1728-P: The Nkx6.1 Binding Partner Mef2D Modulates Beta-Cell Insulin Secretion and Cell Survival

We have explored Nkx6.1 binding partners and have shown that the transcription factor Mef2D is expressed in the beta cell and interacts with Nkx6.1. Interestingly, Mef2D mRNA and protein levels decrease as a function of aging in primary rat islets (77±27.3% reduction in mRNA and 62±13.4% reduction in protein). We sought to understand how changes in Mef2D levels impinge on beta cell insulin secretion, and survival. We observed that Mef2D overexpression impaired mitochondrial respiration at complex I (41±9.6% decrease), complex II (53±6.4% decrease), complex V (43±5.2% decrease), complex II linked oxidative phosphorylation (47±3.1% decrease) and maximal respiration (41±6.1% decrease), while Mef2D knockdown increased complex II linked oxidative phosphorylation (42±11.4%, increase) and maximal respiration (34±13.0%, increase). Mef2D overexpression decreased glucose stimulated insulin secretion (43±4% decreases) and cell survival with etoposide, camptothecin, and thapsigargin treatment (32±4.1%, 38±6.2%, and 16±4.8% decreases, respectfully). Conversely, Mef2D knockdown increased glucose stimulated insulin secretion (75±7% increase) and cell survival with etoposide, and thapsigargin treatment (25±3.7% and 168±11.4% increases, respectfully). The observed changes in respiration, insulin secretion, and cell survival corresponded with modulated electron transport chain component expression, including expression of complex I component mtND6, with Mef2D overexpression decreasing mtND6 mRNA (49±9.7% decrease) and protein (a 37±6.6% decrease). Our findings define Mef2D as a critical factor for modulating insulin secretion and beta cell survival through modulation of beta cell mitochondrial function.