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Publication
Pancreatic T cell protein-tyrosine phosphatase deficiency affects beta cell
function in mice.
Authors Xi Y, Liu S, Bettaieb A, Matsuo K, Matsuo I, Hosein E, Chahed S, Wiede F, Zhang
S, Zhang ZY, Kulkarni RN, Tiganis T, Haj FG
Submitted By Submitted Externally on 11/3/2015
Status Published
Journal Diabetologia
Year 2015
Date Published 1/1/2015
Volume : Pages 58 : 122 - 31
PubMed Reference 25338551
Abstract T cell protein tyrosine phosphatase (TCPTP, encoded by PTPN2) regulates
cytokine-induced pancreatic beta cell apoptosis and may contribute to the
pathogenesis of type 1 diabetes. However, the role of TCPTP in pancreatic
endocrine function and insulin secretion remains largely unknown., To
investigate the endocrine role of pancreatic TCPTP we generated mice with
pancreas Ptpn2/TCPTP deletion (panc-TCPTP KO)., When fed regular chow,
panc-TCPTP KO and control mice exhibited comparable glucose tolerance. However,
when challenged with prolonged high fat feeding panc-TCPTP KO mice exhibited
impaired glucose tolerance and attenuated glucose-stimulated insulin secretion
(GSIS). The defect in GSIS was recapitulated in primary islets ex vivo and after
TCPTP pharmacological inhibition or lentiviral-mediated TCPTP knockdown in the
glucose-responsive MIN6 beta cells, consistent with this being cell autonomous.
Reconstitution of TCPTP in knockdown cells reversed the defect in GSIS
demonstrating that the defect was a direct consequence of TCPTP deficiency. The
reduced insulin secretion in TCPTP knockdown MIN6 beta cells was associated with
decreased insulin content and glucose sensing. Furthermore, TCPTP deficiency led
to enhanced tyrosyl phosphorylation of signal transducer and activator of
transcription 1 and 3 (STAT 1/3), and substrate trapping studies in MIN6 beta
cells identified STAT 1/3 as TCPTP substrates. STAT3 pharmacological inhibition
and small interfering RNA-mediated STAT3 knockdown in TCPTP deficient cells
restored GSIS to control levels, indicating that the effects of TCPTP deficiency
were mediated, at least in part, through enhanced STAT3 phosphorylation and
signalling., These studies identify a novel role for TCPTP in insulin secretion
and uncover STAT3 as a physiologically relevant target for TCPTP in the
endocrine pancreas.




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