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

Abstract

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.

Circular RNAs, Noncoding RNAs, and N6-methyladenosine Involved in the Development of MAFLD

“…In addition, YTHDF2 can enhance the protein expression of OCT4 by retaining m6A methylation of the 5 ′ -UTR of OCT4 mRNA [94]. Pancreatic β cell failure is a hallmark of diabetes, in which OCT4 signaling may be involved [95]. Consequently, YTHDF2 could function by regulating the expression of target genes to influence the development of various diseases, including DM, obesity, and MAFLD.…”