Mechanisms of insulin resistance in obesity

Abstract

Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that, there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.

Keywords

type 2 diabetes / energy expenditure / inflammation / lipotoxicity / mitochondria / hyperinsulinemia / adenosine monophosphate-activated protein kinase (AMPK)

References

[1] Ye J. Role of insulin in the pathogenesis of free fatty acid-induced insulin resistance in skeletal muscle. Endocr Metab Immune Disord Drug Targets2007; 7(1): 65-74

[2] He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab2011; 300(5): E877-E885

[3] Ye J, McGuinness OP. Inflammation during obesity is not all bad: Evidence from animal and human studies. Am J Physiol Endocrinol Metab 2012 Dec 26. [Epub ahead of print]

[4] Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest2006; 116(7): 1793-1801

[5] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science1993; 259(5091): 87-91

[6] Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab2004; 89(6): 2548-2556

[7] Halberg N, Wernstedt-Asterholm I, Scherer PE. The adipocyte as an endocrine cell. Endocrinol Metab Clin North Am2008; 37(3): 753-768, x-xi (x-xi)

[8] Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science2001; 293(5535): 1673-1677

[9] Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature2002; 420(6913): 333-336

[10] Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond)2009; 33(1): 54-66

[11] Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J Biol Chem1996; 271(22): 13018-13022

[12] Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem2002; 277(50): 48115-48121

[13] Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem2000; 275(12): 9047-9054

[14] Gao Z, He Q, Peng B, Chiao PJ, Ye J. Regulation of nuclear translocation of HDAC3 by IκBα is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor gamma function. J Biol Chem2006; 281(7): 4540-4547

[15] Ye J. Regulation of PPARγ function by TNF-α. Biochem Biophys Res Commun2008; 374(3): 405-408

[16] Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol2000; 18(1): 621-663

[17] Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(α) signaling through IKK2. J Biol Chem2008; 283(51): 35375-35382

[18] Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A, White MF. Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest2001; 107(2): 181-189

[19] White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab2002; 283(3): E413-E422

[20] Ye J, Gimble JM. Regulation of stem cell differentiation in adipose tissue by chronic inflammation. Clin Exp Pharmacol Physiol2011; 38(12): 872-878

[21] Xing H, Northrop JP, Grove JR, Kilpatrick KE, Su JL, Ringold GM. TNF α-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARγ without effects on Pref-1 expression. Endocrinology1997; 138(7): 2776-2783

[22] Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes2002; 51(5): 1319-1336

[23] Suzawa M, Takada I, Yanagisawa J, Ohtake F, Ogawa S, Yamauchi T, Kadowaki T, Takeuchi Y, Shibuya H, Gotoh Y, Matsumoto K, Kato S. Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade. Nat Cell Biol2003; 5(3): 224-230

[24] Anforth HR, Bluthe RM, Bristow A, Hopkins S, Lenczowski MJ, Luheshi G, Lundkvist J, Michaud B, Mistry Y, Van Dam AM, Zhen C, Dantzer R, Poole S, Rothwell NJ, Tilders FJ, Wollman EE. Biological activity and brain actions of recombinant rat interleukin-1α and interleukin-1β. Eur Cytokine Netw1998; 9(3): 279-288

[25] García MC, Wernstedt I, Berndtsson A, Enge M, Bell M, Hultgren O, Horn M, Ahrén B, Enerback S, Ohlsson C, Wallenius V, Jansson JO. Mature-onset obesity in interleukin-1 receptor I knockout mice. Diabetes2006; 55(5): 1205-1213

[26] Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med2002; 8(1): 75-79

[27] Xu H, Hirosumi J, Uysal KT, Guler AD, Hotamisligil GS. Exclusive action of transmembrane TNFα in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance. Endocrinology2002; 143(4): 1502-1511

[28] Pamir N, McMillen TS, Kaiyala KJ, Schwartz MW, LeBoeuf RC. Receptors for tumor necrosis factor-α play a protective role against obesity and alter adipose tissue macrophage status. Endocrinology2009; 150(9): 4124-4134

[29] Chida D, Osaka T, Hashimoto O, Iwakura Y. Combined interleukin-6 and interleukin-1 deficiency causes obesity in young mice. Diabetes2006; 55(4): 971-977

[30] Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest2003; 112(12): 1821-1830

[31] Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest2003; 112(12): 1796-1808

[32] Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM, Ranganathan G, Peterson CA, McGehee RE, Kern PA. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes2005; 54(8): 2305-2313

[33] Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm2006; 74: 443-477

[34] Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature2007; 447(7148): 1116-1120

[35] Hevener AL, Olefsky JM, Reichart D, Nguyen MTA, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M. Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest2007; 117(6): 1658-1669

[36] Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest2007; 117(1): 175-184

[37] Gordon S. Alternative activation of macrophages. Nat Rev Immunol2003; 3(1): 23-35

[38] Mosser DM. The many faces of macrophage activation. J Leukoc Biol2003; 73(2): 209-212

[39] Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes2007; 56(6): 1517-1526

[40] Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T, Schwendener RA, Brekken RA, Kang G, Oike Y, Choi TS, Suda T, Yoo OJ, Koh GY. Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res2007; 100(4): e47-e57

[41] Lijnen HR. Angiogenesis and obesity. Cardiovasc Res2008; 78(2): 286-293

[42] Pang C, Gao Z, Yin J, Zhang J, Jia W, Ye J. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am J Physiol Endocrinol Metab2008; 295(2): E313-E322

[43] Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res2005; 46(11): 2347-2355

[44] Clavien PA. IL-6, a key cytokine in liver regeneration. Hepatology1997; 25(5): 1294-1296

[45] Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-κB. Nat Med2005; 11(2): 183-190

[46] Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-β links inflammation to obesity-induced insulin resistance. Nat Med2005; 11(2): 191-198

[47] Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Jung DY, Ko HJ, Ong H, Kim JK, Mynatt R, Martin RJ, Keenan M, Gao Z, Ye J. Uncoupling of inflammation and insulin resistance by NF-κB in transgenic mice through elevated energy expenditure. J Biol Chem2010; 285(7): 4637-4644

[48] Jiao P, Feng B, Ma J, Nie Y, Paul E, Li Y, Xu H. Constitutive activation of IKKβ in adipose tissue prevents diet-induced obesity in mice. Endocrinology2012; 153(1): 154-165

[49] Pedersen BK. IL-6 signalling in exercise and disease. Biochem Soc Trans2007; 35(5): 1295-1297

[50] Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab2012; 16(2): 153-166

[51] Straub RH, Cutolo M, Buttgereit F, Pongratz G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med2010; 267(6): 543-560

[52] Ye J, Keller JN. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging (Albany NY)2010; 2(6): 361-368

[53] Holloszy JO. Exercise-induced increase in muscle insulin sensitivity. J Appl Physiol2005; 99(1): 338-343

[54] Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science2005; 307(5708): 384-387

[55] Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol2012; 8(2): 92-103

[56] Holloszy JO. Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance. Am J Clin Nutr2009; 89(1): 463S-466S

[57] Pagel-Langenickel I, Bao J, Pang L, Sack MN. The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance. Endocr Rev2010; 31(1): 25-51

[58] Muoio DM. Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim Biophys Acta2010; 1801(3): 281-288

[59] Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest2005; 115(12): 3587-3593

[60] 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 USA2003; 100(13): 7996-8001

[61] Sreekumar R, Halvatsiotis P, Schimke JC, Nair KS. Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes2002; 51(6): 1913-1920

[62] Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C. Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest1991; 88(3): 960-966

[63] Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest1996; 97(12): 2859-2865

[64] Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, Roden M, Gnaiger E, Nohl H, Waldhäusl W, Fürnsinn C. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes2004; 53(4): 1052-1059

[65] Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J2000; 348(3): 607-614

[66] Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab2008; 294(1): E148-E156

[67] Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM, Hardie DG. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab2010; 11(6): 554-565

[68] Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care2008; 31(Suppl 2): S262-S268

[69] Corkey BE. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes2012; 61(1): 4-13

[70] Gray SL, Donald C, Jetha A, Covey SD, Kieffer TJ. Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic β-cell leptin signaling. Endocrinology2010; 151(9): 4178-4186

[71] Zhao AZ, Bornfeldt KE, Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest1998; 102(5): 869-873

[72] Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, Botezelli JD, Asadi A, Hoffman BG, Kieffer TJ, Bamji SX, Clee SM, Johnson JD. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab2012; 16(6): 723-737

[73] Valera Mora ME, Scarfone A, Calvani M, Greco AV, Mingrone G. Insulin clearance in obesity. J Am Coll Nutr2003; 22(6): 487-493

[74] Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell2000; 6(1): 87-97

[75] Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA2003; 100(7): 4162-4167

[76] Farris W, Mansourian S, Leissring MA, Eckman EA, Bertram L, Eckman CB, Tanzi RE, Selkoe DJ. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid β-protein. Am J Pathol2004; 164(4): 1425-1434

[77] Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes2002; 51(10): 2951-2958

[78] Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science2003; 300(5622): 1140-1142

[79] Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab2007; 5(2): 151-156

[80] Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature2006; 440(7086): 944-948

[81] Nair KS, Bigelow ML, Asmann YW, Chow LS, Coenen-Schimke JM, Klaus KA, Guo ZK, Sreekumar R, Irving BA. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes2008; 57(5): 1166-1175

[82] Bergman RN, Ader M. Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab2000; 11(9): 351-356

[83] Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest2000; 106(2): 171-176

[84] Boden G. Free fatty acids and insulin secretion in humans. Curr Diab Rep2005; 5(3): 167-170

[85] Paolisso G, Tataranni PA, Foley JE, Bogardus C, Howard BV, Ravussin E. A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia1995; 38(10): 1213-1217

[86] Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord2004; 28(Suppl 4): S12-S21

[87] Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev1998; 12(20): 3182-3194

[88] Schenk S, Horowitz JF. Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J Clin Invest2007; 117(6): 1690-1698

[89] Yadav H, Quijano C, Kamaraju AK, Gavrilova O, Malek R, Chen W, Zerfas P, Zhigang D, Wright EC, Stuelten C, Sun P, Lonning S, Skarulis M, Sumner AE, Finkel T, Rane SG. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab2011; 14(1): 67-79

[90] Tan CK, Leuenberger N, Tan MJ, Yan YW, Chen Y, Kambadur R, Wahli W, Tan NS. Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet. Diabetes2011; 60(2): 464-476

[91] Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab2005; 1(1): 15-25

[92] Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab2009; 9(5): 407-416

[93] Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem2003; 278(39): 37041-37051

[94] Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, Häring HU, Schleicher ED. Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-κB. J Biol Chem2004; 279(23): 23942-23952

[95] Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol2004; 18(8): 2024-2034

[96] Brose N, Rosenmund C. Move over protein kinase C, you’ve got company: alternative cellular effectors of diacylglycerol and phorbol esters. J Cell Sci2002; 115(23): 4399-4411

[97] Ballou LR, Laulederkind SJ, Rosloniec EF, Raghow R. Ceramide signalling and the immune response. Biochim Biophys Acta1996; 1301(3): 273-287

[98] Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science2004; 306(5695): 457-461

[99] de Luca C, Olefsky JM. Stressed out about obesity and insulin resistance. Nat Med2006; 12(1): 41-42, discussion 42

[100] Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG Jr, Ozcan U. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab2009; 9(1): 35-51

[101] Schröder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res2005; 569(1-2): 29-63

[102] Lee J, Sun C, Zhou Y, Lee J, Gokalp D, Herrema H, Park SW, Davis RJ, Ozcan U. p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat Med2011; 17(10): 1251-1260

[103] Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science2006; 313(5790): 1137-1140

[104] Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med2002; 165(5): 670-676

[105] Iiyori N, Alonso LC, Li J, Sanders MH, Garcia-Ocana A, O’Doherty RM, Polotsky VY, O’Donnell CP. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med2007; 175(8): 851-857

[106] Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab2007; 293(4): E1118-E1128

[107] Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev2009; 89(1): 27-71

[108] Greene EL, Lu G, Zhang D, Egan BM. Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. Hypertension2001; 37(2): 308-312

[109] Lu G, Greene EL, Nagai T, Egan BM. Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. Hypertension1998; 32(6): 1003-1010

[110] Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest2004; 114(12): 1752-1761

[111] Lin Y, Berg AH, Iyengar P, Lam TKT, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE. The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem2005; 280(6): 4617-4626

[112] Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes2003; 52(1): 1-8

[113] Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet β cells in diabetes. J Biol Chem2004; 279(41): 42351-42354

[114] Aragonés J, Fraisl P, Baes M, Carmeliet P. Oxygen sensors at the crossroad of metabolism. Cell Metab2009; 9(1): 11-22

[115] Prabhakar NR, Kumar GK, Nanduri J, Semenza GL. ROS signaling in systemic and cellular responses to chronic intermittent hypoxia. Antioxid Redox Signal2007; 9(9): 1397-1403

[116] Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes1999; 48(1): 1-9

[117] Ceriello A. Oxidative stress and glycemic regulation. Metabolism2000; 49(2 Suppl 1): 27-29

[118] Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, Ono H, Fujishiro M, Kushiyama A, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Gotoh Y, Komuro I, Fujita T. Oxidative stress induces insulin resistance by activating the nuclear factor-κB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia2004; 47(5): 794-805

[119] Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med2001; 345(11): 790-797

[120] He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature2012; 481(7382): 511-515

[121] Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature1999; 401(6748): 73-76

[122] Zhang Y, Ye J. Mitochondrial inhibitor as a new class of insulin sensitizer. Acta Pharmaceutica Sinica B 2012; 2(4): 341– 349

Acknowledgments

Jianping Ye is supported by the National Institute of Health research projects (DK085495, DK068036).

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg