Insulin treatment

Basal insulin.

Malcolm Nattrass (Birmingham, U.K.) discussed basal insulin analogs, noting that the ideal approach will lead to “a flat profile that is reproducible.” The development of basal insulin began with protamine zinc insulin in 1936, followed by NPH insulin in 1946 and zinc insulins lente, semilente, and ultralente in 1951. All of these preparations have high variability, making them less than optimal for treatment. Natrass reviewed studies of persons given four injections of 0.4 units/kg NPH in the thigh, with measurement of the glucose infusion rate required to maintain euglycemia. Great variability in biologic activity was shown. Early strategies pursued with insulin analogs included changes in the isoelectric point leading to precipitation at pH 7.4 with NovoSol Basal (1) and strengthening hexamer formation with Co(III)-hexamer insulin. Neither strategy led to successful development of a commercial product. Subsequent research led to insulin glargine, which is stable and soluble in acidic solution, precipitating following injection into subcutaneous tissues. Compared with NPH, there is major improvement in variability comparable to that with continuous subcutaneous insulin infusion (CSII) and a considerably “flatter” action profile than seen with NPH. Another method involves acylation of the insulin molecule with hydrophobic residues. Insulin detemir has a myristic acid fatty acid side chain that strengthens self-association, leading to increased hexamer formation and to albumin binding at the injection site and in the circulation. The binding to albumin may buffer insulin action.

Nattrass reviewed a number of studies of glargine and of detemir. In a study of 619 persons with type 1 diabetes, insulin glargine given at bedtime was associated with lower fasting glucose and with lower variability in fasting glucose level than NPH insulin given …