Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetes.
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.
Le Roith
Derek
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Department of Medicine, The Mount Sinai School of Medicine, New York, NY 10029-6574, USA. derek.leroith@mssm.edu
D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007328:Insulin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D008657:Metabolic Clearance Rate; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D011972:Receptor, Insulin