GPR183 and GPR19 Activation Improves Pancreatic Alpha Cell‐Induced Glucose Homeostasis

Abstract

Diabetes mellitus (DM) is characterised by pancreatic islet failure and dysregulation. The pancreatic islet is comprised of three primary cell types: alpha, beta and delta cells. Pancreatic beta cell destruction is responsible for the onset of classical symptoms of DM consequent to loss of endogenous insulin production and has been the subject of decades of research effort. The mechanisms underlying alpha cell dysfunction are less well understood, but no less important. Alpha cell dysfunction contributes to counter regulatory failure and predisposes to severe hypoglycemia, a disabling and potentially fatal diabetic complication. Thus, it is critical to identify new targets for the treatment of alpha cell dysfunction. Using a PCR‐based screen of AlphaTC1‐9 cells, we identified G‐protein coupled receptors 183 and 19 as highly expressed in alpha cells. G‐protein coupled receptor 183 (GPR183, also known as EB12) is the receptor for the potent GPR183 agonist 7alpha 25‐dihydroxycholesterol. GPR183 expression is increased in human pancreatic beta cells and GPR183 activation by 7alpha 25‐dihydroxycholesterol promotes both insulin transcription and release in these beta cells. G‐protein coupled receptor 19 (GPR19) is the receptor for adropin, a small peptide which plays roles in metabolism and energy homeostasis. Circulating adropin acts on the liver to enhance Insulin receptor substrate (IRS) sensitivity and reduce hepatic glucose release. Adropin levels are reduced in obesity, and adropin administration to diet‐induced‐obese mice reduces insulin resistance and lowers fasting blood glucose. The effect of adropin on pancreatic alpha cell function had not been examined prior to this study. We hypothesize that GPR183 and GPR19 act in the pancreatic alpha cell to facilitate glucose homeostasis. To test this hypothesis, Alpha TC1‐9 cells were treated with GPR183 agonist, 7alpha 25‐dihydroxycholesterol, at 1nM, 10nM, and 100nM, or GPR19 agonist, adropin, at 1nM, 3nM, or 9nM. AlphaTC1‐9 were treated with agonists unstimulated, stimulated for 1 hour at 25mM glucose (HG) and treated at 5.5mM glucose (NG), or stimulated for 1 hour at 25mM glucose and treated at 2.2mM glucose (LG). Treatment with the GPR183 agonist 7alpha 25‐dihydroxycholesterol increased proglucagon transcript and reduced GPR183 and GPPR19 transcript in alphaTC1‐9 cells. Treatment with adropin had no effect on proglucagon transcript and robustly increased GPR183 transcript. These results suggest GPR183 and GPR19 as novel therapeutic targets to reduce the incidence of hypoglycemia in DM.Support or Funding InformationNIDDK