International Journal of Endocrinology and Metabolism

Published by: Kowsar

Role of Insulin in the Type 2 Diabetes Therapy: Past, Present and Future

Carlo Maria Rotella 1 , * , Laura Pala 2 and Edoardo Mannucci 3
Authors Information
1 Obesity Agency, University of Florence Medical School, Careggi Teaching Hospital, Firenze, Italy
2 Endocrinolgy Unit , University of Florence Medical School, Careggi Teaching Hospital, Firenze, Italy
3 Diabetes Agency, University of Florence Medical School, Careggi Teaching Hospital, Firenze, Italy
Article information
  • International Journal of Endocrinology and Metabolism: July 01, 2013, 11 (3); 137-144
  • Published Online: July 1, 2013
  • Article Type: Review Article
  • Received: August 1, 2012
  • Revised: September 26, 2012
  • Accepted: September 28, 2012
  • DOI: 10.5812/ijem.7551

To Cite: Maria Rotella C, Pala L, Mannucci E. Role of Insulin in the Type 2 Diabetes Therapy: Past, Present and Future, Int J Endocrinol Metab. 2013 ; 11(3):137-144. doi: 10.5812/ijem.7551.

Copyright © 2013, Research Institute For Endocrine Sciences and Iran Endocrine Society. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Context
2. Evidence Acquisition
3. Results
4. Conclusions
  • 1. Pala L, Monami M, Lamanna C, Cresci B, Colombi C, Bardini G, et al. Failure to metformin and insulin secretagogue monotherapy: an observational cohort study. Acta Diabetol. 2010; 47 Suppl 1: 7-11[DOI][PubMed]
  • 2. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999; 281(21): 2005-12[PubMed]
  • 3. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352(9131): 837-53[PubMed]
  • 4. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321(7258): 405-12[PubMed]
  • 5. Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008; 371(9626): 1753-60[DOI][PubMed]
  • 6. Rosenstock Julio, Riddle Matthew C. Insulin therapy in type 2 diabetes. The CADRE Handbook of Diabetes Management. New York: Medical Information Pr. 2004; : 145-68
  • 7. Anderson JH, Jr, Brunelle RL, Koivisto VA, Pfutzner A, Trautmann ME, Vignati L, et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group. Diabetes. 1997; 46(2): 265-70[PubMed]
  • 8. Mannucci E, Monami M, Marchionni N. Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: a meta-analysis. Diabetes Obes Metab. 2009; 11(1): 53-9[DOI][PubMed]
  • 9. Pala L, Mannucci E, Dicembrini I, Rotella CM. A comparison of mealtime insulin aspart and human insulin in combination with metformin in type 2 diabetes patients. Diabetes Res Clin Pract. 2007; 78(1): 132-5[DOI][PubMed]
  • 10. Kotsanos JG, Vignati L, Huster W, Andrejasich C, Boggs MB, Jacobson AM, et al. Health-related quality-of-life results from multinational clinical trials of insulin lispro. Assessing benefits of a new diabetes therapy. Diabetes Care. 1997; 20(6): 948-58[PubMed]
  • 11. Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis. Diabetes Obes Metab. 2009; 11(4): 372-8[DOI][PubMed]
  • 12. Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract. 2008; 81(2): 184-9[DOI][PubMed]
  • 13. Raskin P, Gylvin T, Weng W, Chaykin L. Comparison of insulin detemir and insulin glargine using a basal-bolus regimen in a randomized, controlled clinical study in patients with type 2 diabetes. Diabetes Metab Res Rev. 2009; 25(6): 542-8[DOI][PubMed]
  • 14. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012; 35(6): 1364-79[DOI][PubMed]
  • 15. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009; 32(1): 193-203[DOI][PubMed]
  • 16. Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007; 357(17): 1716-30[DOI][PubMed]
  • 17. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012; 12(3): 159-69[DOI][PubMed]
  • 18. Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev. 2009; 30(6): 586-623[DOI][PubMed]
  • 19. Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli R, Squatrito S, et al. Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia. 2010; 53(8): 1743-53[DOI][PubMed]
  • 20. Janghorbani M, Dehghani M, Salehi-Marzijarani M. Systematic review and meta-analysis of insulin therapy and risk of cancer. Horm Cancer. 2012; 3(4): 137-46[DOI][PubMed]
  • 21. Bowker SL, Yasui Y, Veugelers P, Johnson JA. Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia. 2010; 53(8): 1631-7[DOI][PubMed]
  • 22. Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012; 367(4): 319-28[DOI][PubMed]
  • 23. Oleksiewicz MB, Bonnesen C, Hegelund AC, Lundby A, Holm GM, Jensen MB, et al. Comparison of intracellular signalling by insulin and the hypermitogenic AspB10 analogue in MCF-7 breast adenocarcinoma cells. J Appl Toxicol. 2011; 31(4): 329-41[DOI][PubMed]
  • 24. Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000; 49(6): 999-1005[PubMed]
  • 25. Colhoun HM. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009; 52(9): 1755-65[DOI][PubMed]
  • 26. Hemkens LG, Grouven U, Bender R, Gunster C, Gutschmidt S, Selke GW, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009; 52(9): 1732-44[DOI][PubMed]
  • 27. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009; 52(9): 1766-77[DOI][PubMed]
  • 28. Morden NE, Liu SK, Smith J, Mackenzie TA, Skinner J, Korc M. Further exploration of the relationship between insulin glargine and incident cancer: a retrospective cohort study of older Medicare patients. Diabetes Care. 2011; 34(9): 1965-71[DOI][PubMed]
  • 29. Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012; 55(1): 51-62[DOI][PubMed]
  • 30. Lind M, Fahlen M, Eliasson B, Oden A. The relationship between the exposure time of insulin glargine and risk of breast and prostate cancer: an observational study of the time-dependent effects of antidiabetic treatments in patients with diabetes. Prim Care Diabetes. 2012; 6(1): 53-9[DOI][PubMed]
  • 31. Mannucci E, Monami M, Balzi D, Cresci B, Pala L, Melani C, et al. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2010; 33(9): 1997-2003[DOI][PubMed]
  • 32. Suissa S, Azoulay L, Dell'Aniello S, Evans M, Vora J, Pollak M. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia. 2011; 54(9): 2254-62[DOI][PubMed]
  • 33. Potenza MA, Addabbo F, Montagnani M. Vascular actions of insulin with implications for endothelial dysfunction. Am J Physiol Endocrinol Metab. 2009; 297(3)-77[DOI][PubMed]
  • 34. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358(24): 2545-59[DOI][PubMed]
  • 35. Currie CJ, Johnson JA. The safety profile of exogenous insulin in people with type 2 diabetes: justification for concern. Diabetes Obes Metab. 2012; 14(1): 1-4[DOI][PubMed]
  • 36. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ. 1997; 314(7093): 1512-5[PubMed]
  • 37. Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study. Diabetologia. 2011; 54(6): 1308-17[DOI][PubMed]
  • 38. Chaitman BR, Hardison RM, Adler D, Gebhart S, Grogan M, Ocampo S, et al. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation. 2009; 120(25): 2529-40[DOI][PubMed]
  • 39. Puskarich MA, Runyon MS, Trzeciak S, Kline JA, Jones AE. Effect of glucose-insulin-potassium infusion on mortality in critical care settings: a systematic review and meta-analysis. J Clin Pharmacol. 2009; 49(7): 758-67[DOI][PubMed]
  • 40. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002; 346(6): 393-403[DOI][PubMed]
  • 41. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002; 359(9323): 2072-7[DOI][PubMed]
  • 42. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006; 368(9541): 1096-105[DOI][PubMed]
  • 43. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344(18): 1343-50[DOI][PubMed]
  • 44. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003; 290(4): 486-94[DOI][PubMed]
  • 45. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, 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 randomised controlled trial. Lancet. 2005; 366(9493): 1279-89[DOI][PubMed]
  • 46. Mannucci E, Dicembrini I. Incretin-based therapies and cardiovascular risk. Curr Med Res Opin. 2012; 28(5): 715-21[DOI][PubMed]
  • 47. Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin. 2011; 27 Suppl 3: 57-64[DOI][PubMed]
  • 48. Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2009; 19(9): 604-12[DOI][PubMed]
  • 49. Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S, Melani C, et al. Metformin and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2011; 34(1): 129-31[DOI][PubMed]
  • 50. Rizos EC, Ntzani EE, Papanas N, Tsimihodimos V, Mitrogianni Z, Maltezos E, et al. Combination Therapies of DPP4 Inhibitors and GLP1 Analogues with Insulin in Type 2 Diabetic Patients: A Systematic Review. Curr Vasc Pharmacol. 2012; [PubMed]
  • 51. Fonseca V, Gill J, Zhou R, Leahy J. An analysis of early insulin glargine added to metformin with or without sulfonylurea: impact on glycaemic control and hypoglycaemia. Diabetes Obes Metab. 2011; 13(9): 814-22[DOI][PubMed]
  • 52. Mannucci E, Monami M, Di Bari M, Lamanna C, Gori F, Gensini GF, et al. Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials. Int J Cardiol. 2010; 143(2): 135-40[DOI][PubMed]
  • 53. Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012; 29(8): 2104-14[DOI][PubMed]
  • 54. Nishimura E, Sorensen AR, Hansen BF, Stidsen CE, Olsen GS, Schaffer L, et al. Insulin degludec: a new ultra-long, basal insulin designed to maintain full metabolic effect while minimizing mitogenic potential. Diabetologia. 2010; 53
  • 55. Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012; 379(9825): 1498-507[DOI][PubMed]
  • 56. Jacober Scott J, Rosenstock J, Bergenstal RM, Prince MJ, Yongming Qu, Beals JM. Contrasting Weight Changes with LY2605541, a Novel Long-Acting Insulin, and Insulin Glargine Despite Similar Improved Glycemic Control in T1D and T2D. American Diabetes Association's 72nd Scientific Sessions. 2012;
  • 57. Steiner S, Hompesch M, Pohl R, Simms P, Flacke F, Mohr T, et al. A novel insulin formulation with a more rapid onset of action. Diabetologia. 2008; 51(9): 1602-6[DOI][PubMed]
  • 58. Vaughn DE, Yocum RC, Muchmore DB, Sugarman BJ, Vick AM, Bilinsky IP, et al. Accelerated pharmacokinetics and glucodynamics of prandial insulins injected with recombinant human hyaluronidase. Diabetes Technol Ther. 2009; 11(6): 345-52[DOI][PubMed]
  • 59. Meneghini L, Sparrow-Bodenmiller J. Practical aspects and considerations when switching between continuous subcutaneous insulin infusion and multiple daily injections. Diabetes Technol Ther. 2010; 12 Suppl 1-14[DOI][PubMed]
  • 60. Pickup JC, Renard E. Long-acting insulin analogs versus insulin pump therapy for the treatment of type 1 and type 2 diabetes. Diabetes Care. 2008; 31 Suppl 2-5[DOI][PubMed]
  • 61. Skyler JS. Continuous subcutaneous insulin infusion--an historical perspective. Diabetes Technol Ther. 2010; 12 Suppl 1-9[DOI][PubMed]
  • 62. Monami M, Lamanna C, Marchionni N, Mannucci E. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in type 2 diabetes: a meta-analysis. Exp Clin Endocrinol Diabetes. 2009; 117(5): 220-2[DOI][PubMed]
  • 63. Anhalt H, Bohannon NJ. Insulin patch pumps: their development and future in closed-loop systems. Diabetes Technol Ther. 2010; 12 Suppl 1-8[DOI][PubMed]
  • 64. Hovorka R. Continuous glucose monitoring and closed-loop systems. Diabet Med. 2006; 23(1): 1-12[DOI][PubMed]
  • 65. Renard E, Place J, Cantwell M, Chevassus H, Palerm CC. Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery: feasibility study testing a new model for the artificial pancreas. Diabetes Care. 2010; 33(1): 121-7[DOI][PubMed]
  • 66. Zarogoulidis P, Papanas N, Kouliatsis G, Spyratos D, Zarogoulidis K, Maltezos E. Inhaled insulin: too soon to be forgotten? J Aerosol Med Pulm Drug Deliv. 2011; 24(5): 213-23[DOI][PubMed]
  • 67. Palermo A, Maddaloni E, Pozzilli P. Buccal spray insulin (Oralgen) for type 2 diabetes: what evidence? Expert Opin Biol Ther. 2012; 12(6): 767-72[DOI][PubMed]
  • 68. Cernea S, Kidron M, Wohlgelernter J, Modi P, Raz I. Dose-response relationship of oral insulin spray in healthy subjects. Diabetes Care. 2005; 28(6): 1353-7[PubMed]
  • 69. Guevara-Aguirre J, Guevara M, Saavedra J, Mihic M, Modi P. Beneficial effects of addition of oral spray insulin (Oralin) on insulin secretion and metabolic control in subjects with type 2 diabetes mellitus suboptimally controlled on oral hypoglycemic agents. Diabetes Technol Ther. 2004; 6(1): 1-8[DOI][PubMed]
  • 70. Guevara-Aguirre J, Guevara M, Saavedra J, Mihic M, Modi P. Oral spray insulin in treatment of type 2 diabetes: a comparison of efficacy of the oral spray insulin (Oralin) with subcutaneous (SC) insulin injection, a proof of concept study. Diabetes Metab Res Rev. 2004; 20(6): 472-8[DOI][PubMed]
  • 71. Palermo A, Napoli N, Manfrini S, Lauria A, Strollo R, Pozzilli P. Buccal spray insulin in subjects with impaired glucose tolerance: the prevoral study. Diabetes Obes Metab. 2011; 13(1): 42-6[DOI][PubMed]
  • 72. Wiseman AC, Gralla J. Simultaneous pancreas kidney transplant versus other kidney transplant options in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2012; 7(4): 656-64[DOI][PubMed]
  • 73. Di Pasquale G, Dicembrini I, Raimondi L, Pagano C, Egan JM, Cozzi A, et al. Sustained exendin-4 secretion through gene therapy targeting salivary glands in two different rodent models of obesity/type 2 diabetes. PLoS One. 2012; 7(7)[DOI][PubMed]
  • 74. Han J, McLane B, Kim EH, Yoon JW, Jun HS. Remission of diabetes by insulin gene therapy using a hepatocyte-specific and glucose-responsive synthetic promoter. Mol Ther. 2011; 19(3): 470-8[DOI][PubMed]
Creative Commons License Except where otherwise noted, this work is licensed under Creative Commons Attribution Non Commercial 4.0 International License .

Search Relations:



Create Citiation Alert
via Google Reader

Readers' Comments