Targeting hepatic glutaminase activity to ameliorate hyperglycemia

Nature Medicine 24, 518 (2018). doi:10.1038/nm.4514 Authors: 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 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 catalyze...
Source: Nature Medicine - Category: General Medicine Authors: Tags: Letter Source Type: research