The islets of Langerhans play a central role in blood glucose homeostasis through glucose regulated dose-dependent hormone secretion. The therapeutic success of insulin has led most diabetes research to be focused on ?-cells. Recently however, glucagon (secreted by ?-cells) has been shown to significantly contribute to the pathophysiology of diabetes. In both type 1 and type 2 diabetes, glucagon secretion is inappropriately elevated and dysregulated, further exacerbating hyperglycemia. Thus, understanding the mechanisms underlying ?-cell function and glucagon secretion represents an important avenue in the development of new therapeutic strategies for diabetes management. In combination with current treatments, therapeutics based on novel ?-cell targets will benefit patients with type 1 and type 2 diabetes by addressing multiple causes of hyperglycemia. Despite the important physiologic role of glucagon, the mechanisms regulating its secretion remain poorly understood. The Piston lab has recently published data suggesting that GIGS is not intrinsic to ?-cells, and that the inhibition of glucagon secretion is independent of Ca2+ influx. Our data show that similar to diabetic patients, pure populations of sorted ?-cells displa an increase in glucagon secretion at low glucose and a loss of glucose-inhibition of glucagon secretion (GIGS). Additionally, intracellular [Ca2+] is elevated in ?-cells in response to increase in glucose that inhibit glucagon secretion. The necessity of the intraislet environment for appropriate glucagon secretion cannot be explained solely through paracrine signaling, as sorted ?-cells are no longer sensitive to proposed paracrine inhibitors (insulin and somatostatin). Here, we propose a new juxtacrine signaling dependent model of GIGS that regulates glucagon secretion downstream of Ca2+ influx. Juxtacrine signaling through the EphA-ephrin-A signaling pathways has been shown to play an important role in both the basal and glucose dependent hormone secretion from islet ?-cells. Since the ?-cell is closely related to the ?-cell, we speculate that a similar mechanism plays a role in basal glucagon secretion and GIGS. Interestingly, both human and mouse ?-cells only express a single Eph receptor, EphA4. In preliminary studies pharmacologically inhibiting EphA4 receptor signaling, glucagon secretion was elevated at basal glucose and secretion was inappropriately stimulated response to glucose. These two findings mirror the glucagon secretion patterns observed in both sorted ?-cells and diabetic patients, indicating the importance of EphA4 receptor signaling in mediating glucagon secretion at basal and elevated glucose. We hypothesize that EphA4 receptor signaling in ?-cells is required for the appropriate suppression of glucagon secretion at basal glucose and for GIGS. Additionally, we hypothesize EphA4 receptor signaling is permissive for additional paracrine inhibitory signals (insulin and/or somatostatin).
Recent studies suggest that abnormal glucagon secretion from pancreatic ?-cells plays an important role in the development and pathology of diabetes. Despite the emerging importance of glucagon regulation, the cellular and molecular mechanisms underlying its secretion from ?-cells remain largely unknown. Elucidation of these mechanisms will provide possible therapeutic targets for the regulation of glucagon secretion that can be used for novel treatment strategies in both type 1 and type 2 diabetes.
| Hutchens, Troy; Piston, David W (2015) EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From ?-Cells. Diabetes 64:3839-51 |
