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

Abstract：

OBJECTIVE: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. METHODS: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). RESULTS: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 for either 2 or 6 weeks had similar patterns of gene expression, although the changes were generally larger with longer GCGR knockout. CONCLUSIONS:These findings demonstrate that the effects of glucagon to mitigate diabetic hyperglycemia are not through acute signaling but require compensations that take weeks to develop.

journal_name

Mol Metab

journal_title

Molecular metabolism

authors

Rivero-Gutierrez B,Haller A,Holland J,Yates E,Khrisna R,Habegger K,Dimarchi R,D'Alessio D,Perez-Tilve D

doi

10.1016/j.molmet.2018.07.012

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

28-38

issn

2212-8778

pii

S2212-8778(18)30649-5

journal_volume

17

pub_type

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