Disease relevance of Gcgr

• Gcgr(-/-) mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to alpha cell, and to a lesser extent, delta cell proliferation [1].
• RESULTS: In comparison with wild-type mice, Gcgr (-/-) mice exhibited decreased body weight and food intake, reduced plasma glucose levels, and improved oral and intraperitoneal glucose tolerance [2].
• Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia [2].
• Metabolic stress from moderate hypoglycemia led to late-onset loss of retinal function in Gcgr(-/-) mice, loss of visual acuity, and eventual death of retinal cells [3].
• N-Ethylmaleimide treatment of rat liver plasma membranes results in an adenylyl cyclase (EC 4.6.1.1) system that shows no measurable cyclizing activity but retains both an active glucagon receptor and a receptor-sensitive regulatory component N as assessed by reconstitution into cyclase-negative (cyc-) membranes from S49 murine lymphoma [4].

High impact information on Gcgr

• We assessed the impact of low blood glucose on the vision of C57BL/6J mice rendered hypoglycemic by a null mutation of the glucagon receptor gene, Gcgr [3].
• At 10 months of age Gcgr(-/-) mice began to lose visual acuity and exhibit changes in retinal anatomy, including an increase in cell death that was initially more pronounced in the inner retina [3].
• Furthermore, the lean phenotype of Gcgr(-/-) mice suggests glucagon action may be involved in the regulation of whole body composition [1].
• Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice [1].
• These experiments indicate that the glucagon receptor facilitates activation of N by: (i) decreasing the apparent Km of N for Mg2+, and (ii) increasing the extent of activation that can be elicited by saturating concentrations of guanine nucleotide [4].

Biological context of Gcgr

• Elevated glucagon-like peptide-1 levels and reduced gastric emptying were also observed in Gcgr (-/-) mice, which also had reduced HFD-induced hyperinsulinaemia and hyperleptinaemia, and were resistant to the development of hepatic steatosis [2].
• CONCLUSIONS/INTERPRETATION: This study demonstrates that blocking glucagon signalling by targeted Gcgr gene deletion leads to an improvement in metabolic control in this mouse model [2].
• To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr(-/-)) [1].
• DNA sequence analysis of a partial mouse glucagon receptor cDNA demonstrated a high degree of sequence conservation across rodent species [5].
• We have cloned and sequenced the murine GR cDNA, gene and promoter region, and studied its tissue distribution [6].

Anatomical context of Gcgr

• In addition, Gcgr (-/-) mice were resistant to STZ-induced hyperglycaemia and pancreatic beta cell destruction [2].
• Reverse transcription-polymerase chain reaction also detected glucagon receptor mRNA transcripts in both fetal and adult pancreas and lung, jejunum, and ileum, but not in the large intestine [5].
• The ability of GR-ASOs to inhibit glucagon receptor mRNA expression was demonstrated in primary mouse hepatocytes by quantitative real-time RT-PCR [7].
• By RT-PCR analysis, we have determined that GR is expressed predominantly in liver, kidney, adrenal, lung and stomach, while lower levels of expression are detected in brown and white adipose tissue, cerebellum, duodenum and heart [6].
• Promoter analysis using deletion constructs in a rat cell line (CA-77) expressing the glucagon receptor, showed that the region from -64 to +127 relative to the proximal transcription start site was sufficient for maximal proximal promoter activity [8].

Associations of Gcgr with chemical compounds

• Furthermore, the acute insulin response (AIR) to intravenous glucose was higher in Gcgr(-/-) mice [9].
• In contrast, AIR to intravenous administration of other secretagogues was either not affected (carbachol) or significantly reduced (arginine, cholecystokinin octapeptide) in Gcgr(-/-) mice [9].
• METHODS: Gcgr (-/-) mice were challenged with a high-fat diet (HFD) and with streptozotocin, which induces beta cell damage [2].
• In addition, a 1000-bp region of the GR promoter has been sequenced which contains consensus sequences for putative DNA-binding proteins involved in tissue specificity (c/EBP; HNFI) or hormonal regulation (steroid receptor) [6].
• There was no significant effect on fasting plasma cholesterol or triglyceride levels associated with deletion of the glucagon receptor [10].

Other interactions of Gcgr

• These issues were examined in a line of mice with a global deletion of the GLU receptor (Gcgr-/-), which are characterized by lower blood glucose levels and by alpha- and delta-cell hyperplasia in adults [11].
• These data suggest multiple modes of action of OXM: 1) it directly elevates murine intrinsic HR through a GLP-1R-independent mechanism, perhaps via the glucagon receptor or an unidentified OXM receptor, and 2) it lowers food intake, activity, and T(b) in a GLP-1R-dependent fashion [12].

Analytical, diagnostic and therapeutic context of Gcgr

• Glucagon receptor mRNA transcripts were detectable by Northern blotting in poly(A)+ RNA from liver and kidney [5].
• Cloning and sequence analysis of the murine glucagon receptor-encoding gene [6].

References