Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia.

Molecular Metabolism
Belen Rivero-GutierrezDiego Perez-Tilve

Abstract

Mice with congenital loss of the glucagon receptor gene (Gcgr-/- mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that includes hormonal signals with hypoglycemic activity. We combined temporally-controlled GCGR deletion with pharmacological treatments to dissect the direct contribution of GCGR signaling to glucose control in a common mouse model of T1DM. We induced experimental T1DM by injecting the beta-cell cytotoxin streptozotocin (STZ) in mice with congenital or temporally-controlled Gcgr loss-of-function using tamoxifen (TMX). Disruption of Gcgr expression, using either an inducible approach in adult mice or animals with congenital knockout, abolished the response to a long-acting Gcgr agonist. Mice with either developmental Gcgr disruption or inducible deletion several weeks before STZ treatment maintained normoglycemia. However, mice with inducible knockout of the Gcgr one week after the onset of STZ diabetes had only partial correction of hyperglycemia, an effect that was reversed by GLP-1 receptor blockade. Mice with Gcgr deletion fo...Continue Reading

Citations

Feb 6, 2019·JCI Insight·Megan E CapozziJonathan E Campbell
Feb 19, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Sean M Hartig, Aaron R Cox
Jun 11, 2019·Diabetes·Brian FinanJonathan E Campbell
Nov 27, 2020·Diabetes·Nadejda Bozadjieva KramerErnesto Bernal-Mizrachi
Jul 29, 2021·Endocrinology·Maigen BetheaDarleen A Sandoval
Jul 26, 2019·ACS Chemical Biology·Florence M BrunelRichard D DiMarchi

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Methods Mentioned

BETA
protein assay
electrophoresis
ELISA
Assay

Software Mentioned

ImageJ
GraphPad Prism
GraphPad

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