Engineering Novel, Prolonged-Acting Insulins

Insulin-dependent diabetic patients need a constant supply of basal insulin to control blood glucose between meals, in addition to meal-related bolus insulin to counter the peak in glucose following a meal. Intensive basal/bolus insulin regimens have been introduced in order to improve blood glucose control, particularly in Scandinavia and England. The long-acting insulins used to provide the basal supply come in the form of neutral, crystalline suspensions, obtained by crystallization using eitherZn2+ (Lente-type preparations) or protamine (NPHtype preparations). These suspensions require thorough shaking prior to injection in order to ensure homogeneity of the suspension and correct dosage. Furthermore, the inter-and intra-patient absorption of insulin suspensions is extremely variable: the T50% (i.e., the time taken for 50% of the insulin to disappear from the injection site) ranges from 8 to 72 hr (Lauritzen et al., 1979). Whereas the homogeneity problem of suspensions could be overcome if a soluble, prolonged-acting insulin was made available, the variability in absorption caused by the physiological conditions, like blood flow at the site of injection, could hardly be totally eliminated by applying new principles of prolongation.