PTPN2 Regulates Metabolic Flux to Affect ß-Cell Susceptibility to Inflammatory Stress.

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 ß-cell survival in the context of T1D. To test whether PTPN2 contributed to ß-cell dysfunction in an inflammatory environment, we generated a ß-cell-specific deletion of Ptpn2 in mice (PTPN2-ß knockout [ßKO]). Whereas unstressed animals exhibited normal metabolic profiles, low- and high-dose streptozotocin-treated PTPN2-ßKO 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 ß-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.