Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.

Therapeutic potential of VIP vs PACAP in diabetes

Type 2 diabetes (T2D) is characterized by chronic insulin resistance and a progressive decline in beta-cell function. Although rigorous glucose control can reduce morbidity and mortality associated with diabetes, achieving optimal long-term glycemic control remains to be accomplished in many diabetic patients. As beta-cell mass and function inevitably decline in T2D, exogenous insulin administration is almost unavoidable as a final outcome despite the use of oral antihyperglycemic agents in many diabetic patients. Pancreatic islet cell death, but not the defect in new islet formation or beta-cell replication, has been blamed for the decrease in beta-cell mass observed in T2D patients. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve the management of T2D, because of its potential to reverse diabetes not just ameliorate glycemia. Therefore, an ideal beta-cell-preserving agent is expected to protect beta cells from apoptosis and stimulate postprandial insulin secretion along with increasing beta-cell replication and/or islet neogenesis. One such potential agent, the islet endocrine neuropeptide vasoactive intestinal peptide (VIP) strongly stimulates postprandial insulin secretion. Because of its broad spectrum of biological functions such as acting as a potent anti-inflammatory factor through suppression of Th1 immune response, and induction of immune tolerance via regulatory T cells, VIP has emerged as a promising therapeutic agent for the treatment of many autoimmune diseases including diabetes.

Synergistic Effect of Hyperglycemia and Suppression on Adult Mouse Islet Beta Cell Replication

The complementary role of hyperglycemia and suppression on islet beta cell regeneration was investigated in a syngeneic mouse model. gene silencing was performed by infecting islets of C57BL/6 with shRNA lentiviral particles. At 54 hours after viral infection, protein content in cultured targeting islets was 22% of that in freshly isolated islets. Six days after transplantation to diabetic mice, targeting islet graft had considerably more cells with Ki67-staining nuclei than nontargeting islets. The mice in the targeting-islet group had a significantly shorter duration of temporary hyperglycaemia than mice in the non-targeting-islet group. The long-termex vivobeneficial effect of silencing on graft function was also indicated by the significantly higher cumulative cure rate for diabetes in mice receiving 200 targeting islets than that in mice receiving 200 non-targeting islets. Our data suggest that hyperglycemia and persistent suppression have a synergistic effect on islet beta cell replication in adult mice.