The adipocyte-enriched secretory protein tetranectin exacerbates type 2 diabetes by inhibiting insulin secretion from β cells

• DOI: 10.1126/sciadv.abq1799
• Publication Date: 2022-09-21T17:58:34Z
• Authors: Fen Liu; Zixin Cai; Yan Yang; George Plasko; Piao Zhao; Xiangyue Wu; Cheng Tang; Dandan Li; Ting Li; Shanbiao Hu; Lei Song; Shaojie Yu; Ran Xu; Hairong Luo; Libin Fan; Ersong Wang; Zhen Xiao; Yujiao Ji; Rong Zeng; Rongxia Li; Juli Bai; Zhiguang Zhou; Feng Liu; Jingjing Zhang
• Keywords: 0301 basic medicine; p38 Mitogen-Activated Protein Kinases; 3. Good health; Mice; 03 medical and health sciences; Glucose; Thioredoxins; Diabetes Mellitus, Type 2; Insulin-Secreting Cells; Insulin Secretion; Adipocytes; Animals; Insulin; Lectins, C-Type; Biomedicine and Life Sciences

Pancreatic β cell failure is a hallmark of diabetes. However, the causes of β cell failure remain incomplete. Here, we report the identification of tetranectin (TN), an adipose tissue–enriched secretory molecule, as a negative regulator of insulin secretion in β cells in diabetes. TN expression is stimulated by high glucose in adipocytes via the p38 MAPK/TXNIP/thioredoxin/OCT4 signaling pathway, and elevated serum TN levels are associated with diabetes. TN treatment greatly exacerbates hyperglycemia in mice and suppresses glucose-stimulated insulin secretion in islets. Conversely, knockout of TN or neutralization of TN function notably improves insulin secretion and glucose tolerance in high-fat diet–fed mice. Mechanistically, TN binds with high selectivity to β cells and inhibits insulin secretion by blocking L-type Ca 2+ channels. Our study uncovers an adipocyte–β cell cross-talk that contributes to β cell dysfunction in diabetes and suggests that neutralization of TN levels may provide a new treatment strategy for type 2 diabetes.