1738-P: Stress-Independent Continuous Activation of ATF6α in Pancreatic ß-Cells In Vivo Causes Diabetes

Introduction & Objective: β-cell dysfunction is a required step in the progression to T2D. ATF6α is a key component of the Unfolded Protein Response (UPR) during Endoplasmic Reticulum (ER) stress. While ATF6α increases β-cell proliferation in certain conditions, pathological UPR activation harms β-cells. Whether excess ATF6α activation impairs in vivo β-cell function is not known.

Methods: Using destabilized-domain technology, our lab generated knock-in mice expressing the N-terminal fragment of human ATF6α fused to a ligand-dependent Dihydrofolatereductase (DHFR-ATF6α). These mice allow cell-type-specific (via Cre recombinase) temporal activation (via Trimethoprim (TMP)) of ATF6α in β-cells in live mice.

Results: Intraperitoneal (acute) or dietary (chronic) TMP exposure increased mRNA abundance of ATF6α target genes Pdia4, Grp78, Chop, Hyou1, Herpud1, Sel1l, but not sXBP1 target genes Erdj4, Sec24d, Ssr3 in islets from DHFR-ATF6α mice compared to Cre controls. After 7- and 14-days of dietary TMP exposure, both male and female DHFR-ATF6α mice had markedly impaired glucose tolerance, which was associated with normal insulin sensitivity and β-cell mass suggesting glucose intolerance was due to a defect in either insulin production or secretion. In vivo glucose-stimulated insulin secretion was reduced at 7-days while islet insulin content was reduced at 14-days but not 7-days. Ins1 and Ins2 mRNA were unchanged at either time point. Consistent with reduced insulin content, fewer mature insulin granules were observed at 14-days by TEM, along with marked morphological changes in β-cell ultrastructure. Preliminary confocal analysis suggested expansion of ER-marker KDEL in β-cells after ATF6α activation.

Conclusion: Continuous activation of ATF6α in β-cells in live mice causes β-cell dysfunction, with impaired insulin production and insulin secretion, and morphological abnormalities. Dysregulated ATF6α activation may participate in T2D pathogenesis.