Insulin Resistance the Link between T2DM and CVD: Basic Mechanisms and Clinical Implications

Author(s): Muhammad A. Abdul-Ghani*, Amin Jayyousi, Ralph A. DeFronzo, Nidal Asaad, Jassim Al-Suwaidi.

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Insulin resistance (IR) is a cardinal feature of type 2 diabetes mellitus (T2DM). It also is associated with multiple metabolic abnormalities which are known cardiovascular disease (CVD) risk factors. Thus, IR not only contributes to the development of hyperglycemia in T2DM patients, but also to the elevated CVD risk. Improving insulin sensitivity is anticipated to both lower the plasma glucose concentration and decrease CVD risk in T2DM patients, independent of glucose control. We review the molecular mechanisms and metabolic consequences of IR in T2DM patients and discuss the importance of addressing IR in the management of T2DM.

Keywords: Insulin resistance, type 2 diabetes, cardiovascular disease, insulin sensitizers, HDL, LDL.

[1]
DeFronzo RA. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58: 773-95.
[2]
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: Metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 1997; 5: 177-269.
[3]
DeFronzo RA. The triumvirate: Beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667-87.
[4]
Reaven GM Insulin resistance/compensatory hyperinsulinemia, essential hypertension, and cardiovascular disease. J Clin Endocrinol Metab 2003; 88: 2399-403.
[5]
Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607.
[6]
DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173-94.
[7]
DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: The missing links. Diabetologia 2010; 53: 1270-87.
[8]
Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: The San Antonio heart study. Diabetes Care 2002; 25: 1177-84.
[9]
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: 318-24.
[10]
Stern MP. Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes 1995; 44: 369-74.
[11]
Groop LC, Bonadonna RC, Del Prato S, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 1989; 84: 205-13.
[12]
DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent diabetes mellitus. J Clin Invest 1985; 76: 149-55.
[13]
DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: Contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989; 38: 387-95.
[14]
Cherrington AD. Control of glucose uptake and release by the liver in vivo. Diabetes 1999; 48: 1198-214.
[15]
Matsuda M, DeFronzo RA, Glass L, et al. Glucagon dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic patients and normal individuals. Metabolism 2002; 51: 1111-9.
[16]
Ferrannini E, Bjorkman O, Reichard GA Jr, et al. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes 1985; 34: 580-8.
[17]
Groop LC, Saloranta C, Shank M, Bonadonna RC, Ferrannini E, DeFronzo RA. The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1991; 72: 96-107.
[18]
Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: Peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004; 89: 463-78.
[19]
Bajaj M, Suraamornkul S, Romanelli A, et al. Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty acyl-Coas and insulin action in type 2 diabetic patients. Diabetes 2005; 54: 3148-53.
[20]
Daniele G, Eldor R, Merovci A, et al. Chronic reduction of plasma FFA improves mitochondrial function and whole body insulin sensitivity in obese and type 2 diabetic individuals. Diabetes 2014; 63: 2812-20.
[21]
Belfort R, Mandarino L, Kashyap S, et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 2005; 54: 1640-8.
[22]
Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799-806.
[23]
Kanzaki M. Insulin receptor signals regulating GLUT4 translocation and actin dynamics. Endocr J 2006; 53: 267-93.
[24]
Whitehead JP, Clark SF, Urso B, James DE. Signaling through the insulin receptor. Curr Opin Cell Biol 2000; 12: 222-8.
[25]
Caro JF, Ittoop O, Pories WJ, Meelheim D, Flickinger EG, Thomas F. Studies on the mechanism of insulin resistance in the liver from humans with non-insulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest 1986; 78: 249-58.
[26]
Ruderman N, Kapeller R, White MF, Cantley LC. Activation of phosphatidylinositol-3-kinase by insulin. Proc Natl Acad Sci USA 1990; 87: 1411-5.
[27]
Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest 1994; 94: 2511-5.
[28]
Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: A novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94: 1172-9.
[29]
Kuboki K, Jiang ZY, Takahara N, et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo. Circulation 2000; 101: 676-81.
[30]
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: 1539-45.
[31]
Du XI, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001; 108: 1341-8.
[32]
Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is independent of Ca3 but requires phosphorylation by Akt at Ser (1179). J Biol Chem 2001; 276: 30392-8.
[33]
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: 746-52.
[34]
Pepine CJ. The impact of nitric oxide in cardiovascular medicine: Untapped potential utility. Am J Med 2009; 122: 1-5.
[35]
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: 4427-34.
[36]
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: 710-5.
[37]
Ruiz-Torres A, Melon J, Munoz FJ. Insulin stimulates collagen synthesis in vascular smooth muscle cells from elderly patients. Gerontology 1998; 44: 144-8.
[38]
King GL, Goodman D, Buzney S, Moses A, Kahn CR. 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: 1028-36.
[39]
Low CC, Wang L, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes 2004; 53: 2735-40.
[40]
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: 311-20.
[41]
Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999; 103: 931-43.
[42]
Nolan JJ, Friedenberg G, Henry R, Reichart D, Olefsky JM. Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes and obesity. J Clin Endocrinol Metab 1994; 78: 471-7.
[43]
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signaling pathways: Insights into insulin action. Nat Rev Mol Cell Biol 2006; 7: 85-96.
[44]
Xi XP, Graf K, Goetze S, Hsueh WA, Law RE. Inhibition of MAP kinase blocks insulin-mediated DNA synthesis and transcriptional activation of c-fos by Elk-1 in vascular smooth muscle cells. FEBS Lett 1977; 417: 283-6.
[45]
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: 447-57.
[46]
Diamond MP, Thornton K, Connolly-Diamond M, Sherwin RS, DeFronzo RA. Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance. J Soc Gynecol Investig 1995; 2: 708-15.
[47]
Stern SE, Williams K, Ferrannini E, DeFronzo RA, Bogardus C, Stern MP. Identification of individuals with insulin resistance using routine clinical measurements. Diabetes 2005; 54: 333-9.
[48]
Olefsky JM, Farquhar JW, Reaven GM. Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med 1974; 57: 551-60.
[49]
Rabøl R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci USA 2011; 108: 13705-9.
[50]
Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995; 75: 473-86.
[51]
Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014; 384: 626-35.
[52]
Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: A scientific statement from the American heart association. Circulation 2011; 123: 2292-33.
[53]
Boullart AC. de GJ, Stalenhoef AF. Serum triglycerides and risk of cardiovascular disease. Biochim Biophys Acta 2012; 1821: 867-75.
[54]
Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet 2014; 384: 618-25.
[55]
Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350-7.
[56]
Solini A, DeFronzo RA. Insulin resistance, hypertension, and cellular ion transport systems. Acta Diabetologica 1992; 29: 196-200.
[57]
DeFronzo RA, Ferrannini E, Hendler R, Wahren J, Felig P. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci 1978; 75: 5173-7.
[58]
Freidenberg GR, Reichart D, Olefsky JM, Henry RR. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin dependent diabetes mellitus. Effect of weight loss. J Clin Invest 1988; 82: 1398-406.
[59]
Wilding JP. The importance of weight management in type 2 diabetes mellitus. Int J Clin Pract 2014; 68: 682-91.
[60]
Feldstein AC, Nichols GA, Smith DH. Weight change in diabetes and glycemic and blood pressure control. Diabetes Care 2008; 31: 1960-5.
[61]
Pastors JG, Warshaw H, Daly A. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care 2002; 25: 608-13.
[62]
UK Prospective Diabetes Study (UKPDS) Group. UK Prospective Diabetes Study 7: Response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients. Metabolism 1990; 39: 905-12.
[63]
Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: Normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506-14.
[64]
Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012; 366: 1577-85.
[65]
Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012; 366: 1567-76.
[66]
Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: A new perspective for an old disease. Ann Surg 2004; 239: 1-11.
[67]
DeFronzo RA, Bode BW, Kushner RF, et al. Effects of liraglutide 3.0 mg cessation on efficacy and safety/tolerability following a 56-week randomized treatment period in obese/overweight adults with type 2 diabetes (SCALETM Diabetes). Diabetes 2014; 63(Suppl. 1): A518.
[68]
Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): A randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012; 95: 297-308.
[69]
Wing RR, Bahnson JL, Bray GA, et al. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the Look AHEAD trial. Arch Intern Med 2010; 170: 1566-75.
[70]
Rock CL, Flatt SW, Pakiz B, et al. Weight loss, glycemic control, and cardiovascular disease risk factors in response to differential diet composition in a weight loss program in type 2 diabetes: A randomized controlled trial. Diabetes Care 2014; 37: 1573-80.
[71]
Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145-54.
[72]
Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight-loss maintenance: A meta-analysis of US studies. Am J Clin Nutr 2001; 74: 579-84.
[73]
Dansinger ML, Tatsioni A, Wong JB, Chung M, Balk EM. Meta-analysis: The effect of dietary counseling for weight loss. Ann Intern Med 2007; 147: 41-50.
[74]
Gregg EW, Jakicic JM, Blackburn G, et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: A post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2016; 4: 913-21.
[75]
Tuomilehto H, Seppä J, Uusitupa M. Obesity and obstructive sleep apnea--clinical significance of weight loss. Sleep Med Rev 2013; 17: 321-9.
[76]
DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care 2010; 33: 951-7.
[77]
Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 2011; 32: 515-31.
[78]
Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014; 124: 509-14.
[79]
Daniele G, Xiong J, Merovci A, et al. Dapagliflozin enhances fat oxidation and ketone production in type 2 diabetes patients. Diabetes Care 2016; 39: 2036-41.
[80]
Bunck MC, Diamant M, Corner A, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: A randomized, controlled trial. Diabetes Care 2009; 32: 762-88.
[81]
Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes 2012; 36: 843-54.
[82]
Rossetti L, Giaccari A, DeFronzo RA. Glucotoxicity. Diabetes Care Rev 1990; 13: 610-30.
[83]
Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucsoe cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014; 124: 499-508.
[84]
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375: 311-22.
[85]
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375: 1834-44.
[86]
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373: 2117-28.
[87]
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 17; 377(7): 644-57..
[88]
Abdul-Ghani M, DeFronzo R, Del Prato S, Chilton R, Ryder REJ. Cardiovascular disease and T2DM: Has the dawn of a new era arrived? Diabetes Care 2017; 40: 813-20.
[89]
Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: Lessons learned from the empirial outcome Trial. Diabetes Care 2016; 39: 717-25.
[90]
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333: 541-9.
[91]
Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996; 81: 4059-67.
[92]
DeFronzo RA, Buse JB, Kim T, Skare S, Barron A, Fineman M. Dissociation between metformin plasma exposure and its glucose-lowering effect: A novel gut-mediated mechanism of action. Diabetes 2013; 62(Suppl. 1): A281.
[93]
Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510: 542-6.
[94]
Cusi K, DeFronzo RA. Metformin: A review of its metabolic effects. Diabetes Rev 1998; 6: 89-131.
[95]
Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ 2000; 321: 405-12.
[96]
Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169: 616-25.
[97]
Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013; 36: 1304-11.
[98]
Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43.
[99]
Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: A meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 2017; 60: 1620-9.
[100]
Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev 2017; 40: 31-44.
[101]
Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351: 1106-18.
[102]
Bajaj M, Baig R, Suraamornkul S, et al. RA Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010; 95: 1916-23.
[103]
Miyazaki Y, He H, Mandarino LJ, DeFronzo RA. Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Diabetes 2003; 52: 1943-50.
[104]
Coletta DK, Sriwijitkamol A, Wajcberg E, et al. Pioglitazone stimulates AMP-activated protein kinase signaling and increases the expression of genes involved in adiponectin signaling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: A randomised trial. Diabetologia 2009; 52: 723-32.
[105]
Colca JR, McDonald WG, Kletzien RF. Mitochondrial target of thiazolidinediones. Diabetes Obes Metab 2014; 16: 1048-54.
[106]
Shannon CE, Daniele G, Galindo C, Abdul-Ghani MA, DeFronzo RA, Norton L. Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes. FEBS J 2017; 284: 451-65.
[107]
Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Physiol Endocrinol Metab 2007; 292: 871-83.
[108]
Miyazaki Y, DeFronzo RA. Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab 2008; 10: 1204-11.
[109]
Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2004; 89: 4312-9.
[110]
Miyazaki Y, Mahankali A, Matsuda M, et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001; 24: 710-9.
[111]
Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297-307.
[112]
Glass LC, Cusi K, Berria R, et al. Pioglitazone improvement of fasting and postprandial hyperglycaemia in Mexican-American patients with Type 2 diabetes: A double tracer OGTT study. Clin Endocrinol (Oxf) 2010; 73: 339-45.
[113]
Dormandy JA, Charbonnel B, Eckland DJ, et al. 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; 366: 1279-89.
[114]
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: 2784-91.
[115]
Goldberg RB, Kendall DM, Deeg MA, et al. GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005; 28: 1547-54.
[116]
Straznicky NE, Grima MT, Sari CI, et al. A randomised controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome. J Clin Endocrinol Metab 2014; 99: 1701-7.
[117]
Rizzo M, Avogaro A, Montalto G, Rizvi AA. Non-glycemic effects of pioglitazone and incretin-based therapies. Expert Opin Ther Targets 2013; 17: 739-42.
[118]
Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: A randomized trial. JAMA 2006; 296: 2572-81.
[119]
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: 1561-73.
[120]
Saremi A, Schwenke DC, Buchanan TA, et al. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2013; 33: 393-9.
[121]
Kernan WN, Viscoli CM, Furie KL, et al. IRIS Trial investigators. pioglitazone after ischemic stroke or transient ischemic attack. N Engl Med 2016; 374: 1321-31.
[122]
Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: An intent-to-treat analysis of the DPP/DPPOS. Diabetes Care 2012; 35: 723-30.
[123]
Erdmann E, Song E, Spanheimer R, van Troostenburg de Bruyn AR, Perez A. Observational follow-up of the Proactive study: A 6-year update. Diabetes Obes Metab 2014; 16: 63-74.
[124]
Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 2015; 314: 265-77.
[125]
Filipova E, Uzunova K, Kalinov K, Vekov T. Pioglitazone and the risk of bladder cancer: A meta-analysis. Diabetes Ther 2017; 8: 705-26.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 2
Year: 2019
Page: [153 - 163]
Pages: 11
DOI: 10.2174/1570161115666171010115119
Price: $58

Article Metrics

PDF: 38
HTML: 1