Binding of phenol to R6 insulin hexamers*

Abstract

Small amounts of phenolic compounds are being used as preservatives in pharmaceutical insulin preparations. It has been shown previously that these compounds bind to specific sites on the insulin hexamer and act as allosteric effectors, inducing a transformation of the T6 hexamer to the R6 hexamer, via a T3R3 intermediate. In this article, the crystal structures of eight different insulin derivatives, all in the phenol‐containing R6 form, are analyzed with respect to their phenol‐binding sites. While six phenol molecules are normally bound per insulin hexamer, one of the engineered insulins appears to contain only three phenols but yet exists in an R6 conformation. This observation provides additional evidence for an inherent nonequivalence of the two trimers in the insulin hexamer. The unusual observation of a seventh phenol molecule bound to the hexamer of crystalline A21Gly–B31,B32Arg2 insulin (HOE 901), a long‐acting derivative currently undergoing phase III clinical trials, provides a partial explanation for its protracted activity. © 1999 John Wiley & Sons, Inc. Biopoly 51: 165–172, 1999

Crystal structure of destripeptide (B28–B30) insulin: implications for insulin dissociation

“…The aggregation of the three molecules (molecules II) which are no longer coordinated to a zinc ion becomes loose and one end of the cylinder channel in the center of the three dimers opens. Non-equivalence of the two trimers in the insulin hexamer is common [26], although not as obvious as in DTRI. The movements of the solvent molecules in the cylinder become more active and the hexamer becomes unstable.…”

Differences in metabolic and mitogenic signalling of insulin glargine and insulin aspart B10 in rats

“…In contrast, glucose lowering was delayed with insulin glargine, as expected for a long-acting insulin analogue, where the mode of action involves precipitation and subsequent slow release from the tissue depot [41]. As in humans [11, 42], the lowering of blood glucose could be correlated to the biotransformation of insulin glargine into the M1 metabolite, which lacks the di-arginine residues [8].…”

The Future of Basal Insulin

“…The precipitate reduces the absorption of insulin glargine, giving it a longer duration of action. 14 Insulin glargine demonstrated a nearly 24-h action with flat time-action profile and reduced variability compared with NPH and ultralente in individuals with diabetes. [15][16][17][18] Because it was peakless, it was associated with decreased nocturnal hypoglycemia.…”