A Maharaj1, L Zhu, F Huang, H Qiu, H Li, C Y Zhang, T Jin, Q Wang. 1. Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada.
Abstract
AIMS/HYPOTHESIS: Excessive secretion of glucagon partially contributes to the development of diabetic hyperglycaemia. However, complete blocking of glucagon action will lead to adverse effects, since glucagon exerts certain beneficial effects via its receptor in many organs. We aimed to study the effects of a 'decoy receptor' for circulating glucagon on modulating beta cell function and glucose homeostasis in mice by over-producing the glucagon receptor (GCGR) in skeletal muscles. METHODS: We generated transgenic mice in which the expression of Gcgr is driven by the muscle specific creatine kinase (Mck) promoter, and assessed the effects of glucagon on the modulation of glucose homeostasis under conditions of extremes of glucose influx or efflux. RESULTS: Mck/Gcgr mice showed increased circulating levels of glucagon and insulin, resulting in an unchanged ratio of glucagon-to-insulin. The levels of hepatic glucose-6-phosphatase (G6PC) and fructose-1,6-bisphosphatase (F1,6P2ase) were significantly decreased, whereas the phosphorylation level of pancreatic cAMP-response-element-binding-protein (CREB) was significantly increased in these transgenic mice. Under basal conditions, the mice displayed normal blood glucose levels and unchanged glucose tolerance and insulin sensitivity when compared with their age-matched wild-type (WT) littermates. However, following multiple low-dose streptozotocin injections, Mck/Gcgr mice exhibited a delay in the onset of hyperglycaemia compared with the WT controls. This was associated with preserved beta cell mass and beta cell secretory capacity in response to glucose challenge. CONCLUSIONS/ INTERPRETATION: We suggest that mild and chronic hyperglucagonaemia, through a strategy involving neutralising peripheral glucagon action, provides beneficial effects on beta cell function and glucose homeostasis. Mck/Gcgr mice thus represent a novel mouse model for studying the physiological effects of glucagon.
AIMS/HYPOTHESIS: Excessive secretion of glucagon partially contributes to the development of diabetic hyperglycaemia. However, complete blocking of glucagon action will lead to adverse effects, since glucagon exerts certain beneficial effects via its receptor in many organs. We aimed to study the effects of a 'decoy receptor' for circulating glucagon on modulating beta cell function and glucose homeostasis in mice by over-producing the glucagon receptor (GCGR) in skeletal muscles. METHODS: We generated transgenic mice in which the expression of Gcgr is driven by the muscle specific creatine kinase (Mck) promoter, and assessed the effects of glucagon on the modulation of glucose homeostasis under conditions of extremes of glucose influx or efflux. RESULTS:Mck/Gcgrmice showed increased circulating levels of glucagon and insulin, resulting in an unchanged ratio of glucagon-to-insulin. The levels of hepatic glucose-6-phosphatase (G6PC) and fructose-1,6-bisphosphatase (F1,6P2ase) were significantly decreased, whereas the phosphorylation level of pancreaticcAMP-response-element-binding-protein (CREB) was significantly increased in these transgenic mice. Under basal conditions, the mice displayed normal blood glucose levels and unchanged glucose tolerance and insulin sensitivity when compared with their age-matched wild-type (WT) littermates. However, following multiple low-dose streptozotocin injections, Mck/Gcgrmice exhibited a delay in the onset of hyperglycaemia compared with the WT controls. This was associated with preserved beta cell mass and beta cell secretory capacity in response to glucose challenge. CONCLUSIONS/ INTERPRETATION: We suggest that mild and chronic hyperglucagonaemia, through a strategy involving neutralising peripheral glucagon action, provides beneficial effects on beta cell function and glucose homeostasis. Mck/Gcgrmice thus represent a novel mouse model for studying the physiological effects of glucagon.
Authors: A Gastaldelli; S Baldi; M Pettiti; E Toschi; S Camastra; A Natali; B R Landau; E Ferrannini Journal: Diabetes Date: 2000-08 Impact factor: 9.461
Authors: Yin Liang; Melville C Osborne; Brett P Monia; Sanjay Bhanot; William A Gaarde; Chantal Reed; Pengxiang She; Thomas L Jetton; Keith T Demarest Journal: Diabetes Date: 2004-02 Impact factor: 9.461