Targeting hepatic glutaminase activity to ameliorate hyperglycemia

• Published in: Nature medicine Vol. 24; no. 4; pp. 518 - 524
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2018; Nature Publishing Group
• Subjects: 13/95; 631/337; 631/443/163; 631/443/319/1642/2037; 631/443/319/320; 82/58; Amino acids; Animals; Biomedicine; Calcium (reticular); Cancer Research; Care and treatment; Cells, Cultured; Cryopreservation; Development and progression; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Endoplasmic reticulum; Fasting; Fluctuations; Flux; Genetic diversity; Genome-wide association studies; Genomes; Glucagon; Glucagon - metabolism; Gluconeogenesis; Glucose; Glutaminase; Glutaminase - metabolism; Glutamine; Glutamine - metabolism; Glycogen; Health aspects; Hepatocytes; Hepatocytes - metabolism; Hepatology; Humans; Hydrolases; Hyperglycemia; Hyperglycemia - enzymology; Infectious Diseases; Insulin; Ketoglutaric acid; Kinases; Kinetics; letter; Liver; Liver - enzymology; Metabolic Diseases; Metabolic Flux Analysis; Metabolism; Mice, Inbred C57BL; Mice, Knockout; Missense mutation; Mitochondria; Molecular Medicine; Mutation; Neurosciences; Oxoglutarate dehydrogenase (lipoamide); Physiological aspects; Protein kinase A; Signaling
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4514

In mice, elevated glucagon during type 2 diabetes promotes more hepatic glutamine flux and greater gluconeogenesis, while reducing glutamine metabolism in the liver lowers hyperglycemia.
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 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
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.