2166-P: Sel1L-Hrd1 ERAD Is a Key Regulator of Beta-Cell Function and Identity

Abstract

βcell survival and dedifferentiation are two hotly-debated mechanisms underlying βcell loss in type 2 diabetes; however, the underlying molecular mechanism remains largely unclear. Here we compare two principal protein quality control mechanisms, ER-associated protein degradation (ERAD) and autophagy and find that ERAD plays an important role in βcell dedifferentiation. Mice with βcell-specific Sel1L-Hrd1 deletion exhibit early-onset hyperglycemia and glucose intolerance as early as ~5 weeks of age. Surprisingly, in contrast to other tissue specific models of Sel1L-Hrd1 ERAD deficiency in which prohormones accumulate within the ER, Sel1L-Hrd1 ERAD deficiency impairs βcell function by attenuating insulin expression without an overt defect in proinsulin maturation and also triggers marked βcell dedifferentiation. There is, however, no overt activation of unfolded protein response (UPR) or proinsulin aggregation. In striking contrast to ERAD deficiency, loss of macroautophagy, a major mechanism for bulk protein degradation and organelle turnover, in βcells causes massive cell loss and hyperglycemia, but not βcell dedifferentiation. Thus, our data reveal a novel role of Sel1L-Hrd1 ERAD in the maintenance of βcell identify and demonstrate that impairment of ERAD contributes to the progression of type 2 diabetes in a manner distinct from that of autophagy. Disclosure N. Shrestha: None. X. Li: None. Y. Ji: None. R.B. Reinert: None. P. Arvan: None. L. Qi: None. Funding National Institutes of Health