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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #309017
Title: Differential pathway coupling efficiency of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody

Author
item BEDINGER, DANIEL - Xoma Corporation
item GOLDFINE, IRA - Xoma Corporation
item CORBIN, JOHN - Xoma Corporation
item ROELL, MARINA - Xoma Corporation
item Adams, Sean

Submitted to: Journal of Pharmacology and Experimental Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/22/2015
Publication Date: 1/22/2015
Citation: Bedinger, D.H., Goldfine, I.D., Corbin, J.A., Roell, M.K., Adams, S.H. 2015. Differential pathway coupling efficiency of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody. Journal of Pharmacology and Experimental Therapeutics. 353(1):35-43. doi: 10.1124/jpet.114.221309.

Interpretive Summary: Insulin is the critical hormone in the body that regulates blood sugar, and its effectiveness can wane in persons with pre-diabetes despite high levels in the blood. In type 2 diabetes, blood insulin becomes inadequate to control glucose, and often insulin treatment is needed. Understanding how the insulin-glucose axis operates at a molecular level is of paramount importance to consider new strategies to thwart type 2 diabetes through nutritional or other means, and this will also shed light on physiological processes in the body. Furthermore, since insulin is often injected repeatedly throughout the day, and can be difficult to dose properly to achieve optimal blood sugar control, it is of interest to identify agents that can mimic insulin’s actions long-term without triggering untoward activities of insulin (i.e., it is a growth-promoting hormone that has been implicated in abnormal cell proliferation, and it may elicit insulin resistance if its concentration is chronically high). XMetA, an anti-insulin receptor (IR) monoclonal antibody, is an allosteric partial agonist of the insulin receptor (IR). We have previously reported that XMetA activates the “metabolic-biased” Akt kinase signaling pathway while having little or no effect on the “mitogenic” MAPK signaling pathwayof ERK 1/2. To investigate the nature of this selective signaling, a detailed investigation of XMetA was conducted to evaluate specific phosphorylation and activation of the IR and related pathways in cells expressing the human IR (IR-A orIR-B respectively). These studies confirmed that XMetA stimulated the activation of Akt much more strongly than ERK(1/2) in cell lines that expressed either the IR-A and IR-B form of the IR. These data indicate that the “preferential signaling” of XMetA is due to a convergence of pathway sensitivity (i.e., an innate, differential Akt vs. ERK responses to IR activation by either insulin or XMetA), and partial agonism of 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 in terms of therapeutic agents designed to regulate blood glucose levels while minimizing potential undesirable outcomes of excessive insulin receptor activation. Since XMetA is an antibody that resides in the tissues and blood for a extended times, it raises the possibility that it might be used as a long-acting insulin-like factor to control blood sugar in type 2 diabetes.

Technical Abstract: XMetA, an anti-insulin receptor (IR) monoclonal antibody, is an allosteric partial agonist of the IR. We have previously reported that XMetA activates the “metabolic-biased” Akt kinase signaling pathway while having little or no effect on the “mitogenic” MAPK signaling pathwayof ERK 1/2. To investigate the nature of this selective signaling, a detailed investigation of XMetA was conducted to evaluate specific phosphorylation and activation of the IR, Akt, and ERK(1/2) in CHO cell lines expressing either the short or long form of the human IR (IR-A orIR-B respectively). These studies confirmed that XMetA stimulated the activation of Akt much more strongly than ERK(1/2) in cell lines that expressed either the IR-A and IR-B form of the IR. Studies with insulin revealed that, while the hormone activated both pathways in both isoforms, the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. The EC50s were 120 pM vs. 1,450 pM, respectively, in CHO-hIR-A (P-Value = 0.0085), and the EC50 s were 42 pM vs. 837 pM, respectively, in CHO-hIR-B cells; (P-value = 0.013)). Maximal 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 a convergence of pathway sensitivity (i.e., an innate, differential Akt vs. ERK responses to IR activation by either insulin or XMetA), and partial agonism of 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 in terms of therapeutic agents designed to regulate blood glucose levels while minimizing potential undesirable outcomes of excessive IR mitogenic activation.