D.
German Institute for Human Nutrition, D-14558 Potsdam-Rehbrücke, GermanyFrank Isken, M.D.
Charité University Medicine, D-12200 Berlin, GermanyMichael Ristow, M.D.
German Institute for Human Nutrition, D-14558 Potsdam-Rehbrücke, Germany
mristow@mristow.org 1
Vorgerd M ,Schols L ,Hardt C ,Ristow M ,Epplen JT ,Zange J . Mitochondrial impairment of human muscle in Friedreich ataxia in vivo. Neuromuscul Disord 2000;10:430-435
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Ristow M ,Pfister MF ,Yee AJ , et al. Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc Natl Acad Sci U S A 2000;97:12239-12243
CrossRef | Web of Science | Medline3
Ristow M ,Mulder H ,Pomplun D , et al. Frataxin-deficiency in pancreatic islets causes diabetes due to loss of beta cell mass. J Clin Invest 2003;112:527-534
Web of Science | Medline4
Hebinck J ,Hardt C ,Schols L , et al. Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans. Diabetes 2000;49:1604-1607
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with Short et al. and Raubenheimer that our study does not prove a cause-and-effect relationship between defects in mitochondrial oxidative-phosphorylation activity and insulin resistance. However, in contrast to previous in vitro studies that showed altered expression of mitochondrial gene expression or mitochondrial enzyme activity,1-3 our study revealed reduced in vivo mitochondrial phosphorylation activity in young, healthy, insulin-resistant offspring of persons with type 2 diabetes who were all lean and free of any potential confounding factors such as obesity, diabetes, or use of medications that might affect mitochondrial gene expression or mitochondrial activity. Furthermore, in contrast to the subjects in the previous studies, the subjects in our study were normoglycemic and the groups were carefully matched for body weight, body-mass index, and activity. The importance of eliminating confounding factors that might affect mitochondrial activity or biogenesis is reflected by a recent oligonucleotide microarray study that showed down-regulation of mitochondrial electron-transport genes in streptozotocin-treated mice and a reversal of that process with insulin treatment.4
In contrast to the hypothesis proposed by Bajaj and Mandarino, we do not believe that alterations in plasma adiponectin concentrations can explain our findings, since we did not observe any differences in plasma adiponectin concentrations between the insulin-resistant offspring and the insulin-sensitive controls. We believe that the differences between our results and those of Pellme et al.5 can be attributed to the fact that our subjects were lean and were matched for body-mass index. In contrast, the insulin-resistant first-degree relatives studied by Pellme et al. were significantly heavier than their age-matched control subjects (body-mass index, 25.8±2.6 vs. 24.6±2.6; P<0.05) and had significantly more body fat (19.5±6.1 kg vs. 16.5±6.6 kg, P<0.03). We are currently in the process of performing gene-chip microarray studies to assess the expression of adiponectin receptors and other hormone receptors in muscle from lean, insulin-resistant subjects.
Finally, we thank Möhlig et al. for their comments regarding the relation between inherited defects in mitochondrial dysfunction and insulin resistance in patients with Friedreich's ataxia. These studies offer further support for our hypothesis regarding a potential causative role of mitochondrial dysfunction in predisposing persons to intracellular lipid accumulation and insulin resistance.6
6 ReferencesKitt Falk Petersen, M.D.
Yale University School of Medicine, New Haven, CT 06512Gerald I. Shulman, M.D., Ph.D.
Howard Hughes Medical Institute, New Haven, CT 06512
gerald.shulman@yale. edu 1
Kelley DE ,He J ,Menshikova EV ,Ritov VB . Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002;51:2944-2950
CrossRef | Web of Science | Medline2
Mootha VK ,Lindgren CM ,Eriksson KF , et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003;34:267-273
CrossRef | Web of Science | Medline3
Patti ME ,Butte AJ ,Crunkhorn S , et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 2003;100:8466-8471
CrossRef | Web of Science | Medline4
Yechoor VK ,Patti ME ,Saccone R ,Kahn CR . Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice. Proc Natl Acad Sci U S A 2002;99:10587-10592
CrossRef | Web of Science | Medline5
Pellme F ,Smith U ,Funahashi T , et al. Circulating adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients. Diabetes 2003;52:1182-1186
CrossRef | Web of Science | Medline6
Shulman GI . Cellular mechanisms of insulin resistance. J Clin Invest 2000;106:171-176
CrossRef | Web of Science | Medline
- Citing Articles (6)
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Li Fu, Xiaolei Liu, Yanmei Niu, Hairui Yuan, Ning Zhang, Ehud Lavi. (2011) Effects of high-fat diet and regular aerobic exercise on global gene expression in skeletal muscle of C57BL/6 mice. Metabolism
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S. O. Crawford, R. C. Hoogeveen, F. L. Brancati, B. C. Astor, C. M. Ballantyne, M. I. Schmidt, J. H. Young. (2010) Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study. International Journal of Epidemiology 39:6, 1647-1655
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Stephen O. Crawford, Marietta S. Ambrose, Ron C. Hoogeveen, Frederick L. Brancati, Christie M. Ballantyne, J. Hunter Young. (2008) Association of Lactate With Blood Pressure Before and After Rapid Weight Loss. American Journal of Hypertension 21:12, 1337-1342
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L. J. Tamariz, J. H. Young, J. S. Pankow, H.-C. Yeh, M. I. Schmidt, B. Astor, F. L. Brancati. (2008) Blood Viscosity and Hematocrit as Risk Factors for Type 2 Diabetes Mellitus: The Atherosclerosis Risk in Communities (ARIC) Study. American Journal of Epidemiology 168:10, 1153-1160
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Kurt Højlund, Martin Mogensen, Kent Sahlin, Henning Beck-Nielsen. (2008) Mitochondrial Dysfunction in Type 2 Diabetes and Obesity. Endocrinology & Metabolism Clinics of North America 37:3, 713-731
CrossRef6
S. F. E. Praet, H. M. M. De Feyter, R. A. M. Jonkers, K. Nicolay, C. van Pul, H. Kuipers, L. J. C. van Loon, J. J. Prompers. (2007) 31P MR spectroscopy and in vitro markers of oxidative capacity in type 2 diabetes patients. Magnetic Resonance Materials in Physics, Biology and Medicine 19:6, 321-331
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