title: Acute Treatment With XMetA Activates Hepatic Insulin Receptors and Lowers Blood Glucose in Normal Mice.
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 min 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 β-hydroxybutyrate levels in plasma; however, only insulin reduced both non-esterified fatty acids (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.
authors: XOMA Corporation, Berkeley, California.|Molecular, Cellular and Integrative Physiology Graduate Group, University of California, Davis, California.
authors: Daniel H
authors: DH
authors: Bedinger
authors: Graduate Group in Nutritional Biology -and- Department of Nutrition, University of California, Davis, California.
authors: Dorothy A
authors: DA
authors: Kieffer
authors: XOMA Corporation, Berkeley, California.
authors: Ira D
authors: ID
authors: Goldfine
authors: XOMA Corporation, Berkeley, California.
authors: Marina K
authors: MK
authors: Roell
authors: Molecular, Cellular and Integrative Physiology Graduate Group, University of California, Davis, California.|Graduate Group in Nutritional Biology -and- Department of Nutrition, University of California, Davis, California.|Arkansas Children's Nutrition Center -and- University of Arkansas for Medical Sciences, Department of Pediatrics, Little Rock, Arkansas.
authors: Sean H
authors: SH
authors: Adams
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects*; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D007275:Injections, Intravenous; D007328:Insulin / Q000008:administration & dosage* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009132:Muscles / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D007328:Insulin; D011972:Receptor, Insulin; D020155:3-Hydroxybutyric Acid
keywords: CHO CELLS; DIABETES; INSULIN ANALOG; INSULIN RECEPTOR; LIVER; PARTIAL ALLOSTERIC AGONIST