Abstract
The obesity pandemic increases the prevalence of type 2 diabetes (DM2).
DM2 develops when pancreatic β-cells fail and cannot compensate for the decrease in insulin sensitivity. How excessive caloric intake and weight gain cause insulin resistance has not completely been elucidated.
Skeletal muscle is responsible for a major part of insulin stimulated whole-body glucose disposal and, hence, plays an important role in the pathogenesis of insulin resistance.
It has been hypothesized that skeletal muscle mitochondrial dysfunction is involved in the accumulation of intramyocellular lipid metabolites leading to lipotoxicity and insulin resistance. However, findings on skeletal muscle mitochondrial function in relation to insulin resistance in human subjects are inconclusive. Differences in mitochondrial activity can be the result of several factors, including a reduced mitochondrial density, differences in insulin stimulated mitochondrial respiration, lower energy demand or reduced skeletal muscle perfusion, besides an intrinsic mitochondrial defect. The inconclusive results may be explained by the use of different techniques and study populations. Also, mitochondrial capacity is in far excess to meet energy requirements and therefore it may be questioned whether a reduced mitochondrial capacity limits mitochondrial fatty acid oxidation. Whether reduced mitochondrial function is causally related to insulin resistance or rather a consequence of the sedentary lifestyle remains to be elucidated.
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References
Andersen P, Saltin B (1985) Maximal perfusion of skeletal muscle in man. J Physiol 366:233–249
Asmann YW et al (2006) 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. Diabetes 55(12):3309–3319
Bach D et al (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 278(19):17190–17197
Bao S et al (1998) Expression of mRNAs encoding uncoupling proteins in human skeletal muscle: effects of obesity and diabetes. Diabetes 47(12):1935–1940
Baron AD et al (1993) Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure. Hypertension 21(2):129–135
Befroy DE et al (2007) Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 56(5):1376–1381
Belfort R et al (2005) Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 54(6):1640–1648
Berggren JR et al (2008) Skeletal muscle lipid oxidation and obesity: influence of weight loss and exercise. Am J Physiol Endocrinol Metab 294(4):E726–E732
Bergman RN (2007) Orchestration of glucose homeostasis: from a small acorn to the California oak. Diabetes 56(6):1489–1501
Boden G (2002) Interaction between free fatty acids and glucose metabolism. Curr Opin Clin Nutr Metab Care 5(5):545–549
Bonnard C et al (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118(2):789–800
Boss O, Hagen T, Lowell BB (2000) Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49(2):143–156
Bouchard C et al (1999) Familial aggregation of VO(2max) response to exercise training: results from the HERITAGE Family Study. J Appl Physiol 87(3):1003–1008
Boushel R et al (2007) Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50(4):790–796
Brands M et al (2011) Short-term increase of plasma free fatty acids does not interfere with intrinsic mitochondrial function in healthy young men. Metabolism 60(10):1398–1405
Brehm A et al (2006) Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes 55(1):136–140
Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625
Carter SL et al (2001) Changes in skeletal muscle in males and females following endurance training. Can J Physiol Pharmacol 79(5):386–392
Chavez AO et al (2010) Effect of short-term free Fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. J Clin Endocrinol Metab 95(1):422–429
Chi MM et al (1983) Effects of detraining on enzymes of energy metabolism in individual human muscle fibers. Am J Physiol 244(3):C276–C287
Ciapaite J et al (2005) Modular kinetic analysis of the adenine nucleotide translocator-mediated effects of palmitoyl-CoA on the oxidative phosphorylation in isolated rat liver mitochondria. Diabetes 54(4):944–951
Civitarese AE, Ravussin E (2008) Mitochondrial energetics and insulin resistance. Endocrinology 149(3):950–954
Cogswell AM, Cogswell AM, Stevens RJ, Hood DA (1993) Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Am J Physiol 264(2 Pt 1):C383–C389
Costford SR et al (2009) Increased susceptibility to oxidative damage in post-diabetic human myotubes. Diabetologia 52(11):2405–2415
De Feyter HM et al (2008) Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction. Eur J Endocrinol 158(5):643–653
DeFronzo RA et al (1985) Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 76(1):149–155
Florez JC (2008) Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51(7):1100–1110
Frayn KN (1983) Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 55(2):628–634
Frederiksen CM et al (2008) Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes. Diabetologia 51(11):2068–2077
Gadian DG, Radda GK (1981) NMR studies of tissue metabolism. Annu Rev Biochem 50:69–83
Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41(10):1837–1845
Guillet C et al (2009) Changes in basal and insulin and amino acid response of whole body and skeletal muscle proteins in obese men. J Clin Endocrinol Metab 94(8):3044–3050
Hancock CR et al (2008) High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA 105(22):7815–7820
He J, Watkins S, Kelley DE (2001) Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity. Diabetes 50(4):817–823
Heilbronn LK et al (2007) Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J Clin Endocrinol Metab 92(4):1467–1473
Holloszy JO (2009) Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance. Am J Clin Nutr 89(1):463S–466S
Holloway GP et al (2007) Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. Am J Physiol Endocrinol Metab 292(6):E1782–E1789
Holloway GP, Bonen A, Spriet LL (2009) Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals. Am J Clin Nutr 89(1):455S–462S
Hood DA (2001) Invited Review: contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 90(3):1137–1157
Hoppeler H et al (1985) Endurance training in humans: aerobic capacity and structure of skeletal muscle. J Appl Physiol 59(2):320–327
Karakelides H et al (2010) Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes 59(1):89–97
Kelley DE et al (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950
Kemp GJ, Taylor DJ, Radda GK (1993) Control of phosphocreatine resynthesis during recovery from exercise in human skeletal muscle. NMR Biomed 6(1):66–72
Khalfallah Y et al (2000) Regulation of uncoupling protein-2 and uncoupling protein-3 mRNA expression during lipid infusion in human skeletal muscle and subcutaneous adipose tissue. Diabetes 49(1):25–31
Koutsari C, Jensen MD (2006) Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity. J Lipid Res 47(8):1643–1650
Koves TR et al (2005) Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism. Am J Physiol Cell Physiol 288(5):C1074–C1082
Koves TR et al (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7(1):45–56
Krook A et al (1998) Uncoupling protein 3 is reduced in skeletal muscle of NIDDM patients. Diabetes 47(9):1528–1531
Larsson L, Ansved T (1985) Effects of long-term physical training and detraining on enzyme histochemical and functional skeletal muscle characteristic in man. Muscle Nerve 8(8):714–722
Malenfant P et al (2001) Fat content in individual muscle fibers of lean and obese subjects. Int J Obes Relat Metab Disord 25(9):1316–1321
Meex RC et al (2010) Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes 59(3):572–579
Menshikova EV et al (2005) Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity. Am J Physiol Endocrinol Metab 288(4):E818–E825
Menshikova EV et al (2006) Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol A Biol Sci Med Sci 61(6):534–540
Mogensen M et al (2007) Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56(6):1592–1599
Mootha VK et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267–273
Morino K et al (2005) Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 115(12):3587–3593
Nair KS et al (2008) Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes 57(5):1166–1175
Nuutila P et al (2000) Enhanced stimulation of glucose uptake by insulin increases exercise-stimulated glucose uptake in skeletal muscle in humans: studies using [15O]O2, [15O]H2O, [18F]fluoro-deoxy-glucose, and positron emission tomography. Diabetes 49(7):1084–1091
Nyholm B et al (1997) Evidence of an increased number of type IIb muscle fibers in insulin-resistant first-degree relatives of patients with NIDDM. Diabetes 46(11):1822–1828
Oberbach A et al (2006) Altered fiber distribution and fiber-specific glycolytic and oxidative enzyme activity in skeletal muscle of patients with type 2 diabetes. Diabetes Care 29(4):895–900
Ogata T, Yamasaki Y (1997) Ultra-high-resolution scanning electron microscopy of mitochondria and sarcoplasmic reticulum arrangement in human red, white, and intermediate muscle fibers. Anat Rec 248(2):214–223
Patti ME et al (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 100(14):8466–8471
Perseghin G et al (1997) Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 46(6):1001–1009
Petersen KF et al (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350(7):664–671
Pette D, Staron RS (1997) Mammalian skeletal muscle fiber type transitions. Int Rev Cytol 170:143–223
Phielix E et al (2008) Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes 57(11):2943–2949
Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546(Pt 3):851–858
Puntschart A et al (1995) mRNAs of enzymes involved in energy metabolism and mtDNA are increased in endurance-trained athletes. Am J Physiol 269(3 Pt 1):C619–C625
Rabol R et al (2010) Regional anatomic differences in skeletal muscle mitochondrial respiration in type 2 diabetes and obesity. J Clin Endocrinol Metab 95(2):857–863
Rasmussen UF, Rasmussen HN (2000a) Human quadriceps muscle mitochondria: a functional characterization. Mol Cell Biochem 208(1-2):37–44
Rasmussen UF, Rasmussen HN (2000b) Human skeletal muscle mitochondrial capacity. Acta Physiol Scand 168(4):473–480
Richardson DK et al (2005) Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 280(11):10290–10297
Ritov VB, Menshikova EV, Kelley DE (2004) High-performance liquid chromatography-based methods of enzymatic analysis: electron transport chain activity in mitochondria from human skeletal muscle. Anal Biochem 333(1):27–38
Ritov VB et al (2005) Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 54(1):8–14
Ritov VB, Menshikova EV, Kelley DE (2006) Analysis of cardiolipin in human muscle biopsy. J Chromatogr B Analyt Technol Biomed Life Sci 831(1-2):63–71
Roden M (2005) Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes. Int J Obes (Lond) 29(S111)
Rolfe DF, Brand MD (1996) Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate. Am J Physiol 271(4 Pt 1):C1380–C1389
Russell AP et al (2003) Lipid peroxidation in skeletal muscle of obese as compared to endurance-trained humans: a case of good vs. bad lipids? FEBS Lett 551(1–3):104–106
Sahlin K, Sahlin K et al (1997) Phosphocreatine content in single fibers of human muscle after sustained submaximal exercise. Am J Physiol 273(1 Pt 1):C172–C178
Scaduto RC Jr, Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76(1 Pt 1):469–477
Schrauwen P (2007) High-fat diet, muscular lipotoxicity and insulin resistance. Proc Nutr Soc 66(1):33–41
Schrauwen P, Hesselink MK (2004) Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53(6):1412–1417
Schrauwen-Hinderling VB et al (2007) Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia 50(1):113–120
Shoffner JM, Wallace DC (1992) Mitochondrial genetics: principles and practice. Am J Hum Genet 51(6):1179–1186
Short KR et al (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 102(15):5618–5623
Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106(2):171–176
Shulman RG, Rothman DL (2001) 13C NMR of intermediary metabolism: implications for systemic physiology. Annu Rev Physiol 63:15–48
Simoneau JA, Bouchard C (1989) Human variation in skeletal muscle fiber-type proportion and enzyme activities. Am J Physiol 257(4 Pt 1):E567–E572
Sreekumar R et al (2002) Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 51(6):1913–1920
Stump CS et al (2003) Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 100(13):7996–8001
Szendroedi J, Roden M (2008) Mitochondrial fitness and insulin sensitivity in humans. Diabetologia 51(12):2155–2167
Szendroedi J et al (2007) Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Med 4(5):e154
Tanner CJ et al (2002) Muscle fiber type is associated with obesity and weight loss. Am J Physiol Endocrinol Metab 282(6):E1191–E1196
Tarnopolsky MA et al (2007) Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. Am J Physiol Regul Integr Comp Physiol 292(3):R1271–R1278
Thamer C et al (2003) Reduced skeletal muscle oxygen uptake and reduced beta-cell function: two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes. Diabetes Care 26(7):2126–2132
Toledo FG, Watkins S, Kelley DE (2006) Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women. J Clin Endocrinol Metab 91(8):3224–3227
Toledo FG et al (2008) Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes 57(4):987–994
Tonkonogi M, Sahlin K (1997) Rate of oxidative phosphorylation in isolated mitochondria from human skeletal muscle: effect of training status. Acta Physiol Scand 161(3):345–353
Tonkonogi M, Harris B, Sahlin K (1997) Increased activity of citrate synthase in human skeletal muscle after a single bout of prolonged exercise. Acta Physiol Scand 161(3):435–436
Twig G, Hyde B, Shirihai OS (2008) Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 1777(9):1092–1097
Ukropcova B et al (2007) Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle. Diabetes 56(3):720–727
van den Broek NM et al (2010) Increased mitochondrial content rescues in vivo muscle oxidative capacity in long-term high-fat-diet-fed rats. FASEB J 24(5):1354–1364
Vondra K et al (1977) Enzyme activities in quadriceps femoris muscle of obese diabetic male patients. Diabetologia 13(5):527–529
Wang H et al (1999) Relationships between muscle mitochondrial DNA content, mitochondrial enzyme activity and oxidative capacity in man: alterations with disease. Eur J Appl Physiol Occup Physiol 80(1):22–27
Wibom R, Hagenfeldt L, von Dobeln U (2002) Measurement of ATP production and respiratory chain enzyme activities in mitochondria isolated from small muscle biopsy samples. Anal Biochem 311(2):139–151
Wittig I, Schagger H (2009) Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biochim Biophys Acta 1787(6):672–680
Wu Z et al (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1):115–124
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Brands, M., Verhoeven, A.J., Serlie, M.J. (2012). Role of Mitochondrial Function in Insulin Resistance. In: Scatena, R., Bottoni, P., Giardina, B. (eds) Advances in Mitochondrial Medicine. Advances in Experimental Medicine and Biology, vol 942. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2869-1_9
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