Targeting glutamate receptors in human alpha cells restores glucagon secretion in type 1 diabetes

Julia Panzer (University of Miami)

Julia Panzer, Alejandro Tamayo, Alejandro Caicedo

Increased glucagon secretion from the pancreatic alpha cell is the first and most important defense against hypoglycemia. In type 1 diabetes this defensive mechanism is lost, increasing the mortality risk. Thus, understanding the pathophysiological mechanisms that make alpha cells unresponsive to a drop in glycemia during disease progression is therefore of utmost is importance to improve the management of diabetes.

Summary of Results
Studying alpha cell physiology in type 1 diabetes has met major technological roadblocks, as methods conventionally used are very difficult to apply to type 1 diabetic donors. We overcome these limitations by using living pancreas slices, which allow functional assessments of damaged and infiltrated islets within their native environment. We used slices from non-diabetic donors and donors with type 1 diabetes to determine alpha cell responses to (a) changes in glycemia, (b) agonists, antagonists, and positive allosteric modulators of glutamate receptors, and (c) reference stimuli such as adrenaline and KCl depolarization using functional recordings. We further performed in vivo studies using mouse models with defective glucose counter regulation to determine whether alpha cell responses to hypoglycemia can be restored.

We found that alpha cells in slices from type 1 diabetic donors had normal glucagon content and responded to KCl depolarization but failed to respond to decreases in glucose concentration. Furthermore, we found severely dimished Ca2+ responses to both lowering in glucose concentration and glutamate receptor stimulation. By reactivating residual glutamate receptor function with the positive allosteric modulators cyclothiazide and aniracetam we could rescue glucagon secretion in response to hypoglycemia in human tissue slices from donors with T1D.