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CLINICAL DIABETES
VOL. 14 NO. 5 SEPTEMBER/OCTOBER 1996

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EDITORIAL

Insulin Lispro: Genetic Re-engineering to Produce a Truly Fast-Acting Insulin

Alan J. Garber, MD, PhD, Editor

Since the results of the Diabetes Control and Complications Trial were presented at the 1993 American Diabetes Association Annual Meeting and Scientific Sessions, intensive diabetes management has become the standard of care for most patients with type I diabetes and for many patients with type II disease. However, a number of issues and difficulties have limited the implementation of intensive insulin management in America.

Among the most troublesome of these stem from the inadequacies of conventional human regular insulin as a mealtime or rapid-acting insulin preparation. Chief among the problems with human regular insulin is the geometric increase in the incidence of hypoglycemia experienced as glycemic control improves, and especially as normal glycemia is approached.

Hypoglycemia results in large measure because human regular insulin has a prolonged action curve as the result of its tendency to aggregate to a hexameric structure in vitro and to preserve this hexamer following insulin injection into subcutaneous tissue. As a result of a slow dissociation of the hexamer, insulin monomers become available only slowly and continue to appear in the bloodstream long after a meal has been digested and absorbed.

The slow onset of insulin action is overcome in part by injecting regular insulin 30, 45, or even 60 minutes or more before meals. Although such an interval is a satisfying experimental solution to the problem, it is a solution with limited clinical utility in practice settings, because patients are often unable to inject and wait the required time period before eating. Furthermore, owing to the vagaries of customer service, eating in a restaurant can be unpleasant and even hazardous for patients on intensive insulin management programs. More important, however, is the fear of hypoglycemia due to prolonged absorption, which limits the applicability of intensive insulin management in the minds of many patients and physicians.

Hypoglycemia results from prolonged insulin absorption, which in turn results from a slow dissociation of insulin hexamers. Thus, regular insulin, particularly in large doses, may continue to produce absorbed insulin until or even beyond the next meal. This becomes problematic for patients on intensive management programs because a bedtime snack may be insufficient to cover large quantities of regular insulin taken for the evening meal. Patients are therefore placed at risk for nocturnal hypoglycemia, not from intermediate-acting insulin, as is often expected, but rather from the tail end of the regular insulin taken for the evening meal.

To overcome these difficulties, an insulin analog has been produced by genetically re-engineering the B-chain of insulin. Natural human insulin possesses a B-chain terminal sequence of proline, lysine, and threonine at B 28-29-30. Physical chemical analysis reveals that this region is an important participant in the binding and dimerization reaction and ultimately the hexamerization of insulin monomers. However, this portion of the molecule does not participate in the receptor binding region of the insulin molecule.

In contrast, IGF1 has extensive structural homology with human insulin. The B-chain terminal sequence is lysine, proline, and threonine at B 28-29-30. Dimerization and hexamerization does not normally occur with IGF1 because the configuration and direction of the peptide chain is reversed. To confer the diminished dimerization potential of IGF1 upon the insulin molecule, human insulin was re-engineered by inverting the amino acid sequence at B-28 and B-29 to the lysine-proline analog now known as insulin lispro. This reduces the stability of the dimer and hexamer of this insulin analog, allowing it to dissociate spontaneously at a much more rapid rate following subcutaneous injection.

Three major benefits result from such a re-engineered insulin molecule. First, as a mealtime insulin, lispro may be taken 5Ð10 minutes before a meal and yet will produce satisfactory blood levels and glycemic control comparable to conventional insulin taken 30Ð45 minutes before meals. Second, the lispro analog produces better control of postprandial hyperglycemia and yields a lower glycemic excursion than does regular insulin. Third, since the duration of insulin lispro action is ~ 3 hours compared to ~ 5Ð6 hours with regular insulin, less preprandial hypoglycemia is generally observed, particularly at night.

Because hyper- and hypoglycemia are offsetting positive and negative contributors to change in HbA1c levels, the ability of insulin lispro to reduce postprandial hyperglycemia and hypoglycemia may not translate into an observable change in HbA1c levels. Nevertheless, glycemic control evaluated in terms of hypoglycemic episodes, particularly nocturnal hypoglycemia, together with improved postprandial glycemic control, should be observed. Furthermore, the accelerated action of insulin lispro obviates the need for prolonged intervals between injection and meal consumption, thereby improving patient compliance with intensive management programs. Taken as a whole, these changes suggest that insulin lispro will improve both the mechanics and the outcomes of intensive diabetes management programs.

Insulin lispro, therefore, represents the first commercially available insulin analog resulting from genetic re-engineering of the insulin molecule to yield improved pharmacodynamic properties and ultimately more successful diabetes management for patients and practitioners alike.

Note of Disclosure: Dr. Garber has received honoraria for speaking engagements from, and served as a consultant to, Eli Lilly and Company, which manufactures insulin lispro.

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