Insulin resistance: Pathophysiology and rationale for treatment

Annals of Nutrition and Metabolism

Volumn 58, Issue 1, 2011, Pages 25-36

  Muntoni, Sergio ^a,b   Muntoni, Sandro ^a  

^a UNIVERSITY OF CAGLIARI   (Italy)

^b NONE   (Italy)

Author keywords

Diabetes; Insulin; Insulin resistance; Metabolic syndrome; Metformin; Obesity

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ALPHA GLUCOSIDASE INHIBITOR; AMYLIN DERIVATIVE; ANTIINFLAMMATORY AGENT; BIGUANIDE DERIVATIVE; CYCLOOXYGENASE 2 INHIBITOR; DIPEPTIDYL PEPTIDASE IV INHIBITOR; ESTROGEN; GESTAGEN; GLUCAGON LIKE PEPTIDE 1; HEPARIN; INSULIN; INSULIN GLARGINE; METFORMIN; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PIOGLITAZONE; ROSIGLITAZONE; SULFONYLUREA; TRISTEARIN;

ATHEROSCLEROSIS; BETA CHAIN; ENZYME ACTIVATION; FRACTURE; HEART FAILURE; HEART INFARCTION; HUMAN; HYPERINSULINEMIA; INSULIN RESISTANCE; INSULIN TREATMENT; LACTIC ACIDOSIS; LIFESTYLE; METABOLIC DISORDER; METABOLISM; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RECEPTOR BINDING; REVIEW; STIMULATION;

ADIPOSE TISSUE; ANIMALS; DIABETES MELLITUS, TYPE 2; FATTY ACIDS, NONESTERIFIED; HUMANS; HYPERINSULINISM; INSULIN; INSULIN RESISTANCE; METFORMIN; MITOGENS; OBESITY; PHOSPHATIDYLINOSITOL 3-KINASE;

EID: 79551644176     PISSN: 02506807     EISSN: None     Source Type: Journal    
DOI: 10.1159/000323395     Document Type: Review

References (158)

1. Bloomgarden ZT: Insulin resistance concepts. Diabetes Care 2007; 30: 1320-1326. (Pubitemid 46684672)
2. 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.
3. Reaven GM: The metabolic syndrome: is this diagnosis necessary? Am J Clin Nutr 2006; 83: 1237-1247. (Pubitemid 44713049)
4. Haffner S: Diabetes and the metabolic syndrome - when is it best to intervene to prevent? Atheroscler Suppl 2006; 3: 3-10.
5. Morino K, Petersen KF, Shulman GI: Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006; 55(suppl 2):S9-15. (Pubitemid 44927027)
6. Roden M: Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes. Int J Obes 2005; 29(suppl 2):S111-1115.
7. Lettner A, Roden M: Ectopic fat and insulin resistance. Curr Diabetes Rep 2008; 8: 185-191.
8. Boden G. Ceramide: a contributor to insulin resistance or an innocent bystander? Diabetologia 2008; 51: 1095-1096.
9. Paz K, Hemi R, LeRoith D, Karasik A, Eihanani E, Kanety H, Zick Y: A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibit their binding to the iuxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 1997; 272: 29911-29918.
10. Dresner A, Laurent AD, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Anderson DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI: Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999; 103: 253-259. (Pubitemid 29053143)
11. Maassen JA, Romijn JA, Heine RJ: Fatty acidinduced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesityassociated type 2 diabetes mellitus. Diabetologia 2007; 50: 2036-2041. (Pubitemid 47373858)
12. Abdul-Ghani MA, DeFronzo RA: Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus. Curr Diabetes Rep 2008; 8: 173-178.
13. McGarry JD: Banting Lecture 2001:Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2001; 51: 7-18.
14. Wellen KE, Hotamisligil GS: Inflammation, stress and diabetes. J Clin Invest 2005; 115: 1111-1119.
15. Kelley DE, Goodpaster B, Wing RR, Simoneau JA: Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity and weight loss. Am J Physiol 1999; 277:E1130-E1141. (Pubitemid 30046009)
16. Yki-Järvinen H, Puhakainen I, Saloranta C, Groop L, Taskinen M-R: Demonstration of a novel feedback mechanism between FFA oxidation from intracellular and intravascular sources. Am J Physiol 1991; 23:E680-E689.
17. Nikkilä EA, Pikälisto O: Regulation of adipose tissue lipoprotein lipase synthesis by intracellular FFA. Life Sci 1968; 7: 1303-1309.
18. Randle PJ, Garland PB, Hales CN, Newsholme EA: The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;i:785-789.
19. Sidossis LS, Stuart CA, Shulman GI, Lopaschuk GD, Wolff RR: Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria. J Clin Invest 1996; 98: 2244-2250. (Pubitemid 26394197)
20. Muoio DM, Newgard CB: Fatty acid oxidation and insulin action. When less is more. Diabetes 2008; 57: 1455-1456.
21. Zhou G, Myers R, Li Y, Chen Y, Shen Y, Fenyk-Mewlody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshmen MF, Goodyear LJ, Moeller DF: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167-1174. (Pubitemid 32995375)
22. Kim J-Y, Hicknert RC, Cortright RL, Dohm GL, Houmard JA: Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab 2000; 279:E1039-E1044.
23. Kelley DE, Jing H, Menshikova E, Ritov B: Dysfunction of mitochondria in human skeletal muscle. Diabetes 2002; 51: 2944-2950.
24. Blaak EE: Fatty acid metabolism in obesity and type 2 diabetes mellitus. Proc Nutr Soc 2003; 62: 753-760. (Pubitemid 37152861)
25. Goa KL, Brodgen RN: L-Carnitine. Drugs 1987; 34: 1-24.
26. Kerner J, Hoppel C: Fatty acid import into mitochondria. Biochim Biophys Acta 2000; 1846: 1-17. (Pubitemid 30336788)
27. Fallucca F, Fallucca S: Carnitina e diabete. Dialogs 2008; 1: 16-19.
28. Mingrone G: Carnitine in type 2 diabetes. Ann NY Acad Sci 2004; 1033: 99-107. (Pubitemid 39656742)
29. Power RA, Hulver MV, Zhang J-Y, Dubois J, Marchand RM, Ilkayeva O, Muoio DM, Mynatt RL: Carnitine revisited: potential use as adjunctive treatment in diabetes. Diabetologia 2007; 50: 824-832. (Pubitemid 46355838)
30. Muntoni S, Tagliamonte P, Sirigu F, Corsini GU: Demonstration of the mechanism of action of biguanides. Acta Diabetol Lat 1973; 10: 1300-1307.
31. Muntoni S: Inhibition of fatty acid oxidation by biguanides: Implication for metabolic physiopathology. Adv Lipid Res 1974; 12: 311-377.
32. Golay A, Felber JP, Jequier E, DeFronzo RA, Ferrannini E: Metabolic basis of obesity and non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1988; 4: 727-747. (Pubitemid 19019240)
33. Riccio A, Del Prato S, Vigili de Kreutzenberg S, Tiengo A: Glucose and lipid metabolism in non-insulin-dependent diabetes: effect of metformin. Diabetes Metab 1991; 17: 180-184.
34. Perriello G, Misericordia P, Volpi E, Cantucci A, Cantucci C, Ferrannini E, Ventura MM, Santeusanio F, Brunetti P, Bolli GB: Acute antihyperglycaemic mechanism of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 1994; 43: 920-928. (Pubitemid 24196426)
35. Kim JK, Wi JK, Young JH: Plasma free fatty acids decrease insulin-stimulated skeletal muscle glucose uptake by suppressing glycolysis in conscious rat. Diabetes 1996; 45: 394-395.
36. Boden G: Fatty acids and insulin resistance. Diabetes Care 1996; 19: 394-395. (Pubitemid 26115469)
37. Patanè G, Piro S, Rabuazzo AM, Anello M, Vigneri R, Purrello P: Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose. A direct metformin effect on pancreatic β-cells. Diabetes 2000; 49: 735-740. (Pubitemid 30339988)
38. Shulman GI: Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106: 171-176. (Pubitemid 30483118)
39. Bays H, Mandarino L, DeFronzo RA: Role of adipocyte, free fatty acids and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferators-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004; 89: 463-478. (Pubitemid 38269844)
40. Guo Z: Intramyocellular lipid kinetics and insulin resistance. Lipids Health Dis 2007; 6: 18.
41. Szendroedi J, Roden M: Mitochondrial fitness and insulin sensitivity in humans. Diabetologia 2008; 51: 2155-2167.
42. Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ: Insulin resistance differentially affects PI 3-K and MAPkinase-mediated signalling in human muscle. J Clin Invest 2000; 105: 311-320. (Pubitemid 30094451)
43. Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, Johansen M, Kucik DF, Quon MJ, Draznin B: Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 2002; 277: 1794-1799. (Pubitemid 34968751)
44. Wang CCL, Goalstone ML, Draznin B: Molecular mechanism of insulin resistance that impact cardiovascular biology. Diabetes 2004; 53: 2735-2740. (Pubitemid 39425897)
45. Reaven GM: Banting Lecture 1988:Role of insulin resistance in human disease: Diabetes 1988; 37: 1595-1607. (Pubitemid 19004941)
46. Muntoni S, Muntoni S, Draznin B: Effects of chronic hyperinsulinemia in insulin-resistant patients. Curr Diabetes Rep 2008; 8: 233-238.
47. DeFronzo RA, Bonadonna RC, Ferrannini E: Pathogenesis of NIDDM: a balanced overview. Diabetes Care 1992; 15: 318-368.
48. Hoffstedt J, Wahrenberg H, Thörne A, Lönnqvist F: The metabolic syndrome is related to β3-adrenorecptor sensitivity in visceral adipose tissue. Diabetologia 1996; 39: 838-844. (Pubitemid 26228114)
49. Laviola L, Perrini S, Cignarelli M, Giorgino R, Giorgino F: Insulin signalling in human visceral and subcutaneous adipose tissue in vivo. Diabetes 2006; 55: 952-961. (Pubitemid 44100169)
50. Ruderman N, Chisol MD, Pi-Sunyer X, Schneider S: The metabolically obese, normal weight individual revisited. Diabetes 1998; 47: 699-713. (Pubitemid 28201798)
51. Bujalska IJ, Kumar S, Stewart PM: Does central obesity reflect 'Cushing disease of the omentum'? Lancet 1997; 349: 1210-1213. (Pubitemid 27190044)
52. Randle PJ: Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 1998; 14: 263-2683.
53. Lewis GF, Steiner G: Acute effect of insulin in the control of VLDL production in humans. Diabetes Care 1996; 19: 390-393.
54. Lewis GF, Uffelman KD, Szeto LW, Steiner G: Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apo B production in normal weight and obese individuals. Diabetes 1993; 42: 833-842. (Pubitemid 23151575)
55. Sniderman AD, Cianflone K: Substrate delivery as a determinant of hepatic apo B secretion. Arterioscl Thromb 1993; 13: 629-636.
56. Taskinen M-R: Diabetic dyslipidemia: from basic research to clinical practice. Diabetologia 2003; 46: 733-749. (Pubitemid 36831401)
57. Postic C, Girard J: The role of lipogenic pathway in the development of hepatic steatosis. Diabetes Metabol 2008; 34: 643-648.
58. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S: Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350-357. (Pubitemid 17118813)
59. Landsberg L: Insulin and hypertension: lessons from obesity. N Engl J Med 1987; 317: 378-379. (Pubitemid 17118816)
60. Ferrannini E, Natali A, Cerri M, Santori D, Palombo C: Hypertension: a metabolic disorder? Diabète Metabol 1989; 15: 284-291. (Pubitemid 20015064)
61. Quinones Galvan A, Natali A, Baldi S, Frascerra S, Sanna G, Ciociaro D, Ferrannini E: Effect of insulin on uric acid excretion in humans. Am J Phisiol Endocrinol Metab 1995; 268:E1-E5.
62. Ma X, Li Z: Pathogenesis of non-alcoholic steatohepatitis (NASH). Chin J Dig Dis 2006; 7: 7-11.
63. Neuschwander-Tetri BA: Evolving pathophysiology concepts in non-alcoholic steatohepatitis. Gastroenterol Rep 2002; 4: 312-336.
64. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P: High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in non-alcoholic steatohepatitis. Hepatology 2001; 34: 738-744. (Pubitemid 32927998)
65. Haussinger D: Liver fibrosis and Na+/H+ exchanger. Gastroenterol 2001; 120: 572-5.
66. Watanabe T, Ashikaga T, Nishizaki M, Yamawake N, Arita M: Association of insulin with QTc dispersion. Lancet 1997; 350: 1821-1822. (Pubitemid 28036522)
67. Juhan-Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PI, Serradimigni A, Collen D: Plasma plasminogen activator inhibitor-1 in angina pectoris. Arteriosclerosis 1989; 9: 326-367.
68. Anfosso F, Chomiki N, Alessi C, Vague P, Juhan-Vague I: Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin. J Clin Invest 1993; 91: 2185-2193. (Pubitemid 23141495)
69. Sharpless JL: Policystic ovary syndrome and the metabolic syndrome. Clin Diabetes 2003; 21: 154-161.
70. Chen J, Muntner P, Hamm L, Jones DW, Batuman V, Fonseca V, Whelrton PK, He J: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004; 140: 167-174.
71. Dandona P, Aljada A, Mohanty P: The antiinflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 2002; 45: 924-930.
72. Dandona P, Aljada A, Mohanty P, Ghanim BS, Bandyopadhyay A, Chaduri A: Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. Diabetes Care 2003; 26: 3310-3314. (Pubitemid 37466892)
73. Madonna R, Pandolfi A, Massaro M, Consoli A, De Caterina R: Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase. Diabetologia 2004; 47: 532-536. (Pubitemid 38491250)
74. Giovannucci E: The role of insulin resistance and hyperinsulinemia in cancer causation. Curr Med Chem 2005; 5: 53-60. (Pubitemid 40246734)
75. Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature 1990; 343: 425-430.
76. Ness GC, Chambers CM: Feed back and hormonal regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. PSEBM 2000; 224: 8-19. (Pubitemid 30230413)
77. Siperstein MD: Role of cholesterogenesis and isoprenoid synthesis in DNA replication and cell growth. J Lipid Res 1984; 25: 1462-1468. (Pubitemid 15169462)
78. Ferrannini E: Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. Endocr Rev 1998; 19: 477-490. (Pubitemid 29116377)
79. Gerich JH: Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus. Mayo Clin Proc 2003; 78: 447-456.
80. Kahn SE, Zraika S, Utzschneider KM, Hull RL: The β cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia 2009; 52: 1003-1012.
81. Bergman RN, Finegood DT, Kahn SE: The evolution of β-cell dysfunction and insulin resistance in type 2 diabetes. Eur J Clin Invest 2002; 32(suppl 3):35-45. (Pubitemid 41704998)
82. DeFronzo RA: Pathogenesis of type 2 diabetes mellitus. Med Clin N Am 2004; 88; 787-935.
83. Diagnosis and classification of diabetes mellitus: Diabetes Care 2008; 31(suppl 1):S62-S67.
84. DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 31: 281-303.
85. Ballani P, Tran MT, Navar MD, Davidson MB: Clinical experience with U-500 regular insulin in obese, markedly insulin resistant type 2 diabetic patients. Diabetes Care 2006; 29: 2504-2505. (Pubitemid 44912260)
86. Muis MJ, Bots ML, Grobbee DE, Stolk RP: Insulin treatment and cardiovascular disease: friend or foe? A point of view. Diabet Med 2004; 22: 118-126. (Pubitemid 40204316)
87. Stettler C, Allemann S, Jüni P, Cull CA, Holman RR, Egger M, Krähenbühl S, Diem P: Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus. Metaanalysis of randomized trials. Am Heart J 2006; 152: 27-38. (Pubitemid 43974725)
88. DeFronzo RA: Is insulin resistance atherogenic? Possible mechanisms. Atheroscler Suppl 2006; 7: 11-15.
89. Garcia MJ, McNamara P, Gordon T, Kannel WB: Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow up study. Diabetes 1974; 23: 105-111.
90. Janka HU, Ziegler AG, Standl E, Mehnert JH: Daily insulin dose as a predictor of macrovascular disease in insulin treated non-insulin-dependent diabetics. Diabète Metabol 1987; 13: 359-364. (Pubitemid 17105099)
91. Kleinman JC, Donahue RP, Harris M, Finucane FF, Madans JH, Brock DB: Mortality among diabetics in a national sample. Am J Epidemiol 1988; 128: 389-401.
92. Nelson RG, Sievers ML, Knowler WC, Swinburn BA, Pettitt DJ, Saad MF, Liebow IM, Howard BV, Bennett PH: Low incidence of coronary heart disease in Pima Indians despite high prevalence of non-insulin-dependent diabetes. Circulation 1990; 81: 987-995. (Pubitemid 20090397)
93. Muggeo M, Verlato G, Bonora E, Bressan F, Girotto S, Corbellino M, Gemma ML, Mughetti P, Zenere M, Cacciatori V, Zoppini G, De Marco R: The Verona diabetes study: a population-based survey on known diabetes mellitus prevalence and 5-year all-cause mortality. Diabetologia 1995; 38: 318-325.
94. Colwell J, Abraira C, Henderson W, Emanuele N, Levin S, Nuttall F, Sawin C, Comstock J, Pacold I, VACSDM Study Group: VA Cooperative Study on glycemic control and complications in type II diabetes (VACSDM): micro and macrovascular events. Diabetologia 1996; 39(suppl 1):A34.
95. Abraira C, Colwell J, Nuttall F, Sawin TC, Henderson W, Comstock JP, Emanuele MV, Levin SR, Pacold L, Lee HS: Cardiovascular events and correlates in the Veteran Affairs Diabetes Feasibility Trial. Veteran Affairs Cooperative Study on glycemic control and complications in type II diabetes. Arch Intern Med 1997; 157: 181-188. (Pubitemid 27058152)
96. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1988; 352: 837-853.
97. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577-1589.
98. Faglia E, Favales F, Quarantiello A, Calia P, Morabito A: Are insulin-treated type 2 diabetic subjects at higher risk for foot ulcers? Diabetes Care 1999; 22: 1379-1380.
99. Bruno G, Merletti F, Boffetta P, Cavallo-Perin P, Bargero G, Gallone G, Pagano G: Impact of glycaemic control, hypertension and insulin treatment on general and cause-specific mortality: an Italian population-based cohort of type II (non-insulindependent) diabetes mellitus. Diabetologia 1999; 42: 297-301. (Pubitemid 29111435)
100. Saito I, Folsom AR, Brancati FL, Duncan BB, Chambles LE, McGovern PG: Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Arteriosclerosis Risk in Community (ARIC) Study. Ann Intern Med 2000; 33: 81-91. (Pubitemid 30490408)
101. Shichiri M, Kishikawa H, Ohkubo Y, Wake N: Optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000; 23(suppl 2):B21-B29.
102. Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB: Risk of congestive heart failure after the initiation of anti-hyperglycemic therapies. Diabetologia 2003; 46:A364.
103. Kronmal RA, Barzilay H, Tracy RP, Savage PJ, Orchard TJ, Burke GL: The relationship of fasting serum radioimmune insulin levels to incident coronary heart disease in an insulin-treated diabetic cohort. J Clin Endocr Metab 2004; 89: 2852-2858. (Pubitemid 38766376)
104. Smooke S, Horwich TB, Fonarow GC: Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. Am Heart J 2005; 149: 168-174. (Pubitemid 40126505)
105. Tseng C-H: Exogenous insulin use and hypertension in adult patients with diabetes mellitus. Arch Intern Med 2006; 166: 1184-1189. (Pubitemid 43877626)
106. Kronmal RA, Barzilay JL, Smith NL, Psaty BM, Kuller RH, Burke GL, Furberg C: Mortality in pharmacologically treated older adults with diabetes: the Cardiovascular Health Study 1989-2001. Plos Med 2006; 3:e400.
107. Skyler JS, Bergenstal R, Bonow RO, Buse J, Prakash D, Gale EAM, Howard BV, Kirkman MS, Kosiborod M, Reaven P, Shervin RS: Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials. Diabetes Care 2009; 32: 187-192.
108. Chang T-Y, Lewis DA, Spandau DF: Decreased incidence of nonmelanoma skin cancer in patients with type 2 diabetes mellitus using insulin: a pilot study. Br J Dermatol 2005; 153: 552-557. (Pubitemid 41248212)
109. Fortuny J, Benavente Y, Bosh R, Garcia-Villanueva M, de Sevilla A, de Sanjosé S: Type 2 diabetes mellitus, its treatment and risk for lymphoma. Eur J Cancer 2005; 41: 1782-1787. (Pubitemid 41135869)
110. Yang Y-X, Hennessy S, Lewis JD: Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004; 127: 1044-1050. (Pubitemid 39345873)
111. Renehan AG, Shalet SM: Diabetes, insulin therapy, and colorectal cancer. BMJ 2005; 330: 551-552. (Pubitemid 40380345)
112. Bowker SL, Majumdar SR, Veugelers P, Johnson JA: Increased cancer-related mortality for patients with type 2 who use sulfonylureas or insulin. Diabetes Care 2006; 29: 254-258. (Pubitemid 44106500)
113. Monami M, Lamanna C, Petracca M, Balzi D, Dicembrini I, Marchionni N, Rotella CM, Mannucci E: Treatment with insulin secretagogues and cancer related mortality in type 2 diabetic patients. A cohort study. Diabetologia 2007: 50(suppl 1):S1-538 (Abstr 0244).
114. Monami M, Lamanna C, Pala L, Bardini G, Cresci B, Francescani P, Balzi D, Marchionni N, Rotella CM, Mannucci E: Treatment with insulin secretagogues and cancer-related mortality in type 2 diabetes patients. A retrospective cohort study. Exp Clin Endocrinol Diabetes 2008: 116: 164-189.
115. Gerstein HC: Glycosylated haemoglobin finally ready for prime time as a cardiovascular risk factor. Ann Intern Med 2004; 141: 475-476 (Pubitemid 39281884)
116. Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, Trüb T: Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000; 49: 999-1005. (Pubitemid 30349423)
117. Levien TL, Baker DE, White JR, Campbwell RK: Insulin glargine: a new basal insulin. Ann Pharmacol 2002; 36: 1019-1027. (Pubitemid 34564389)
118. Stammberger I, Bube A, Durchfeld-Meyer B, Donaubauer H, Troschau G: Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice. Int J Toxicol 2002; 21: 171-179. (Pubitemid 34803492)
119. Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR: Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-1. J Clin Endocrinol Metab 2001; 86: 5838-5847. (Pubitemid 33152632)
120. Hemkens LG, Gronven U, Bender R, Günster C, Gutschmidt S, Selke GW, Sawicki PT: Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; 52: 1732-1717.
121. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdò ttir S, Steineck G: Insulin glargine use and short-term incidence of malignancies - a population-based followup study in Sweden. Diabetologia 2009; 52: 1245-1254.
122. Colhoun HM, SDRN Epidemiology Group: Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009; 52: 1755-1765.
123. Writing Group for the Women's Health Initiative randomized controlled trial: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333.
124. Lenzer J: FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke. BMJ 2005; 330: 440.
125. Lindberg M, Astrup A: The role of glitazones in management of type 2 diabetes. A dream or a nightmare? Obesity Reviews 2007; 8: 381-384. (Pubitemid 47283947)
126. Rosen CJ: The rosiglitazone story - lessons from FDA Advisory Committee Meeting. N Engl J Med 2007; 357: 844-846. (Pubitemid 47347317)
127. Herrington DM, Howard TD: From presumed benefit to potential harm - hormone therapy and heart disease. N Engl J Med 2003; 349: 512-521.
128. Samaras K, Campbell MV: Increasing incidence of type 2 diabetes in the third millennium. Is abdominal fat the central issue? Diabetes Care 2000; 23: 441-442. (Pubitemid 30185782)
129. Py-Sunyer FX: Obesity epidemic: pathophysiology and consequences of obesity. Obesity Research 2002; 10: 97S-104S.
130. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B: Medical management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustement of therapy. Diabetologia 2009; 52: 17-30.
131. Schulze MB, Manson JE, Willatt WC, Hu FB: Processed meat intake and incidence of type 2 diabetes in younger and middle aged women. Diabetologia 2003; 46: 1465-1473. (Pubitemid 37518567)
132. Song Y, Manson J, Burning JE, Liu S: A prospective study of red meat consumption and type 2 diabetes in middle aged and elderly women. Diabetes Care 2004; 27: 2108-2115. (Pubitemid 39167171)
133. Singh PN, Sabaté J, Fraser GE: Does low meat consumption increase life expectancy in humans? Am J Clin Nutr 2003; 78(suppl):526S-532S. (Pubitemid 40012545)
134. Floyd JC, Fajans SS, Conn JW, Knopf RF: Insulin secretion in response to protein ingestion. J Clin Invest 1966; 45: 1479-1486.
135. Hu FB, van Dam RM, Liu S: Diet and risk of type II diabetes: the role of types of fat and carbohydrate. Diabetologia 2001; 44: 805-817. (Pubitemid 32642452)
136. Evans JM, Ogston SA, Emslie-Smith A, Moreris AD: Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006; 49: 930-936.
137. UK Prospective Diabetes Study (UKPDS) Group: Effects of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-865.
138. Lupi R, Del Guerra S, Fierabracci V, Marselli L, Novelli M, Patanè G, Boggi U, Mosca F, Piro S, Del Prato S, Marchetti P: Lipotoxicity in human pancreatic islets and the protective effect of metformin. Diabetes 2002; 51(suppl 1):S134-S137 (Pubitemid 34761508)
139. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators: effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006; 368: 1096-1105.
140. DeFronzo RA, Banerji MA, Bray G, Buchanan T, Clement S, Henry R, Kitabchi A, Muduliar S, Musi N, Ratner R, Schwenke D, Stenz F, Tripathy D: ACTos NOW for the prevention of diabetes (ACT NOW) study: Late breaking abstract presented at the 68th Annual Meeting of ADA, San Francisco, Calif., 2008.
141. Meymeh RH: Diabetes drug pioglitazone (Actos): risk for fracture. CMAJ 2007; 177: 101.
142. Ramos-Nino ME, MacLean CD, Littenberg B: Association between cancer prevalence and use of thiazolidinediones: results for Vermont Diabetes Information System. BMC Med 2007; 5: 17.
143. Stone DB, Brown JD: In vitro effects of phenformin hydrochloride: observations using isolated fat cells. Ann NY Acad Sci 1968; 148: 623-630.
144. Sirigu F, Tagliamonte P, Corsini GU, Muntoni S: Influence of dimethylbiguanide on plasma FFA and glycerol turnover in man. Riv Farmacol Ter 1973: 4:235-242.
145. Schäfer G: Some new aspects on the interaction of hypoglycaemia-producing biguanides with biological membranes. Biochem Pharmacol 1976; 25: 2005-2014.
146. Davidoff F: Effects of guanidine derivatives on mitochondrial function. III. The mechanism of phenethylbiguanide accumulation and its relationship to in vitro respiratory inhibition. J Biol Chem 1971; 246: 4017-4027.
147. Pressman BC: The effects of guanidine and alkylguanidines on the energy transfer reactions of mitochondria. J Biol Chem 1963; 238: 401-409.
148. Cusi K, DeFronzo RA: Metformin: a review of its metabolic effects. Diabetes Rev 1998; 6: 89-131. (Pubitemid 28554676)
149. Muntoni S, Songini M, Tagliamonte P: Experimental 'metabolic' therapy for phenformin-induced lactic acidosis. Diabetologia 1978; 14: 257.
150. Crisponi G, Lai A, Rossetti ZL, Muntoni S, Corsini GU, Tagliamonte P, Sirigu F: Investigation on biguanide-carnitine interaction by nuclear magnetic resonance spectroscopy. Riv Farmacol Ter 1974; 5: 1-6.
151. Muntoni S: Metformin and fatty acids. Diabetes Care 1999; 22: 179-180.
152. Del Prato S, Marchetto S, Pipitone A, Zanon M, De Kreutzenberg SV, Tiengo A: Metformin and free fatty acid metabolism. Diabetes Metab Rev 1995; 11: 533-541.
153. Essop MF, Opie LH: Metabolic therapy for heart failure. Eur Heart J 2004; 25: 1765-1768. (Pubitemid 39330225)
154. Inzucchi SE: Metformin and heart failure: innocent until proven guilty. Diabetes Care 2005; 28: 2585-2587. (Pubitemid 41384319)
155. Muntoni S: Metformin and heart failure: innocent until proven guilty. Response to Inzucchi. Diabetes Care 2006; 29: 751-752. (Pubitemid 44115405)
156. von Lewinski D, Bruns S, Walther S, Kögler H, Pieske B: Insulin causes [Ca2+]i-dependent and [Ca2+]i-independent positive inotropic effects in failing human myocardium. Circulation 2005; 111: 2588-2595. (Pubitemid 40740857)
157. Gandhy GY, Nuttall GA, Abel MD, Mullany CI, Schaff HV, O'Brien PC, Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA, McMahon MM: Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med 2007; 146: 233-243. (Pubitemid 351650609)
158. Muntoni S, Muntoni S: Insulin treatment in the absence of dependence. Ann Int Med Annals Online 2007, 28 March. http:// www.annals.org/cgi/eletters.