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PTPN2 regulates metabolic flux to affect beta cell susceptibility to inflammatory stress

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posted on 2023-11-28, 17:39 authored by Yong Kyung Kim, Youngjung Rachel Kim, Kristen L, Wells, Dylan Sarbaugh, Michelle Guney, Chia-Feng Tsai, Tiffany Zee, Gerard Karsenty, Ernesto S. Nakayasu, Lori Sussel

Abstract

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 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 Ptpn2 in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, low and high dose streptozotocin (STZ) 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 beta 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 (ACLY) as a novel PTPN2 substrate.


Article Highlights

· Although the T1D susceptibility factor PTPN2 has been shown to function in beta cells in vitro, an unbiased assessment of its in vivo function in the context of T1D was lacking.

· Beta 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 (ACLY) was identified as a novel PTPN2 substrate.

In the absence of PTPN2 beta cells are not able to metabolically compensate to an inflammatory environment.

Funding

DOE DE-AC05-76RL01830

NIDDK P30 DK048520 P30 DK116073 R01 DK12536 R01 DK82590

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