Intra-islet glucagon signalling regulates pulsatile insulin secretion and glucose homeostasis [article]

Kinga Suba, Yateen Patel, Aldara Martin Alonso, Anna Roberts, Ben Hansen, Mariana Norton, Jed Shrewsbury, Rachel Kwok, Vasiliki Kalogianni, Shiqian Chen, Xiaoxuan Liu, Guy A Rutter (+9 others)
2022 bioRxiv   pre-print
Type 2 diabetes (T2D) is characterised by the loss of pulsatile insulin secretion. We studied mice with β-cell specific loss of the glucagon receptor (Gcgr fl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor signalling on pan-islet calcium oscillations and insulin pulsatility. Methods: Frequently sampled intravenous glucose tolerance tests were conducted on Gcgr β-cell-/- and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell
more » ... c 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 β-cell-/- mice exhibited impaired glucose tolerance following intraperitoneal glucose challenge (control 12.7mmol/L vs. Gcgr β-cell-/- 15.4mmol/L at 15 min, p=0.002) ; fasting glycaemia was not different to controls. In vitro, Gcgr β-cell-/- islets showed profound loss of synchronised calcium waves in response to glucose which was only partially rescued in vivo. First-phase insulin pulsatility on peripheral blood sampling (n=5) was significantly disordered in Gcgr β-cell-/- mice (burst mass Gcgr β-cell-/- 0.30 versus 0.84 for controls p=0.04). Diet induced obesity and hyperglycaemia resulted in a loss of co-ordinated [Ca2+]I 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 calcium oscillations and support a possible therapeutic role for glucagonergic agents to restore the insulin pulsatility lost in T2D.
doi:10.1101/2022.09.01.506223 fatcat:tzq6dscnqbdejnh2ty64hmerxe