THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-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 β-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced β-cell function and decreased β-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca2+ stores in β-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 β-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.