Dr. Richard DiMarchi and The Discovery of Insulin Lispro

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Recommended: A reflection on insulins

The discovery of the human insulin analog, insulin lispro (LysB28ProB29), by Dr. Richard DiMarchi and his research team at Eli Lilly and Company is perhaps the most significant recent advances involving the treatment of diabetes mellitus. A group of metabolic diseases characterized by hyperglycemia, diabetes mellitus was put on the forefront medical science following an international conference in Monaco in 1985 by the Juvenile Diabetes Foundation International, which called for the development of fast-acting insulin analogs that mimicked the physiological effects of human insulin (1). While human insulin had been commercially prepared by Eli Lilly and Company since 1923, the efficacy of subcutaneous injections of human insulin was limited by slow absorption in the body due to the propensity of insulin to self-associate into dimers and hexamers (1). For insulin to elicit the necessary biological response, it must dissociate into monomeric subunits before binding to insulin receptors in the liver. Injections must therefore be given 30-45 minutes before a meal, which creates a highly inconvenient regimen for diabetics attempting to control their blood sugar. Researchers recognized the need for an insulin analog that could exist as a hexamers-stabilized complex, yet dissociate rapidly into monomers upon injection in order to mimic the effects of human pancreatic insulin in non-diabetics.
This challenge was met with progress with the finding that Insulin-like growth factor I (IGF-I), a naturally occurring hormone analogous to insulin, does not self-associate into dimers and hexamers in way that human insulin did. The amino acids at positions 28 and 29 of the beta-chain of human insulin are proline-lysine, but it was revealed that th...

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...mann, M. E.; Vignati, L. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group. Diabetes. 1997, 46(2), 265-270.
8. Carnethon, M. R.; Biggs, M. L.; Barzilay, J.; Kuller, L. H.; Mozaffarian, D; Mukamal, K. Diabetes and coronary heart disease as risk factors for mortality in older adults. The American Journal of Medicine. 2010, 123(6), 556.e1-556.e9.
9. Pieber, T. R.; Eugene-Jolchine, I.; & Derobert, E. Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes. Diabetes Care. 2010, 23(2), 157-162.
10. Bolli, G. B.; DiMarchi, R. D.; Park, G. D.; Pramming, S.; & Koivisto; V. A. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999, 42(10), 1151-1167.

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