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J Clin Invest ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30507613


Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained ß cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.

Cell Metab ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30449685


Identification of cell-surface markers specific to human pancreatic ß cells would allow in vivo analysis and imaging. Here we introduce a biomarker, ectonucleoside triphosphate diphosphohydrolase-3 (NTPDase3), that is expressed on the cell surface of essentially all adult human ß cells, including those from individuals with type 1 or type 2 diabetes. NTPDase3 is expressed dynamically during postnatal human pancreas development, appearing first in acinar cells at birth, but several months later its expression declines in acinar cells while concurrently emerging in islet ß cells. Given its specificity and membrane localization, we utilized an NTPDase3 antibody for purification of live human ß cells as confirmed by transcriptional profiling, and, in addition, for in vivo imaging of transplanted human ß cells. Thus, NTPDase3 is a cell-surface biomarker of adult human ß cells, and the antibody directed to this protein should be a useful new reagent for ß cell sorting, in vivo imaging, and targeting.

Cell Rep ; 6(1): 56-69, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24388745


Toxic liver injury is a leading cause of liver failure and death because of the organ's inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo; in zebrafish, nitric-oxide (NO) enhanced liver formation independently of cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition of the enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted with the approved therapy N-acetylcysteine to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates for treating liver injury.

Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , S-Nitrosotióis/farmacologia , Acetaminofen/toxicidade , Aldeído Oxirredutases/metabolismo , Animais , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/uso terapêutico , S-Nitrosotióis/uso terapêutico , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo