The islet of Langerhans plays an important role in blood glucose homeostasis through regulated hormone secretion. The therapeutic success of insulin has led most islet research to focus on ?-cells, although other islet hormones including glucagon (secreted by ?-cells) and somatostatin (secreted by ?-cells) have important physiological actions. Glucagon plays a critical role in the pathology of diabetes, but the mechanisms that regulate glucagon secretion remain poorly understood. Interactions with other islet cell types are likely involved in glucose-inhibition of glucagon secretion (GIGS), since inhibition is lost in vivo after ?-cells are destroyed in Type I or fail in advanced Type 2 diabete. GIGS is also lost in vitro when ?-cells are isolated from the islet. The composition, architecture, and protein expression patterns of islet cell types vary between species, but the amplitude and temporal pattern of GIGS is nearly identical regardless of species. Thus, we propose to leverage species similarities towards uncovering molecular mechanisms underlying GIGS. The secretory product of ?-cells, somatostatin, is a promising molecular mediator of this interaction because GIGS is lost in islets with a genetic deletion of somatostatin, and the somatostatin receptor subtype 2 dominates its signaling in both human and mouse ?-cells. However, somatostatin alone does not inhibit glucagon secretion from isolated ?-cells, which suggests that somatostatin must combine with other cell-cell interactions in the islet for proper GIGS. One potential juxtacrine signaling mechanism that can inhibit exocytosis is ephrinA-EphA forward signaling, and transcriptome studies show that EphA4 is the only Eph receptor expressed in both human and mouse ?-cells. We have shown that islet glucagon secretion is suppressed in response to glucose even though ?-cell Ca2+ levels are elevated. This effect parallels that seen in islets lacking ?-cell gap junctions, where insulin secretion can be inhibited by juxtacrine communication mediated by ephrinA-EphA signaling even when Ca2+ levels are elevated. Since the ?-cell contains only a single Eph receptor sub-type and it is closely related to the ?-cell, we speculate that a similar mechanism may play a role in GIGS from islet ?-cells. Thus, we hypothesize that GIGS requires both paracrine signaling by somatostatin from ?-cells in the islet and juxtacrine communication from ?-cells via EphA4 forward signaling. This hypothesis will be tested via three specific aims: 1) determine the role of juxtacrine EphA4 forward signaling on islet glucagon secretion;2) determine the role of somatostatin-mediated paracrine signaling combined with EphA juxtacrine signaling on GIGS from ?-cells in intact islets;3) determine the roles of these paracrine and juxtacrine signaling pathways on GIGS from human islets of healthy and Type II diabetic donors. These experimental results will further our understanding of ?-cell function in mouse and human islets. This mechanistic information will provide novel therapeutic targets for the regulation of glucagon, which is an emerging opportunity for preventing hypoglycemic episodes and normalizing blood glucose in diabetic patients.

Public Health Relevance

Recent studies suggest that abnormal glucagon secretion from pancreatic ?-cells plays an important role in the development and pathology of diabetes. Despite this 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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Appel, Michael C
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Vanderbilt University Medical Center
Schools of Medicine
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Schwetz, Tara A; Reissaus, Christopher A; Piston, David W (2014) Differential stimulation of insulin secretion by GLP-1 and Kisspeptin-10. PLoS One 9:e113020
Benninger, Richard K P; Hutchens, Troy; Head, W Steven et al. (2014) Intrinsic islet heterogeneity and gap junction coupling determine spatiotemporal Ca²? wave dynamics. Biophys J 107:2723-33