Location: Obesity and Metabolism ResearchTitle: Acute treatment with XMetA activates hepatic insulin receptors and lowers blood glucose in normal mice Author
|Bedinger, Daniel - Xoma Corporation|
|Kieffer, Dorothy - University Of California|
|Goldfine, Ira - Xoma Corporation|
|Roell, Marina - Xoma Corporation|
|Adams, Sean - Arkansas Children'S Nutrition Research Center (ACNC)|
Submitted to: Journal of Cellular Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/19/2015
Publication Date: 7/23/2015
Citation: Bedinger, D.H., Kieffer, D.A., Goldfine, I.D., Roell, M.K., Adams, S.H. 2015. Acute treatment with XMetA activates hepatic insulin receptors and lowers blood glucose in normal mice. Journal of Cellular Biochemistry. 116(9):2109-2119. doi: 10.1002/jcb.25168.
Interpretive Summary: Diabetes is a major health concern with medical complications ranging from hypertension, to kidney disease, blindness and stroke. Direct medical costs are estimated at $176 billion per year. Therefore, improvements to control diabetes would result in lowered medical costs. A key to improved diabetes control is to control blood sugar, normally done with insulin injections. We studied an alternative approach- the use of a monoclonal antibody (XMetA) that mimics insulin. A monoclonal antibody is a man made clone from cells and thus a pure type of the antibody that can be used as a therapeutic agent. Because insulin and the monoclonal antibody differ in size not all body tissues are equally affected by the monoclonal antibody compared to insulin. Our findings showed that XMetA lower blood sugar quickly in a normal mouse, but had limited effect on the insulin receptor activation in muscle and fat. However, XMetA did activate the insulin receptor signal in the liver. Therefore, it appears that XMetA acts on the insulin signaling mechanism in the liver to reduce blood sugar.
Technical Abstract: It has been proposed that monoclonal antibodies may become therapeutics for metabolic diseases such as diabetes mellitus. We have previously characterized an allosteric monoclonal antibody to the human insulin receptor (IR), XMetA, that activated metabolic signaling leading to enhanced glucose transport in cultured cells, and chronically reduced fasting blood glucose levels in mouse models of diabetes mellitus. Under acute dosing conditions, the large size of an IR-binding antibody like XMetA (~150 kDa) could lead to a more rapid access into liver, an insulin sensitive tissue with well fenestrated capillaries, when compared to other insulin sensitive tissues with non-fenestrated capillaries, such as muscle and adipose. Thus, in the present study we administered XMetA (10 mg/kg) and insulin (0.5 U/kg) via IV injection, and for 90 minutes compared their effects on blood glucose lowering and IR activation in three of the major insulin-sensitive tissues of the normal fasted mouse; liver, adipose, and muscle. Like insulin, XMetA lowered blood glucose levels, although the effect was less rapid. Insulin activated IR autophosphorylation and Akt phosphorylation in liver, fat and muscle. In contrast, IR activation by XMetA was primarily observed in the liver. Both insulin and XMetA lowered ß-hydroxybutyrate levels in plasma; however, only insulin reduced both NEFA and glycerol concentrations. These data indicate that, in normal mice, acute glucose regulation by XMetA is largely mediated by its action on the liver.