Partial reduction of sympathetic noradrenaline synthesis enhanced insulin secretion and cell-cycle-associated activity of pancreatic β cells in mice

Type 2 diabetes is caused by dysfunction of pancreatic β cells. Sympathetic neurons innervate pancreatic β cells and noradrenaline inhibits insulin secretion and proliferation of pancreatic β cells in vitro. Previously, we have generated a genetically engineered mice exhibiting inducible and sympathetic neuron-selective loss of the tyrosine hydroxylase gene (<i>Th</i>-cKO mice), resulting in approximately 70% decline of pancreatic noradrenaline levels. In this study, we investigated the effects of sustained and downregulated sympathetic noradrenergic signaling on the pancreatic β cells using <i>Th</i>-cKO mice. Intraperitoneal glucose tolerance test revealed higher glucose tolerance in <i>Th</i>-cKO mice than the control mice without any difference in insulin tolerance test. <i>Th</i>-cKO mice also exhibited higher circulating insulin levels under glucose challenge. We also found that proliferative activity of pancreatic β cells increased in <i>Th</i>-cKO mice. These results indicate that partial and sustained suppression of sympathetic noradrenaline signaling could enhance insulin secretion and proliferative activity of pancreatic β cells. In addition, we found that <i>Th</i>-cKO mice showed partial alleviation of streptozotocin-induced hyperglycemia accompanied by increased β-cell proliferative response. Our data suggest that sympathetic noradrenaline synthesis can be a potential therapeutic target for diabetes.<b>NEW & NOTEWORTHY</b> In this paper, we found that inducible and partial reduction of noradrenaline synthesis in the sympathetic neurons increased circulating insulin levels under glucose challenges and upregulated proliferative activity of pancreatic β cells in mice. Moreover, inducible downregulation of sympathetic noradrenaline signaling also partially attenuated streptozotocin-induced hyperglycemia. These results suggest that sympathetic noradrenaline signaling should control insulin secretion and proliferative activity of β cells and that sympathetic noradrenaline synthesis can be a therapeutic target for diabetes.