Glucagon Receptor Knockout Mice Display Increased Insulin Sensitivity and Impaired β-Cell Function

Abstract

In previous studies, glucagon receptor knockout mice (Gcgr ؊/؊ ) display reduced blood glucose and increased glucose tolerance, with hyperglucagonemia and increased levels of glucagon-like peptide (GLP)-1. However, the role of glucagon receptor signaling for the regulation of islet function and insulin sensitivity is unknown. We therefore explored ␤-cell function and insulin sensitivity in Gcgr G lucagon is a 29 -amino acid peptide secreted from pancreatic ␣-cells. In response to hypoglycemia, glucagon acts as a counterregulatory hormone to insulin, stimulating hepatic glucose production (HGP) and thus increasing blood glucose (1,2). In impaired glucose tolerance, suppression of glucagon secretion is impaired, leading to inappropriate glucagon levels in relation to the blood glucose level (3-5). As glucagon stimulates HGP, elevated glucagon levels may contribute to hyperglycemia in type 2 diabetes (6,7). In fact, several studies have demonstrated a correlation between elevated glucagon levels and increased HGP in type 2 diabetes (8), and animal studies have shown that inhibition of glucagon signaling has glucose-lowering effects (9 -12). Increased glucagon secretion has also been shown to be a strong predictor of the development of type 2 diabetes, suggesting that augmenting glucagon action is of pathophysiologic importance for type 2 diabetes (13). However, although glucagon has profound actions on HGP and also might be involved in diabetes pathophysiology, the role of glucagon for normal glucose homeostasis, insulin sensitivity, and islet function is not known.Mice with a targeted deletion in the glucagon receptor gene (Gcgr Ϫ/Ϫ ) have been developed to enable insights in the physiological actions of glucagon in glucose metabolism (14). Gcgr Ϫ/Ϫ mice have been found to exhibit improved glucose tolerance and reduced blood glucose levels in the presence of normal plasma insulin levels. In contrast, glucagon levels were dramatically increased, probably in compensation to the reduced glucagon receptor signaling. Interestingly, circulating levels of glucagonlike peptide (GLP)-1 of pancreatic origin were markedly increased in Gcgr Ϫ/Ϫ mice, while GLP-1 levels in intestinal extracts were similar to controls. Although islet function was not studied, it was found that the Gcgr Ϫ/Ϫ mice had altered islet architecture with marked islet and ␣-cell hyperplasia but without changes in ␤-cell morphology or pancreatic insulin content (14).The improved glucose tolerance and lowered blood glucose levels in Gcgr Ϫ/Ϫ mice point to a physiological role of glucagon signaling in glucose homeostasis. Here, we have therefore examined ␤-cell function and insulin sensitivity in Gcgr Ϫ/Ϫ mice. Hyperinsulinemic-euglycemic clamp studies were carried out to evaluate the effects of the glucagon receptor knockout on insulin sensitivity. In addition, the effect of glucagon receptor gene disruption on insulin secretion was investigated both in vivo and in vitro in isolated islets. RESEARCH DESIGN AND METHODS GcgrϪ/Ϫ mice were previously generate...

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

“…Pancreas perfusion studies using specific receptor antagonists demonstrated that glucagon stimulates insulin release mainly through GCGR, but not GLP-1 receptors on islet beta cells [33]. The critical role of glucagon in maintaining beta cell function is also supported by the observations in Gcgr −/− mice, which displayed impaired beta cell function due to the lack of glucagon action [34]. Consistently, this perception is further supported by another study showing that beta cell specific over-production of GCGR enhanced glucose-competent insulin secretion and increased beta cell mass [35].…”

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

“…Reduced expression of proglucagon in the alpha cells or altered posttranslational processing to glucagon could explain our findings of reduced plasma glucagon levels during 24 h profiles. Furthermore, it is possible that the apparent insulin secretion defect may be enhanced by impaired paracrine glucagon stimulation of the beta cells [33,34]. Finally, the novel idea that TCF7L2 is involved in the control of plasma glucagon levels is supported by unpublished data (V. Lyssenko and L. Groop) from 580 non-diabetic individuals participating in the Prevalence-Prediction-Prevention study, in which two other single nucleotide polymorphisms of TCF7L2, including rs10885414 and rs4639863 (but not rs7903146), were associated with altered plasma glucagon levels (p=0.03 and p=0.02, respectively).…”

11β-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets

“…Glucagon receptor knockout mice have diminished GSIS compared with WT mice, suggesting that disruption of glucagon signalling affects the insulin secretory pathway [37]. Human beta cells express functional glucagon receptors, which can generate signals for GSIS [38]; a glucocorticoid-mediated reduction in receptor number [34] could therefore impair insulin secretion.…”