Work

SUN-554 PTPN2 regulates mitochondrial function in the context of type 1 diabetes-like stress conditions.

Year: 2025

Type: article

Abstract: Disclosure: Y. Kim: None. J. Moon: None. K. Won: None. L. Sussel: None. Aim/Hypothesis: Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified in human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. Methods: We generated beta cell specific Ptpn2 KO mice using the Ins-Cre and Ptpn2 floxed alleles. We used low-dose multiple STZ injections and cytokine treatment of islets to mimic T1D conditions, in vivo and in vitro, respectively. The treated mice and islets were assessed for beta cell functional properties. Seahorse analyses and metabolic flux assays using 13C glucose were performed on the cytokine treated islets. Results: PTPN2-βKO mice were initially euglycemic but began to display impaired beta cell function after 26 weeks of age. With age, PTPN2-βKO islets also displayed increased mitochondrial numbers, and had reduced OCR and increased ECAR. Consistent with these beta cell defects, streptozotocin treated PTPN2-βKO mice displayed marked increase in hyperglycemia. Furthermore, PTPN2-βKO islets showed reduced glucose stimulated insulin secretion, and altered OCR and ECAR upon cytokine treatment. These results suggest that the PTPN2-βKO islets have underlying metabolic defects that become revealed under T1D-like stress conditions. RNA-Seq analysis identified changes in mitochondria related genes expression, which was confirmed by 13C glucose metabolic flux analysis. Conclusions: These findings indicate that metabolic pathways are compromised in PTPN2-βKO islets under basal conditions, and these defects are exacerbated upon cytokine or low dose STZ treatment. In future studies, we will analyze the phenotype of the PTPN2-βKO on the NOD background to more accurately reflect T1D conditions. Presentation: Sunday, July 13, 2025

Source: Journal of the Endocrine Society

DOI: 10.1210/jendso/bvaf149.1206

Authors: YongKyung Kim, Jun Sung Moon, Kyu Chang Won, Lori Sussel

Institutions: Yeungnam University College, Yeungnam University, Yeungnam University Medical Center, University of Colorado Anschutz, University of Colorado Denver

Language: English

Topic: Pancreatic function and diabetes

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,255