부산대학교 도서관

Protein tyrosine phosphatase N2 (PTPN2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation and models of T1D, suggesting that PTPN2 may be important for β-cell survival in the context of T1D. To test whether PTPN2 contributed to β-cell dysfunction in an inflammatory environment, we generated a β-cell–specific deletion of Ptpn2 in mice (PTPN2-β knockout [βKO]). Whereas unstressed animals exhibited normal metabolic profiles, low- and high-dose streptozotocin-treated PTPN2-βKO mice displayed hyperglycemia and accelerated death, respectively. Furthermore, cytokine-treated Ptpn2 -KO islets resulted in impaired glucose-stimulated insulin secretion, mitochondrial defects, and reduced glucose-induced metabolic flux, suggesting β-cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to maladaptive metabolic fitness. Consistent with the phenotype, proteomic analysis identified an important metabolic enzyme, ATP-citrate lyase, as a novel PTPN2 substrate. Article Highlights: Although the type 1 diabetes (T1D) susceptibility factor protein tyrosine phosphatase N2 (PTPN2) has been shown to function in β-cells in vitro, an unbiased assessment of its in vivo function in the context of T1D was lacking. β-Cells deleted for Ptpn2 have reduced mitochondrial function with age and are more susceptible to inflammatory stress associated with T1D due to maladaptive metabolic fitness. Consistent with the phenotype, the metabolic enzyme ATP-citrate lyase was identified as a novel PTPN2 substrate. In the absence of PTPN2, β-cells are not able to metabolically compensate for an inflammatory environment. [ABSTRACT FROM AUTHOR]