title: Absence of glucagon and insulin action reveals a role for the GLP-1 receptor in endogenous glucose production.
abstract: The absence of insulin results in oscillating hyperglycemia and ketoacidosis in type 1 diabetes. Remarkably, mice genetically deficient in the glucagon receptor (Gcgr) are refractory to the pathophysiological symptoms of insulin deficiency, and therefore, studies interrogating this unique model may uncover metabolic regulatory mechanisms that are independent of insulin. A significant feature of Gcgr-null mice is the high circulating concentrations of GLP-1. Hence, the objective of this report was to investigate potential noninsulinotropic roles of GLP-1 in mice where GCGR signaling is inactivated. For these studies, pancreatic β-cells were chemically destroyed by streptozotocin (STZ) in Gcgr(-/-):Glp-1r(-/-) mice and in Glp-1r(-/-) animals that were subsequently treated with a high-affinity GCGR antagonist antibody that recapitulates the physiological state of Gcgr ablation. Loss of GLP-1 action substantially worsened nonfasting glucose concentrations and glucose tolerance in mice deficient in, and undergoing pharmacological inhibition of, the GCGR. Further, lack of the Glp-1r in STZ-treated Gcgr(-/-) mice elevated rates of endogenous glucose production, likely accounting for the differences in glucose homeostasis. These results support the emerging hypothesis that non-β-cell actions of GLP-1 analogs may improve metabolic control in patients with insulinopenic diabetes.
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Jun
authors.affiliation: BioTechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Rohn L
authors.initials: RL
authors.lastname: Millican
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hawkins
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Konkol
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Showalter
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Christe
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN sloop_kyle_w@lilly.com.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Sloop
mesh_terms: D000818:Animals; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D018027:Receptors, Glucagon; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose