Journal
DIABETES
Volume 67, Issue 7, Pages 1332-1344Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-1352
Keywords
-
Categories
Funding
- American Heart Association [17POST33661194, 15PRE21970002]
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK067912, R01 DK102233]
- Indiana CTSI Predoctoral Award [UL1TR001108]
- JDRF [INO-2014-165-A-V]
- Ruth and Robert Lanman Endowment
- George Schaeffer Award
- Excellence Award through the City of Hope
- National Cancer Institute of the National Institutes of Health [P30CA33572]
Ask authors/readers for more resources
Loss of functional beta-cell mass is an early feature of type 1 diabetes. To release insulin, beta-cells require soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, as well as SNARE complex regulatory proteins like double C2 domain-containing protein beta (Doc2b). We hypothesized that Doc2b deficiency or overabundance may confer susceptibility or protection, respectively, to the functional beta-cell mass. Indeed, Doc2b(+/-) knockout mice show an unusually severe response to multiple-low-dose streptozotocin (MLD-STZ), resulting in more apoptotic beta-cells and a smaller beta-cell mass. In addition, inducible beta-cell-specific Doc2b-overexpressing transgenic (bDoc2b-dTg) mice show improved glucose tolerance and resist MLD-STZ-induced disruption of glucose tolerance, fasting hyperglycemia, beta-cell apoptosis, and loss of beta-cell mass. Mechanistically, Doc2b enrichment enhances glucose-stimulated insulin secretion (GSIS) and SNARE activation and prevents the appearance of apoptotic markers in response to cytokine stress and thapsigargin. Furthermore, expression of a peptide containing the Doc2b tandem C2A and C2B domains is sufficient to confer the beneficial effects of Doc2b enrichment on GSIS, SNARE activation, and apoptosis. These studies demonstrate that Doc2b enrichment in the beta-cell protects against diabetogenic and proapoptotic stress. Furthermore, they identify a Doc2b peptide that confers the beneficial effects of Doc2b and may be a therapeutic candidate for protecting functional beta-cell mass.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available