THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic beta-cell function and preserving beta-cell mass

Impaired insulin secretion is a hallmark in type 2 diabetes mellitus (T2DM). THADA has been identified as a candidate gene for T2DM, but its role in glucose homeostasis remains elusive. Here we report that THADA is strongly activated in human and mouse islets of T2DM. Both global and beta-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced beta-cell function and decreased beta-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca2+ stores in beta-cells by inhibiting Ca2+ re-uptake via SERCA2 and inducing Ca2+ leakage through RyR2. Upon persistent ER stress, THADA interacts with and activates the pro-apoptotic complex comprising DR5, FADD and caspase-8, thus aggravating ER stress-induced apoptosis. Importantly, THADA deficiency protects mice from high-fat high-sucrose diet- and streptozotocin-induced hyperglycemia by restoring insulin secretion and preserving beta-cell mass. Moreover, treatment with alnustone inhibits THADA's function, resulting in ameliorated hyperglycemia in obese mice. Collectively, our results support pursuit of THADA as a potential target for developing T2DM therapies.