Boosting Doc2b Expression in the Pancreatic Beta Cell Is Sufficient to Enhance Whole-Body Glucose Tolerance
Presentation Number: SUN 575
Date of Presentation: April 2nd, 2017
Arianne Aslamy*1, Miwon Ahn2, Eunjin Oh2, Erika Olson2, Ragadeepthi Tunduguru2 and Debbie Thurmond2
1Indiana University School of Medicine, Indianapolis, IN, 2City of Hope, Duarte, CA
Evidence suggests that β-cell dysfunction precedes Type 1 Diabetes (T1D) in humans and rodent models. Normal insulin secretion from pancreatic β-cells requires intact soluble n-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) complexes. SNARE complex formation is mediated by the Double C2-domain protein β (Doc2b). Recent studies revealed that Doc2b deficiency at the mRNA and protein levels were evident in rodent models of diabetes. We hypothesized that Doc2b deficiency may underlie beta cell dysfunction, and that Doc2b overexpression may provide protection from beta cell dysfunction and destruction. Toward this, Doc2b heterozygous knockout mice showed an unusually severe response to a very low dose STZ treatment, supporting the concept that Doc2b deficiency increases susceptibility to T1D-related stress. Conversely, human beta cells overexpressing Doc2b resisted cytokine-induced apoptosis. To determine the protective capacity of Doc2b in vivo, we generated and tested doxycycline-inducible, beta cell specific Doc2b transgenic mice (TRE-DOC2B;INS2-rtTA) for changes in whole body glucose homeostasis. Dox-induced mice showed ~2-3 fold enrichment in beta cell Doc2b levels and exhibited enhanced whole-body glucose tolerance versus control mice, with no effects upon peripheral insulin sensitivity nor fasting hypoglycemia. Furthermore, Doc2b enrichment in clonal beta cells improved SNARE complex formation by 35% via activation of the t-SNARE, Syntaxin 4. Our data show that a truncated form of Doc2b is sufficient to carry forward this mechanistic advantage and improve glucose stimulated insulin secretion, and will be pursued in future studies of Doc2b-directed therapeutics. Given the beta cell specific effect of Doc2b on whole body glucose homeostasis and the potential for Doc2b to protect beta cell mass, our data suggests that Doc2b may be a viable early interventional target for prevention/treatment of T1D.
Nothing to Disclose: AA, MA, EO, EO, RT, DT