Ca2+i and the pancreatic α cell – intrinsic regulation and dysfunction in type 2 diabetes

In type 2 diabetes (T2D), elevated plasma glucagon concentration (hyperglucagonaemia) exacerbates hyperglycaemia due to inappropriate insulin secretion. Despite this, very little is known about why glucagon secreting α cells become dysfunctional. In α cells, intracellular Ca2+ ([Ca2+]i) oscillations drive glucagon secretion but much of their regulation remains obscure. Here we investigate how [Ca2+]i oscillations are regulated, and whether α cell [Ca2+]i dynamics change when mice are fed a high fat diet (to induce a T2D-like state). Mice expressing the genetically encoded calcium sensor GCaMP3 specifically in α cells were fed a control (10% calories from fat; CTL) or high fat (60% calories from fat; HFD) diet. After 12 weeks, glucose tolerance was impaired in HFD fed mice and plasma glucagon levels were elevated. Plasma glucagon was elevated in HFD mice in vivo during insulin-induced hypoglycaemia and in the perfused pancreas in situ. Glucagon secretion from HFD islets was elevated ex vivo suggesting that intra-islet (intrinsic) effects are involved. While the [Ca2+]i oscillation frequency in α cells was reduced by high (6-15 mM) glucose in both CTL and HFD islets, the frequency was higher in HFD fed mice. Following HFD, α cell [Ca2+]i oscillations and glucagon secretion were also less sensitive to inhibition by somatostatin (SST), an effect that correlated with reduced SST secretion from δ cells in mice fed the HFD. Collectively, these data indicate that altered α cell activity underlies hyperglucagonaemia in HFD. These data provide evidence that α cell dysfunction and altered intra-islet signalling manifests early in T2D. Correcting the glucagon secretion defects may provide therapeutic advantages, highlighting the potential of the α cell as a potential pharmacological target.