<b>PTPN2 regulates metabolic flux to affect beta cell susceptibility to inflammatory stress</b>

<p dir="ltr"><b>Abstract</b></p><p dir="ltr"><i>Protein tyrosine phosphatase N2 </i>(<i>Ptpn2</i>) 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 beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory environment, we generated a beta cell-specific deletion of <i>Ptpn2</i> in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, low and high dose streptozotocin (STZ) treated <i>Ptpn2</i> βKO mice displayed hyperglycemia and accelerated death, respectively. Furthermore, cytokine treated <i>Ptpn2</i> KO islets resulted in impaired glucose-stimulated insulin secretion, mitochondrial defects and reduced glucose-induced metabolic flux, suggesting beta cells lacking <i>Ptpn2</i> 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 (ACLY) as a novel PTPN2 substrate.</p><p><br></p><p dir="ltr"><b>Article Highlights</b></p><p dir="ltr">· Although the T1D susceptibility factor PTPN2 has been shown to function in beta cells <i>in vitro</i>, an unbiased assessment of its <i>in vivo</i> function in the context of T1D was lacking.</p><p dir="ltr">· Beta cells deleted for <i>Ptpn2</i> 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 (ACLY) was identified as a novel PTPN2 substrate.</p><p dir="ltr">In the absence of PTPN2 beta cells are not able to metabolically compensate to an inflammatory environment.</p>