In recent years, analogs of human insulin have been engineered with the aim of improving
therapy for people with diabetes. To ensure that the safety profile of the human hormone
is not compromised by the molecular modifications, the toxico-pharmacological properties
of insulin analogs should be carefully monitored. In this study, we compared the insulin
and IGF-I receptor binding properties and metabolic and mitogenic potencies of insulin
aspart (B28Asp human insulin), insulin lispro (B28Lys,B29Pro human insulin), insulin
glargine (A21Gly,B31Arg,B32Arg human insulin), insulin detemir (NN304) [B29Lys(epsilon-tetradecanoyl),
desB30 human insulin], and reference insulin analogs. Receptor affinities were measured
using purified human receptors, insulin receptor dissociation rates were determined
using Chinese hamster ovary cells overexpressing the human insulin receptor, metabolic
potencies were evaluated using primary mouse adipocytes, and mitogenic potencies were
determined in human osteosarcoma cells. Metabolic potencies correlated well with insulin
receptor affinities. Mitogenic potencies in general correlated better with IGF-I receptor
affinities than with insulin receptor off-rates. The 2 rapid-acting insulin analogs
aspart and lispro resembled human insulin on all parameters, except for a slightly
elevated IGF-I receptor affinity of lispro. In contrast, the 2 long-acting insulin
analogs, glargine and detemir, differed significantly from human insulin. The combination
of the B31B32diArg and A21Gly substitutions provided insulin glargine with a 6- to
8-fold increased IGF-I receptor affinity and mitogenic potency compared with human
insulin. The attachment of a fatty acid chain to LysB29 provided insulin detemir with
reduced receptor affinities and metabolic and mitogenic potencies but did not change
the balance between mitogenic and metabolic potencies. The safety implications of
the increased growth-stimulating potential of insulin glargine are unclear. The reduced
in vitro potency of insulin detemir might explain why this analog is not as effective
on a molar basis as human insulin in humans.