Targeting hepatic glutaminase activity to ameliorate hyperglycemia

Russell A. Miller, Yuji Shi, Wenyun Lu, David A. Pirman, Aditi Jatkar, Matthew Blatnik, Hong Wu, César Cárdenas, Min Wan, J. Kevin Foskett, Junyoung O. Park, Yiyi Zhang, William L. Holland, Joshua D. Rabinowitz, Morris J. Birnbaum

Research output: Contribution to journalArticle

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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. 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 α-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; 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.

Original languageEnglish (US)
Pages (from-to)518-524
Number of pages7
JournalNature Medicine
Volume24
Issue number4
DOIs
StatePublished - May 1 2018

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Glutaminase
Glucagon
Hyperglycemia
Liver
Glutamine
Glucose
Fasting
Gluconeogenesis
Fluxes
Plasmas
Glycogenolysis
Amino Acids
Genome-Wide Association Study
Medical Genetics
Missense Mutation
Medical problems
Cyclic AMP-Dependent Protein Kinases
Glycogen
Metabolism
Endoplasmic Reticulum

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Miller, R. A., Shi, Y., Lu, W., Pirman, D. A., Jatkar, A., Blatnik, M., ... Birnbaum, M. J. (2018). Targeting hepatic glutaminase activity to ameliorate hyperglycemia. Nature Medicine, 24(4), 518-524. https://doi.org/10.1038/nm.4514

Targeting hepatic glutaminase activity to ameliorate hyperglycemia. / Miller, Russell A.; Shi, Yuji; Lu, Wenyun; Pirman, David A.; Jatkar, Aditi; Blatnik, Matthew; Wu, Hong; Cárdenas, César; Wan, Min; Foskett, J. Kevin; Park, Junyoung O.; Zhang, Yiyi; Holland, William L.; Rabinowitz, Joshua D.; Birnbaum, Morris J.

In: Nature Medicine, Vol. 24, No. 4, 01.05.2018, p. 518-524.

Research output: Contribution to journalArticle

Miller, RA, Shi, Y, Lu, W, Pirman, DA, Jatkar, A, Blatnik, M, Wu, H, Cárdenas, C, Wan, M, Foskett, JK, Park, JO, Zhang, Y, Holland, WL, Rabinowitz, JD & Birnbaum, MJ 2018, 'Targeting hepatic glutaminase activity to ameliorate hyperglycemia', Nature Medicine, vol. 24, no. 4, pp. 518-524. https://doi.org/10.1038/nm.4514
Miller RA, Shi Y, Lu W, Pirman DA, Jatkar A, Blatnik M et al. Targeting hepatic glutaminase activity to ameliorate hyperglycemia. Nature Medicine. 2018 May 1;24(4):518-524. https://doi.org/10.1038/nm.4514
Miller, Russell A. ; Shi, Yuji ; Lu, Wenyun ; Pirman, David A. ; Jatkar, Aditi ; Blatnik, Matthew ; Wu, Hong ; Cárdenas, César ; Wan, Min ; Foskett, J. Kevin ; Park, Junyoung O. ; Zhang, Yiyi ; Holland, William L. ; Rabinowitz, Joshua D. ; Birnbaum, Morris J. / Targeting hepatic glutaminase activity to ameliorate hyperglycemia. In: Nature Medicine. 2018 ; Vol. 24, No. 4. pp. 518-524.
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