Figure 1. Potential roles for PTPN2 in the development of T1D.

Experimental evidence indicates that PTPN2 regulates apoptosis of pancreatic β-cells upon exposure to inflammatory cytokines by modulating phosphorylation of STAT1, which induces the mitochondrial apoptotic pathway. The T1D-associated variant rs1893217 in the PTPN2 gene has been associated with reduced IL-2 receptor signaling in response to IL-2, impacting the maintenance of FOXP3⁺ Tregs in T1D subjects. PTPN2 has also been shown to influence glucose homeostasis by dephosphorylating the insulin receptor b-chain in conjunction with the PTP1B phosphatase. In addition, PTPN2 impacts glucose levels by modulating STAT3 signaling downstream of the leptin receptor in the hypothalamus and in response to IL-6, repressing hepatic gluconeogenesis.