1975-P: Increased Pancreatic a Cell Ca2+ Oscillations Explain Hyperglucagonemia in High-Fat Diet-Fed Mice

Glucagon secretion from pancreatic α cells is elevated in obesity, exacerbating hyperglycaemia and contributing to the development of diabetes. α cells exhibit intracellular calcium (Ca 2+ i ) oscillations, which drive glucagon secretion. To understand these oscillations and their contribution (if any) to the diabetic phenotype, we developed a mouse model for studying α cell Ca 2+ i , and used this to investigate α cell Ca 2+ i dynamics in mice exposed to a high fat diet (HFD). Mice expressing GCaMP3 specifically in α-cells (Gcg Cre x GCaMP3 reporter mouse) were fed a control (10% fat; CTL) or high fat diet (60%; HFD) for 12 weeks. Mice then underwent a glucose tolerance test (GTT). Ca 2+ i imaging and glucagon secretion experiments were carried out on isolated (ex vivo) islets. HFD mice had impaired glucose tolerance compared to CTL mice (p 2+ i oscillation frequency was suppressed by high glucose (p These preliminary data suggest that hyperglucagonemia in HFD mice may have origins intrinsic to the islet. This was not due to reduced paracrine regulation by insulin, as insulin secretion was elevated in HFD mice. Future experiments will aim to fully power this study and understand whether α cell intrinsic mechanisms contribute to the hyperglucagonemic phenotype. Disclosure J. Kellard: None. L. Briant: None. J.G. Knudsen: None. P. Rorsman: None. Funding UK Wellcome Trust