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

ABSTRACT: 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 pr

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC9950491 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature