Intra-islet Glucagon Signalling Regulates Beta-cell Connectivity, First-phase Insulin Secretion and Glucose Homoeostasis

Objective: Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective loss of the glucagon receptor (Gcgr X Ins-1), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca] activity and insulin secretion.

Methods: Metabolic profiling was conducted on Gcgr and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment.

Results: Gcgr mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgr 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgr islets showed profound loss of pan-islet [Ca] waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca] waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n = 8).

Conclusion: These data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised [Ca] waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D.