Insulin glargine and receptor‐mediated signalling: clinical implications in treating type 2 diabetes

Abstract

Most patients with type 2 diabetes mellitus will eventually require insulin therapy to achieve or maintain adequate glycaemic control. The introduction of insulin analogues, with pharmacokinetics that more closely mimic endogenous insulin secretion, has made physiologic insulin replacement easier to achieve for many patients. However, there are also concerns regarding alteration of binding affinities for the insulin receptor (IR) or insulin-like growth factor-1 receptor (IGF-1R) may increase the mitogenic potential of some analogues. Therefore, this article will review the relevant preclinical and clinical data to assess the mitogenic potential of insulin glargine, a basal insulin analogue, compared with regular human insulin (RHI). Searches of the PubMed database were performed using terms that included 'IR,' 'insulin-like growth factor-1,' 'IGF-1R,' 'type 2 diabetes mellitus,' and 'insulin glargine.' Original articles and reviews of published literature were retrieved and reviewed. Although one study reported increased binding affinity of insulin glargine for the IGF-1R and increased mitogenic potential in cells with excess IGF-1Rs (Saos/B10 osteosarcoma cells), most in vitro binding-affinity and cell-culture studies have demonstrated behaviour of insulin glargine comparable to that of RHI for both IR and IGF-1R binding, insulin signalling, and metabolic and mitogenic potential.Currently published in vivo carcinogenic studies and human clinical trial data have shown that insulin glargine is not associated with increased risk for either cancer or the development or progression of diabetic retinopathy.

Supramolecular Protein Engineering

“…The principle of isoelectric precipitation underlies the prolonged action of insulin glargine, an analog in broad clinical use (Lantus) (11,12,30). Although slow release of zinc-free monomers enables basal metabolic regulation, concerns have been raised regarding IGF-1R-mediated mitogenicity (14) and possible dose-dependent cancer risk (15,16).…”

“…Longer acting analogs are designed to promote self-assembly in the subcutaneous depot (10) or retard disassembly (11,12). These classes each exploit an inverse relationship between the size of a subcutaneous protein complex and rate of capillary absorption (8,9,12).…”

“…This property underlies the design of long acting analog insulin glargine (the active ingredient of Lantus) (12). Its B-chain is extended by paired Arg residues (Fig.…”

“…Its B-chain is extended by paired Arg residues (Fig. 1A, top, red) whose positively charged side chains shift the pI from 5.8 to 7.0 (11,12). Lantus is formulated at pH 4 as a clear unbuffered solution that, following subcutaneous injection, undergoes pH-dependent precipitation to form a slow release depot (11).…”

“…Lantus is formulated at pH 4 as a clear unbuffered solution that, following subcutaneous injection, undergoes pH-dependent precipitation to form a slow release depot (11). Insulin glargine exhibits increased cross-binding to the type 1 insulin-like growth factor receptor (IGF-1R), 3 a homolog of the insulin receptor (IR) (12,14). Augmented mitogenic signaling inhibits apoptosis and can drive the proliferation of cancer cells (14).…”