Glucagon receptors on human islet cells contribute to glucose competence of insulin release

Abstract

Previous studies on rat beta cells in vitro have suggested that insulin release is synergistically regulated by signalling molecules derived from glucose metabolism on the one hand and adenylate cyclase stimulation by glucagon or related peptides on the other [1±3]. In rodent beta cells, regulation of the cAMPdependent signalling pathway has been shown [3±7] to depend on expression of specific receptors for glucagon-like peptide-1-(7±36) amide (GLP-1), glucosedependent insulinotropic polypeptide (GIP) and glucagon. The gastrointestinal hormones GLP-1 and GIP effectively increase glucose-induced insulin release in vitro [8±10]; their pivotal role as incretin hormones has been recently illustrated in two mouse models with homozygous null mutations in the respective genes [11,12]. It is not clear whether similar mechanisms operate in human beta cells. More than three decades ago insulin release in humans was shown to be dually stimulated by glucose and glucagon [13,14], the glucagon effect appearing independent of enhanced glucose mobilisation from the liver ]-glucagon-amide (n = 8; p < 0.05), indicating participation of endogenously released glucagon in the process of glucose-induced insulin release. The glucagon-receptor antagonist also suppressed the potentiation of glucose-induced insulin release by addition of 10 nmol/l glucagon. Conclusion/interpretation. These data suggest that human beta cells express functional glucagon receptors which can, similar to incretin hormone receptors, generate synergistic signals for glucose-induced insulin secretion.

Interleukin-6 regulates pancreatic α-cell mass expansion

“…In vitro, we found that IL-6 increases pro-glucagon expression in addition to regulating ␣-cell fate. It is known that the pancreatic ␣-cell helps to maintain ␤-cell glucose competence via glucagon (25), and the glucagon receptor KO mice has impaired ␤-cell function (26). Recently, establishment of a ␤-cell overexpressing glucagon receptor transgenic mouse confirmed this paradigm, as these mice have improved glucose tolerance and increased insulin secretion in response to glucose (27).…”

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.…”