Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009

R A DeFronzo, R A DeFronzo

Abstract

Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients.

Figures

Fig. 1
Fig. 1
Insulin-stimulated glucose disposal (40 mU m−2 min−1, euglycaemic–hyperinsulaemic clamp) in lean healthy control (CON) participants, obese normal-glucose-tolerant participants (NGT), lean drug-naive type 2 diabetic participants (T2DM), lean normal-glucose-tolerant hypertensive participants (HTN), NGT hypertriacylglycerolaemic (Hypertriacyl) participants and non-diabetic participants with coronary artery disease (CAD). White sections, non-oxidative glucose disposal (glycogen synthesis); black sections, glucose oxidation. **p < 0.01 vs CON; ***p < 0.001 vs CON. Figure adapted with permission from Kashyap et al. [19] and DeFronzo et al. [20]. To change glucose uptake into SI units, divide by 180
Fig. 2
Fig. 2
a Association between insulin resistance (HOMA-IR) and 8-year incidence of CVD in non-diabetic participants in the San Antonio Heart Study before (black bars) and after (white bars) adjustment for age, sex, blood pressure, plasma lipids, smoking, exercise and waist circumference. Events, n = 187, participants, n = 2,569. Panel adapted with permission from Hanley et al. [67]. b Bar graph of 6.9 year risk of CVD in 3,606 participants with the metabolic syndrome (MS) and with individual components of the metabolic syndrome, i.e. dyslipidaemia (Dyslip), hypertension (HTN), obesity (OB) and insulin resistance (IR, highest HOMA quartile) in the Botnia Study. Panel adapted with permission from Isomaa et al. [68]
Fig. 3
Fig. 3
a Predictive value (%) of CVD using the Framingham risk engine in Framingham Heart Study (FHS), the Atherosclerosis Risk in Community Study (ARIC), the Honolulu Heart Program (HHP), the Puerto Rico Heart Health Program (PR), the Strong Heart Study (SHS) and the Cardiovascular Health Study (CHS). On mean, the Framingham Risk engine predicts only 69% of the risk of a future cardiovascular event. Panel adapted with permission from D’Agostino et al. [74]. b Excess carotid intima–media thickness (IMT) in relation to the individual components of the insulin resistance (metabolic) syndrome as listed. Amer, American; HTN, hypertension; F, female; M, male; TG, triacylglycerol; GLU, glucose. Fields in dotted lines, unexplained risk (a 31%; b, 30%). Panel adapted with permission from Goldsen et al. [76]
Fig. 4
Fig. 4
a Insulin signal transduction system in individuals with normal glucose tolerance (see text for a detailed discussion). NOS, nitric oxide synthase. b In type 2 diabetic participants insulin signalling is impaired at the level of IRS-1 leading to decreased glucose transport/phosphorylation/metabolism and impaired nitric oxide synthase activation/endothelial function. At the same time, insulin signalling through the MAP kinase pathway is normally sensitive to insulin. The compensatory hyperinsulinaemia (due to insulin resistance in the IRS-1/PI-3 kinase pathway) results in excessive stimulation of this pathway, which is involved in inflammation, cell proliferation and atherogenesis (see text for a detailed discussion). SHC, Src homology collagen. Reproduced from DeFronzo [1]
Fig. 5
Fig. 5
a Intramyocellular lipid content (measured by magnetic resonance spectroscopy) and (b) muscle long-chain fatty acyl CoA (LC-FACoA) content in control (CON) and type 2 diabetic (T2DM) participants. **p < 0.01 for T2DM vs CON. c Relationship between the increment in insulin-stimulated rate of glucose disposal (Rd) and decrement in muscle LC-FACoA content in type 2 diabetic participants after treatment with acipimox. p < 0.01; r = 0.74. Figure adapted with permission from Bajaj et al. [143]
Fig. 6
Fig. 6
Relationship between intracellular fatty acyl CoA levels, IkB/NFkB and the insulin signal transduction pathway (see text for a detailed discussion). iNOS, inducible nitric oxide synthase
Fig. 7
Fig. 7
Schematic representation of the toll-like receptor 4 (TLR-4) pathway and its activation by NEFA. Dissociation of NFkB from IkB allows it to diffuse into the nucleus where it can turn on genes associated with inflammation, atherosclerosis and insulin resistance (see text for a detailed discussion). CD14, cluster of differentiation 14; IRAK, interleukin-1 receptor associated kinase, MD-2, myb regulated gene; MYD88, myeloid differentiation primary response gene; TRAF, TNFa receptor associated factor
Fig. 8
Fig. 8
Fat topography in type 2 diabetes and effect of thiazolidine-diones (TZD) (see text for a detailed discussion)
Fig. 9
Fig. 9
Rosiglitazone (ROSI) treatment of type 2 diabetic patients (T2DM) for 4 months markedly augmented insulin signalling through the IRS-1/PI-3 kinase pathway without altering (a) insulin receptor tyrosine phosphorylation, (b) IRS-1 tyrosine phosphorylation, (c) association of p85 subunit of PI-3 kinase with IRS-1 and (d) association of PI-3 kinase with IRS-1. *p < 0.05; **p < 0.01. Figure adapted with permission from Miyazaki et al. [126]
Fig. 10
Fig. 10
PGC-1α and PGC-1β expression in muscle of (a, b) individuals with normal-glucose-tolerance and without family history (FH−) of diabetes, insulin-resistant normal-glucose-tolerant offspring of two type 2 diabetic parents (FH+) and participants with type 2 diabetes mellitus (T2DM). c A strong linear relationship exists between PGC-1α mRNA and PDHA1 mRNA, and the expression of other mitochondrial genes (not shown) involved in oxidative phosphorylation. White diamonds, FH−; black triangles, type 2 diabetes mellitus; hatched squares, FH+. d, e Pioglitazone (PIO) treatment of type 2 diabetic patients significantly increased the expression of PGC-1α and PGC-1β mRNA in muscle. *p < 0.05 for FH + vs FH−; **p < 0.01 for FH+ and T2DM vs FH−, and (d, e) *p < 0.05 for PIO vs Basal. Figure adapted with permission from Patti et al. [182] and Coletta et al. [175]
Fig. 11
Fig. 11
Amelioration of lipotoxicity by action of pioglitazone in increasing the plasma adiponectin concentration and levels of adiponectin receptors (ADIPOR) 1 and 2. See text for a detailed discussion. ACC, acetyl CoA carboxylase; CPT-1, carnitine palmitoyl transferase-1; CREB, cAMP response element binding; DAG, diacylglycerol; MEF2C, myocyte enhancer factor 2C. Figure adapted with permission from Civitarese et al. [187] and Coletta et al. [175]

References

    1. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–795.
    1. Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–986.
    1. Stratton LM, Adler AJ, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–412.
    1. Morrish NJ, Wang SL, Stevens LK, et al. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001;44(Suppl 2):S14–S21.
    1. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–234.
    1. Giorda CB, Avogaro A, Maggini M, et al. Recurrence of cardiovascular events in patients with type 2 diabetes. Diabetes Care. 2008;31:2154–2159.
    1. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2345–2359.
    1. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med. 2008;358:2560–2725.
    1. Duckworth W, Abraira C, Mortiz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–139.
    1. UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet. 1998;352:837–853.
    1. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589.
    1. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type I diabetes. N Engl J Med. 2005;22:2643–53.
    1. Henry RR, Gumbiner B, Ditzler T, et al. Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-month outpatient trial. Diabetes Care. 1993;16:21–31.
    1. Holman RR, Thorne KI, Farmer AJ, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357:1716–1730.
    1. Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of U.S. adults. New Engl J Med. 1999;341:1097–1105.
    1. Allison DB, Fontaine KR, Manson JE, et al. Annual deaths attributable to obesity in the United States. JAMA. 1999;282:1530–1538.
    1. Del Prato S, Leonetti F, Simonson DC, et al. Effect of sustained physiologic hyperinsulinemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia. 1994;37:1025–1035.
    1. Iozzo P, Pratipanawatr T, Pijl H, et al. Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis. Am J Physiol. 2001;280:E712–E719.
    1. Kashyap SR, DeFronzo RA. The insulin resistance syndrome: physiologic considerations. Diab Vasc Dis Res. 2007;4:13–19.
    1. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD. Diabetes Care Reviews. 1991;14:173–194.
    1. DeFronzo RA. Is insulin resistance atherogenic? Possible mechanisms. Atherosclerosis. 2006;7:11–15.
    1. Koopmans SJ, Kushwaha RS, DeFronzo RA. Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis in conscious normal rats. Metabolism. 1999;48:330–337.
    1. Tobey TA, Greenfield M, Kraemer F, et al. Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in normotriglyceridemic man. Metabolism. 1981;30:165–171.
    1. Azzout-Marniche D, Becard D, Guichard C, et al. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J. 2000;350:389–393.
    1. Stout TW. The effect of insulin on the incorporation of (1-C) sodium acetate into the lipids of the rat aorta. Diabetologia. 1971;7:367–372.
    1. King GL, Goodman D, Buzney S, et al. Receptors and growth promoting effects of insulin and insulin like growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest. 1985;75:1028–1036.
    1. Coletta D, Balas B, Chavez AO, et al. Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo. Am J Physiol Endo Metab. 2008;294:E910–E917.
    1. Nakao J, Ito H, Kanayasu T, et al. Stimulatory effect of insulin on aortic smooth muscle cell migration induced by 12-L-hydroxy-5, 8, 10, 14-eicosatetraenoic acid and its modulation by elevated extracellular glucose levels. Diabetes. 1985;34:185–191.
    1. Pfeifle B, Ditschuneit H. Effect of insulin on the growth of cultured arterial smooth muscle cells. Diabetologia. 1981;20:155–158.
    1. Cruz AB, Amatuzio DS, Grande F, et al. Effect of intra-arterial insulin on tissue cholesterol and fatty acids in alloxan-diabetic dogs. Circ Res. 1961;9:39–43.
    1. Duff GL, McMillan GC. The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit. J Exp Med. 1949;89:611–630.
    1. Stamler J, Pick R, Katz LN. Effect of insulin in the induction and regression of atherosclerosis in the chick. Circ Res. 1960;8:572–526.
    1. Meehan WP, Buchanan TA, Hsueh W. Chronic insulin administration elevates blood pressure in rats. Hypertension. 1994;23:1012–1017.
    1. Wang L, Sapuri-Butin AR, Aung HH, et al. Triglyceride-rich lipoprotein lipolysis increases aggregation of endothelial membrane microdomains and produces reactive oxygen species. Am J Physiol Heart Circ Physiol. 2008;295:H237–H244.
    1. Felton CV, Crook D, Davies MJ, et al. Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Arterio Throm Vasc Biol. 1997;17:1337–1345.
    1. Felton CV, Crook D, Davies MJ, et al. Dietary polyunsaturated fatty acids and composition of human aortic plaques. Lancet. 1994;344:1195–1196.
    1. Stachowska E, Doxegowska B, Chlubek D, et al. Dietary trans fatty acids and composition of human atheromatous plaques. Eur J Nutr. 2004;43:313–318.
    1. Third report of the National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421.
    1. Miranda PJ, DeFronzo RA, Califf RM, et al. The metabolic syndrome: evaluation of pathologic and therapeutic outcomes. Am Heart J. 2005;149:20–45.
    1. Reaven GM. Banting lecture. Role of insulin resistance in human disease. Diabetes. 1988;37:1594–1607.
    1. DeFronzo RA. Lilly lecture. The triumvirate: beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37:667–687.
    1. DeFronzo RA, Gunnarsson R, Bjorkman O, et al. Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76:149–155.
    1. Bonadonna R, Groop L, Kraemer N, et al. Obesity and insulin resistance in man: a dose response study. Metabolism. 1990;39:452–459.
    1. Bajaj M, DeFronzo RA. Metabolic and molecular basis of insulin resistance. J Nucl Cardiol. 2003;10:311–323.
    1. Shulman GI, Rothman Dl, Jue T, et al. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990;322:223–238.
    1. Chen IY-D, Jeng C-Y, Hollenbeck CB, et al. Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes. J Clin Invest. 1988;82:21–25.
    1. Reaven G. Insulin resistance, hypertension, and coronary heart disease. J Clin Hypertens. 2003;5:269–274.
    1. Sironi AM, Pingitore A, Ghione S, et al. Early hypertension is associated with reduced regional cardiac function, insulin resistance, epicardial, and visceral fat. Hypertension. 2008;51:282–288.
    1. Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. New Eng J Med. 1987;317:350–357.
    1. Solini A, DeFronzo RA. Insulin resistance, hypertension, and cellular ion transport systems. Acta Diabetologica. 1992;29:196–200.
    1. DeFronzo RA. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. Neth J Med. 1997;50:191–197.
    1. Rana JS, Visser ME, Arsenault BJ et al. (2010) Metabolic dyslipidemia and risk of future coronary heart disease in apparently healthy men and women: The EPIC-Norfolk prospective population study. Int J Cardiol doi:10.1016/j.ijcard2009.03.123
    1. Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434–444.
    1. Jeppesen J, Hollenbeck CB, Zhou MY, et al. Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial lipemia. Arteriosclerosis Thromb Vasc Biol. 1995;15:320–324.
    1. Sheu WH, Shieh SM, Fuh MM, et al. Insulin resistance, glucose intolerance, and hyperinsulinemia. Hypertriglyceridemia vs hypercholesterolemia. Arteriosc Throb. 1993;13:367–370.
    1. Galvan AQ, Santoro D, Natali A, et al. Insulin sensitivity in familial hypercholesterolemia. Metabolism. 1993;42:1359–1364.
    1. Kudolo GB, Bressler P, DeFronzo RA. Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment. J Lipid Mediat Cell Signal. 1997;17:97–113.
    1. Howard BV, Robbins DC, Sievers ML, et al. LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study. Arterioscler Thromb Vasc Biol. 2000;20:830–835.
    1. Bressler P, Bailey S, Matsuda M, et al. Insulin resistance and coronary artery disease. Diabetologia. 1996;39:1345–1350.
    1. Paternostro G, Camici PG, Lammerstma AA, et al. Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography. J Clin Invest. 1996;98:2094–2099.
    1. Iozzo P, Chareonthaitawee P, Dutka D, et al. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002;51:3020–3024.
    1. Lautamaki R, Juhani Airaksinen KE, Seppanen M, et al. Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease. Diabetes. 2005;54:2787–2794.
    1. Abdul-Ghani M, Tripathy D, DeFronzo RA. Contribution of beta cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29:1130–1139.
    1. Abdul-Ghani M, Jenkinson C, Richardson D, et al. Insulin secretion and insulin action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study (VAGES) Diabetes. 2006;55:1430–1435.
    1. Gulli G, Ferrannini E, Stern M, et al. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes. 1992;41:1575–1586.
    1. Kashyap SR, DeFronzo RA. The insulin resistance syndrome: physiological considerations. Diabetes Vasc Dis Res. 2007;4:13–19.
    1. Hanley AJ, Williams K, Stern MP, et al. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002;25:1177–1184.
    1. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683–689.
    1. Bonora E, Kiechl S, Willeit J, et al. Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck Study. Diabetes Care. 2007;30:318–324.
    1. Bonora E, Formentini G, Calcaterra F, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care. 2002;25:1135–1141.
    1. Howard G, O’Leary DH, Zaccaro D, et al. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation. 1996;93:1809–1817.
    1. Bedblad B, Nilsson P, Janzon L, et al. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmö, Sweden. Diabet Med. 2002;17:299–307.
    1. Ferrannini E, Balkau B, Coppack SW, et al. Insulin resistance, insulin response, and obesity as indicators of metabolic risk. J Clin Endocrinol Metab. 2007;92:2885–2892.
    1. D’Agostino RB, Sr, Grundy S, Sullivan LM, et al. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001;286:180–187.
    1. Wilson PWF, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factors categories. Circ. 1998;97:1837–1847.
    1. Goldsen SH, Folsom AR, Coresh J, et al. Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the atherosclerosis risk in communities study. Diabetes. 2002;51:3069–3076.
    1. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signaling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.
    1. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications of identifying diabetes genes. Diabetes Rev. 1997;5:177–269.
    1. White MF, Livingston JN, Backer JM, et al. Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell. 1992;54:641–649.
    1. Sun XJ, Miralpeix M, Myers MG, Jr, et al. Expression and function of IRS-1 in insulin signal transmission. J Biol Chem. 1992;267:22662–22672.
    1. Ruderman N, Kapeller R, White MF, et al. Activation of phosphatidylinositol-3-kinase by insulin. Proc Natl Acad Sci USA. 1990;87:1411–1415.
    1. Brady MJ, Nairin AC, Saltiel AR. The regulation of glycogen synthase by protein phosphatase 1 in 3T3-I 1 adipocytes. J Biol Chem. 1997;272:29698–29703.
    1. Dent P, Lavoinne A, Nakielny S, et al. The molecular mechanisms by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature. 1990;348:302–308.
    1. Osawa H, Sutherland C, Robey R, et al. Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem. 1996;272:16690–16694.
    1. Cross D, Alessi DR, Vandenhead JR, et al. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem. 1994;303:21–26.
    1. Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest. 1994;94:1172–1179.
    1. Zeng G, Nystrom FH, Ravichandran LV, et al. Roles of insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000;101:1539–1545.
    1. Montagnani M, Chen H, Barr VA, et al. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179) J Biol Chem. 2001;276:30392–30398.
    1. Brunner H, Cockcroft JR, Deanfield J, et al. Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23:233–246.
    1. Naruse K, Shimizu K, Muramatsu M, et al. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation. Arterioscler Thromb. 1994;14:746–752.
    1. Tokudome T, Horio T, Yoshihara F, et al. Direct effects of high glucose and insulin on protein synthesis in cultured cardiac myocytes and DNA and collagen synthesis in cardiac fibroblasts. Metabolism. 2004;53:710–715.
    1. Sasaoka T, Ishiki M, Sawa T, et al. Comparison of the insulin and insulin-like growth factor 1 mitogenic intracellular signaling pathways. Endocrinology. 1996;137:4427–4434.
    1. Wang L, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes. 2004;53:2735–2740.
    1. Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000;105:311–320.
    1. Jiang ZY, Lin YW, Clemont A, et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 1999;104:447–457.
    1. Lazer DF, Wiese RJ, Brady MJ, et al. Mitogen-activated protein kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem. 1995;270:20801–20807.
    1. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293:1673–1677.
    1. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420:333–336.
    1. Lonroth P, Digirolamo M, Krotkiewski M, et al. Insulin binding and responsiveness in fat cells from patients with reduced glucose tolerance and type II diabetes. Diabetes. 1983;32:748–754.
    1. Caro JF, Sinha MK, Raju SM, et al. Insulin receptor kinase in human skeletal muscle from obese subjects with and without non-insulin dependent diabetes. J Clin Invest. 1987;79:1330–1337.
    1. Nyomba BL, Ossowski VM, Bogardus C, et al. Insulin-sensitive tyrosine kianse relationship with in vivo insulin action in humans. Am J Physiol. 1990;258:E964–E974.
    1. Freidenberg GR, Reichart D, Olefsky JM, et al. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin dependent diabetes mellitus. Effect of weight loss. J Clin Invest. 1988;82:1398–1406.
    1. Pratipanawatr W, Pratipanawatr T, Cusi K, et al. Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes. 2001;50:2572–2578.
    1. Pendergrass M, Bertoldo A, Bonadonna R, et al. Muscle glucose transport and phosphorylation in type 2 diabetic, obese non-diabetic, and genetically predisposed individuals. Am J Physiol Endocrinol Metab. 2007;292:E92–E100.
    1. Pendergrass M, Koval J, Vogt C, et al. Insulin-induced hexokinase II expression is reduced in obesity and NIDDM. Diabetes. 1998;47:387–394.
    1. Kashyap SR, Roman LJ, McLain J, et al. Insulin resistance is associated with impaired nitric oxide synthase (NOS) activity in skeletal muscle of type 2 diabetic subjects. J Clin Endocrinol Metab. 2005;90:1100–1105.
    1. Kashyap S, Lara A, Zhang R, et al. Insulin reduces plasma arginase activity in type 2 diabetes patients. Diabetes Care. 2008;31:134–139.
    1. Baron AD. Hemodynamic actions of insulin. Am J Physiol. 1994;267:E187–E202.
    1. Cabellero AE, Arora S, Saouaf R, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes. 1999;48:1856–1862.
    1. Cerosismo E, DeFronzo RA. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diab Metab Res Rev. 2006;22:423–436.
    1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.
    1. Hsueh WA, Lyon CJ, Quiñones MJ. Insulin resistance and the endothelium. Am J Med. 2004;117:109–117.
    1. Behrendt D, Ganz P. Endothelial function. From vascular biology to clinical applications. Am J Cardiol. 2002;21:40L–48L.
    1. Draznin B. Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha: the two sides of a coin. Diabetes. 2006;55:2392–2397.
    1. Aguirre V, Werner Ed, Giraud J, et al. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002;277:1531–1537.
    1. Liu YF, Herschkovitz A, Boura-Halfon S, et al. Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance. Mol Cell Biol. 2004;24:9668–9681.
    1. Sasaoka T, Rose DW, Jhun BH, et al. Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin-like growth factor-1, and epidermal growth factor. J Biol Chem. 1994;269:13689–13694.
    1. Hsueh WA, Law RE. Insulin signaling in the arterial wall. Am J Cardiol. 1999;84:21J–24J.
    1. Lettner JW, Kline T, Carel K, et al. Hyperinsulinemia potentiates activation of p21 Ras by growth factors. Endocrinol. 1997;138:2211–2214.
    1. Golovchenko I, Goalstone ML, Watson P, et al. Hyperinsulnemia enhances transcriptional activity of nuclear factor-kB induced by angiotensin II, hyperglycemia, and advanced glycosylation end products in vascular smooth muscle cells. Circ Res. 2000;87:746–762.
    1. Hajra L, Evans AI, Chen M, et al. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. PNAS. 2000;97:9052–9057.
    1. de Winther MP, Kanters E, Kraal G, et al. Nuclear factor kappaB signaling in atherogenesis. Art Throm Vasc Biol. 2005;25:904–914.
    1. Gao Z, Hwang D, Bataille F, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem. 2002;277:48115–48121.
    1. Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP, et al. Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. J Clin Invest. 1997;100:2158–2169.
    1. Uusitupa MI, Niskanen LK, Siitonen O, et al. Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia. 1993;36:1175–1184.
    1. Miyazaki Y, He H, Mandarino LJ, et al. Rosiglitazone improves downstream insulin-receptor signaling in type 2 diabetic patients. Diabetes. 2003;52:1943–1950.
    1. Bajaj M, Baig R, Suraamornkul S et al. (2010) Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab doi:10.1210/jc.2009-0911
    1. Vinik AI, Stansberry KB, Barlow PM. Rosiglitazone treatment increased nitric oxide production in human peripheral skin: a controlled clinical trial in patients with type 2 diabetes mellitus. J Diab Comp. 2003;17:279–285.
    1. Natali A, Baldeweg S, Toschi E, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004;27:1349–1357.
    1. Pistrosch F, Passauer J, Fischer S, et al. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control. Diabetes Care. 2004;27:484–490.
    1. Bays H, Mandarino L, DeFronzo RA. Role of the adipocytes, FFA, and ectopic fat in the pathogenesis of type 2 diabetes mellitus: PPAR agonists provide a rational therapeutic approach. J Clin Endocrinol Metab. 2004;89:463–478.
    1. Unger RH. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol Metab. 2003;14:398–403.
    1. Kashyap S, Belfort R, Berria R, et al. Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes. Am J Physiol Endocrinol Metab. 2004;287:E537–E546.
    1. Richardson DK, Kashyap S, Bajaj M, et al. Lipid infusion induces an inflammatory/fibrotic response and decreases expression of nuclear encoded mitochondrial genes in human skeletal muscle. J Biol Chem. 2005;280:10290–10297.
    1. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103:253–259.
    1. Kashyap S, Belfort R, Gastaldelli A, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in non-diabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003;52:2461–2474.
    1. Belfort R, Mandarino L, Kashyap S, et al. Dose response effect of elevated plasma FFA on insulin signaling. Diabetes. 2005;54:1640–1648.
    1. Mayerson AB, Hundal RS, Dufour S, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes. 2002;51:797–802.
    1. Belfort R, Harrison SA, Brown K, et al. A placebo controlled trial of pioglitazone in patients with non-alcoholic steatohepatitis. NEJM. 2006;355:2297–2307.
    1. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87:2784–2791.
    1. Bajaj M, Suraamornkul S, Pratipanawatr T, et al. Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes mellitus. Diabetes. 2003;52:1364–1370.
    1. Griffin ME, Marcucci MJ, Cline GW, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999;48:1270–1274.
    1. Bajaj M, Suraamornkul S, Romanelli A, et al. Effect of sustained reduction in plasma free fatty acid concentration on intramuscular long chain-fatty acyl-CoAs and insulin action in patients with type 2 diabetic patients. Diabetes. 2005;54:3148–3153.
    1. Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. PNAS. 2001;98:7522–7527.
    1. Gao Z, Zhang X, Zuberi A, et al. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol. 2004;18:2024–2034.
    1. Morino K, Neschen S, Bliz S, et al. Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle. Diabetes. 2008;57:2644–2651.
    1. Yu CL, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 2-kinase activity in muscle. J Biol Chem. 2002;277:50230–50236.
    1. Itani SI, Ruderman NB, Schmieder F, et al. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and I kappa B-alpha. Diabetes. 2002;51:2005–2011.
    1. Heydrick SJ, Ruderman NB, Kurowski TG, et al. Enhanced stimulation of diacylglycerol and lipid synthesis by insulin in denervated muscle. Altered protein kinase C activity and possible link to insulin resistance. Diabetes. 1991;40:1707–1711.
    1. Adams JM, Pratipanawatr T, Berria R, et al. Ceramide content is increased in skeletal muscle from obese insulin resistant humans. Diabetes. 2004;53:25–31.
    1. Haus JM, Kashyap SR, Kasumov T, et al. Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes. 2009;58:337–343.
    1. Evans JL, Goldfine ID, Maddux BA, et al. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev. 2002;23:599–622.
    1. Garg R, Tripathy D, Dandona P. Insulin resistance as a proinflammatory state: mechanisms, mediators, and therapeutic interventions. Curr Drug Targets. 2003;4:487–492.
    1. Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;41:1241–1248.
    1. Ghanim H, Garg R, Aljada A, et al. Suppression of nuclear factor-kappa β by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. J Clin Endocrinol Metab. 2001;86:1306–1312.
    1. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor to chronic inflammatory diseases. N Engl J Med. 1997;336:1066–1071.
    1. Yamamoto Y, Gaynor RB. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci. 2004;29:72–79.
    1. De Alvaro C, Teruel T, Hernandez R, et al. Tumor necrosis factor alpha produces insulin resistance in skeletal muscle by activation of inhibitor kappaB kinase in a p38 MAPK-dependent manner. J Biol Chem. 2004;279:17070–17078.
    1. Sriwijitkamol A, Christ-Roberts C, Berria R, et al. Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. Diabetes. 2006;55:760–767.
    1. Sinha S, Perdomo G, Brown JF, et al. Fatty acid-induced insulin resistance in L6 myotubes is prevented by inhibition of activation and nuclear localization of nuclear factor kappa B. J Biol Chem. 2004;279:41294–41301.
    1. Bhatt BA, Dube JJ, Dedousis N, et al. Diet-induced obesity and acute hyperlipidemia reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type dependent manner. Am J Physiol Regu Integr Comp Physiol. 2006;290:R233–R240.
    1. Reyna SM, Ghosh S, Tantiwong P, et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes. 2008;57:2595–2602.
    1. Perbal B. CCN proteins: multifunctional signaling regulators. Lancet. 2004;363:62–64.
    1. Cicha I, Yilmaz A, Klein M, et al. Connective tissue growth factor is overexpressed in complicated atherosclerotic plaques and induces mononuclear cell chemotaxis in vitro. Art Throm Vas Biol. 2005;25:1008–1013.
    1. Steinberg HO, Chaker H, Leaming R, et al. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;97:2601–2610.
    1. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230–1239.
    1. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785–1788.
    1. Lapidus L, Bengtsson C, Larsson B, et al. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. BMJ. 1984;289:1257–1261.
    1. Despre JP, Moorjani S, Lupien PJ, et al. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arterioscler Thromb Vas Biol. 1990;10:497–511.
    1. Anderson JW, Kendall CW, Jenkins DJ. Importance of weight management in type 2 diabetes: review with meta-analysis of clinical studies. J Am Coll Nutr. 2003;22:331–339.
    1. Triplitt C, DeFronzo RA. Exenatide: first in class incretin mimetic for the treatment of type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2006;1:329–341.
    1. Miyazaki Y, Glass L, Triplitt C, et al. Effect of rosiglitazone on glucose and free fatty acid metabolism in type 2 diabetic patients. Diabetologia. 2001;44:2210–2219.
    1. Miyazaki Y, Mahankali A, Matsuda M, et al. Improved glycemic control and enhanced insulin sensitivity in liver and muscle in type 2 diabetic subjects treated with pioglitazone. Diabetes Care. 2001;24:710–719.
    1. Gastaldelli A, Miyazaki Y, Mahankali A, et al. The effect of pioglitazone on the liver. Diabetes Care. 2006;29:2275–2281.
    1. Coletta DK, Sriwijitkamol A, Wajcberg E, et al. Pioglitazone stimulates AMPK signaling and increases the expression of genes involved in adiponectin signaling. Mitochondrial function and fat oxidation in human skeletal muscle in vivo. Diabetologia. 2009;52:723–732.
    1. Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300:1140–1142.
    1. Petersen KF, Dufour S, Shulman GI. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Medicine. 2005;2:879–884.
    1. Phielix E, Schrauwen-Hinderling VB, Mensink M, et al. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes. 2008;57:2943–2949.
    1. Abdul-Ghani MA, DeFronzo RA. Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus. Curr Diab Rep. 2008;8:173–178.
    1. Abdul-Ghani MA, Jani R, Chavez A, et al. Mitochondrial reactive oxygen species generation in obese non-diabetic and type 2 diabetic participants. Diabetologia. 2009;52:574–582.
    1. Abdul-Ghani MA, Muller FL, Liu Y, et al. Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance. Am J Physiol. 2008;295:E678–E685.
    1. 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 USA. 2003;100:8466–8471.
    1. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24:78–90.
    1. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–946.
    1. Yamauchi T, Kadowaki T. Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obesity. 2008;32:S13–S18.
    1. Kubota N, Terauchi Y, Yamauchi T, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. 2002;277:25863–25866.
    1. Civitarese AE, Jenkinson CP, Richardson D, et al. Adiponectin receptor gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without family history of type 2 diabetes. Diabetologia. 2004;47:816–820.
    1. Civitarese AE, Ukropcova B, Carling S, et al. Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab. 2006;4:74–87.
    1. Miyazaki Y, Glass L, Triplitt C, et al. Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2002;46:E1135–E1143.
    1. Kelly JE, Hans TS, Walsh K, et al. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care. 1999;22:288–293.
    1. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–1184.
    1. Gastaldelli A, Ferrannini E, Miyazaki Y, et al. Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Phyisol Endocrinol Metab. 2007;292:E871–E883.
    1. Moibi JA, Gupta D, Jetton TL, et al. Peroxisome proliferator-activated receptor-gamma regulates expression of PDX-1 and NKX6.1 in INS-1 cells. Diabetes. 2007;56:88–95.
    1. Matsui J, Terauchi Y, Kubota N, et al. Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-gamma-deficient mice on a high-fat diet. Diabetes. 2004;53:2844–2854.
    1. Del Prato S, Marchetti P. Targeting insulin resistance and beta-cell dysfunction: the role of thiazolidinediones. Diabetes Tech Thera. 2004;6:719–731.
    1. Lupi R, del Guerra S, Marselli L, et al. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPARgamma2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab. 2004;286:E560–E567.
    1. Sharma S, Adrogue JV, Golfman L, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 2004;18:1692–1700.
    1. Kankaanpaa M, Lehto HR, Parkka JP, et al. Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J Clin Endocrinol Metab. 2006;91:4689–4695.
    1. McGavock JM, Lingvay I, Zib I, et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation. 2007;116:1170–1175.
    1. Zib I, Jacob AN, Lingvay I, et al. Effect of pioglitazone therapy on myocardial and hepatic steatosis in insulin-treated patients with type 2 diabetes. J Investig Med. 2007;55:230–236.
    1. Deeg MA, Buse JB, Goldberg RB, et al. Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2007;30:2458–2464.
    1. Chiquette E, Ramirez G, DeFronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med. 2004;164:2097–2104.
    1. Miyazaki M, de Filippis E, Bajaj M, et al. Predictors of improved glycaemic control with rosiglitazone therapy in type 2 diabetic patients: a practical approach for the primary care physician. Br J Diabetes Vasc Dis. 2005;5:28–35.
    1. Dormandy JA, Charbonnel B, Eckland DJ, et al. Proactive investigators: secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial in macroVascular Events): a randomized controlled trial. Lancet. 2005;266:1279–1289.
    1. Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–1188.
    1. Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2: a randomized trial. JAMA. 2006;296:2572–2581.
    1. Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the Periscope randomized controlled trial. JAMA. 2008;299:1561–1573.
    1. Sarruf DA, Yu F, Nguyen HT, et al. Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology. 2008;150:707–712.

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