Increasing evidence shows that β-cell dysfunction precedes the clinical onset of type 1 diabetes ( 4, 5). Type 1 diabetes is characterized by hyperglycemia caused by autoimmune destruction of islet β-cells, leading to a decline in β-cell function and mass. In the U.S., type 1 diabetes currently affects an estimated 1.25 million people, and its prevalence is predicted to rise to 5 million Americans by 2050 ( 1– 3). Furthermore, they identify a Doc2b peptide that confers the beneficial effects of Doc2b and may be a therapeutic candidate for protecting functional β-cell mass.
These studies demonstrate that Doc2b enrichment in the β-cell protects against diabetogenic and proapoptotic stress. 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. 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. In addition, inducible β-cell–specific Doc2b-overexpressing transgenic (βDoc2b-dTg) mice show improved glucose tolerance and resist MLD-STZ–induced disruption of glucose tolerance, fasting hyperglycemia, β-cell apoptosis, and loss of β-cell mass. Indeed, Doc2b +/− knockout mice show an unusually severe response to multiple-low-dose streptozotocin (MLD-STZ), resulting in more apoptotic β-cells and a smaller β-cell mass. We hypothesized that Doc2b deficiency or overabundance may confer susceptibility or protection, respectively, to the functional β-cell mass.
To release insulin, β-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 β (Doc2b). Loss of functional β-cell mass is an early feature of type 1 diabetes.