Insulin glargine and cancer--an unsubstantiated allegation.

1 Barbara Davis Center for Childhood Diabetes , Aurora, Colorado.
Diabetes Technology &amp Therapeutics (Impact Factor: 2.29). 08/2009; 11(8):473-6. DOI: 10.1089/dia.2009.1705
Source: PubMed
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    ABSTRACT: The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), that activates the "metabolic" Akt kinase signaling pathway while having little or no effect on the "mitogenic" ERK signaling pathway. To investigate the nature of this selective signaling, we have now conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in CHO cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the "preferential signaling" of XMetA is due to an innate difference in pathway sensitivity of Akt vs. ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathway-biased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 01/2015; 353(1). DOI:10.1124/jpet.114.221309 · 3.86 Impact Factor
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    ABSTRACT: Advances in insulin therapy have made a positive contribution to improving disease management in both Type 1 and Type 2 diabetes. The development of insulin analogs with time–action characteristics has made it easier to mimic physiological insulin secretion. The parallel improvement in delivery devices has also made insulin therapy more convenient, flexible and acceptable. The inevitable progression of Type 2 diabetes means that the majority of those people will also require insulin therapy at some point in their disease course. Current treatment options are many; when to initiate insulin and which regimen to choose are among the major questions confronting physicians in today’s rapidly evolving environment. This article summarizes the current strategies for initiating and optimizing the use of the basal insulin analog, insulin glargine, in Type 2 diabetes, leading to the intermediate stage of insulin therapy with the introduction of meal-related, rapid-acting insulin analogs in a stepwise manner prior to a full replacement basal-bolus regimen.
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    ABSTRACT: An observational study in Germany implicated the specific action of insulin glargine to increase cancer risk; however, this study accumulated a number of methodological errors. There was no confirmation of these results in the three other European studies commissioned by the editor in chief of Diabetologia to validate or to refute the German data. Indeed, more generally, a moderate increase of cancer risk, with the exception of prostate cancer, has been shown in type 2 diabetic patients and in those with abnormal glucose tolerance, mainly digestive sites, independently of obesity. Insulin-resistance with compensatory hyperinsulinemia, and elevated levels of circulating growth factors are usually considered as the link between cancer and hyperglycemia, through activated cell proliferation. Treatments for diabetes that elevate plasma insulin seem to increase cancer risk and, in contrast, insulin-sensitizer drugs for diabetes (metformin, thiazolidinediones) seem to reduce cancer risk.


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