LY2605541—A Preferential Hepato-Specific Insulin Analogue

Abstract

The first generation of basal insulin analogs, insulin glargine and detemir, are characterized by a more predictable day-to-day insulin absorption rate, a flatter time/action profile, and a longer duration than the older, intermediate-acting NPH insulin (1). The duration of insulin glargine is longer than insulin detemir (1). The second-generation basal insulin analog insulin degludec has an even longer half-life of about 25 h, a very flat profile of action with a duration exceeding 42 h, and a reduced risk of nocturnal hypoglycemia in both type 1 and type 2 diabetic patients compared with insulin glargine (2). Yet, there is still room for further refinements of the basal insulin analogues. Insulin treatment commonly results in weight gain; thus, an insulin analog associated with no weight gain or weight loss will be a great therapeutic advance. The peripheral administration of insulin does not replicate the two- to threefold higher portal versus systemic circulating insulin levels, causing an imbalance between hepatic and peripheral metabolic actions. Therefore, an insulin analog with hepatic specificity could be of interest. In this issue, Moore et al. (3) report on the effect of the novel basal insulin LY2605541 on hepatic and nonhepatic glucose uptake in their elegant dog model. During peripheral intravenous infusion of LY2605541, a switch from hepatic glucose output to uptake was reported, and nonhepatic glucose uptake increased less than in control experiments with human insulin, indicating that LY2605541 possesses preferential hepatic effects, thereby mimicking endogenously secreted insulin (3). The active component of LY2605541 is insulin lispro, a short-acting insulin analog, which is covalently coupled to a single 20-kilodalton polyethylene glycol (PEG) moiety via an urethane bound to lysine B28 (Fig. 1) (4,5). This results in …