The human insulin analog insulin lispro improves insulin binding on circulating monocytes of intensively treated insulin-dependent diabetes mellitus patients.
The rapidly absorbed analog of human insulin, insulin lispro (LP), is characterized by a faster onset of action, a higher peak insulin level, and a shorter duration of action compared with regular insulin (RI). The aim of this study was to investigate whether intensified treatment with either LP or RI influences insulin receptor status. Twelve patients with insulin-dependent diabetes mellitus (IDDM) participating in a multicenter randomized cross-over trial were allocated to this study. Four patients began with LP, whereas eight patients started with RI. Each patient was switched to the other insulin after a 3-month treatment period. Competitive [125I]A-14-insulin binding studies were performed with isolated monocytes. Treatment with insulin lispro increased the total number of insulin binding sites from 9,400 +/- 2,200 (RI) to 20,300 +/- 3,000 (LP)/monocyte (P < 0.001). The insulin concentration required for a 50% competition of [125I]insulin binding (IC50) decreased from 0.6 +/- 0.2 (RI) to 0.1 +/- 0.03 (LP) nmol/L, indicating significantly higher affinity of insulin binding sites during LP treatment (P < 0.001). In additional experiments, the time course of insulin binding was determined after an oral meal. In LP-treated IDDM patients, the affinity and capacity of insulin binding showed a nadir 1 h after insulin injection and a regained binding affinity and capacity 5 h later. These changes observed after LP treatment were comparable to the effect of endogenous insulin secretion in healthy control subjects. In contrast, the IDDM patients who injected RI showed a decreasing insulin binding affinity and capacity, most markedly expressed after 5 h. The corresponding serum levels of insulin were inversely correlated with the affinity and capacity of insulin-binding sites. Pretreatment of cultured human IM-9 lymphoblasts with LP or RI yielded no difference in the down-regulation of insulin binding. In summary, intensified conventional insulin therapy with LP increased the number and affinity of insulin receptors on circulating monocytes to a level similar to that observed in healthy subjects. We conclude that the improved insulin receptor status observed during LP treatment is caused by its more physiological pharmacokinetic profile.
Jehle
P M
PM
Department of Internal Medicine, University of Ulm, Germany.
Fussgaenger
R D
RD
Kunze
U
U
Dolderer
M
M
Warchol
W
W
Koop
I
I
D000328:Adult; D002460:Cell Line; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D015536:Down-Regulation; D004435:Eating; D005260:Female; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use; D061268:Insulin Lispro; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism
D007328:Insulin; D061268:Insulin Lispro; D011972:Receptor, Insulin