Targeting hepatic glutaminase activity to ameliorate hyperglycemia
Author
dc.contributor.author
Miller, Russell A.
Author
dc.contributor.author
Shi, Yuji
Author
dc.contributor.author
Lu, Wenyun
Author
dc.contributor.author
Pirman, David A.
Author
dc.contributor.author
Jatkar, Aditi
Author
dc.contributor.author
Blatnik, Matthew
Author
dc.contributor.author
Wu, Hong
Author
dc.contributor.author
Cárdenas Matus, Julio
Author
dc.contributor.author
Wan, Min
Author
dc.contributor.author
Foskett, J. Kevin
Author
dc.contributor.author
Park, Junyoung O.
Author
dc.contributor.author
Zhang, Yiyi
Author
dc.contributor.author
Holland, William L.
Author
dc.contributor.author
Rabinowitz, Joshua D.
Author
dc.contributor.author
Birnbaum, Morris J.
Admission date
dc.date.accessioned
2018-07-24T22:32:13Z
Available date
dc.date.available
2018-07-24T22:32:13Z
Publication date
dc.date.issued
2018
Cita de ítem
dc.identifier.citation
Nature medicine, 24 (4): 518–524
es_ES
Identifier
dc.identifier.other
10.1038/nm.4514
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/150231
Abstract
dc.description.abstract
Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids(1). In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood. Contrary to the prevailing belief that glucagon acts primarily on cytoplasmic and nuclear targets, we find glucagon-dependent stimulation of mitochondrial anaplerotic flux from glutamine that increases the contribution of this amino acid to the carbons of glucose generated during gluconeogenesis. This enhanced glucose production is dependent on protein kinase A (PKA) and is associated with glucagon-stimulated calcium release from the endoplasmic reticulum, activation of mitochondrial alpha-ketoglutarate dehydrogenase, and increased glutaminolysis. Mice with reduced levels of hepatic glutaminase 2 (GLS2), the enzyme that catalyzes the first step in glutamine metabolism, show lower glucagon-stimulated glutamine-to-glucose flux in vivo, and GLS2 knockout results in higher fasting plasma glucagon and glutamine levels with lower fasting blood glucose levels in insulin-resistant conditions. As found in genome-wide association studies (GWAS), human genetic variation in the region of GLS2 is associated with higher fasting plasma glucose(2,3); here we show in human cryopreserved primary hepatocytes in vitro that these natural gain-of-function missense mutations in GLS2 result in higher glutaminolysis and glucose production. These data emphasize the importance of gluconeogenesis from glutamine, particularly in pathological states of increased glucagon signaling, while suggesting a possible new therapeutic avenue to treat hyperglycemia.
es_ES
Patrocinador
dc.description.sponsorship
US NIH
CA211437
FONDECYT
1160332
CONICYT/FONDAP
15150012