Inhibition of the malate-aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion

The Biochemical Journal
Jelena A StamenkovicPeter Spégel

Abstract

Altered secretion of insulin as well as glucagon has been implicated in the pathogenesis of Type 2 diabetes (T2D), but the mechanisms controlling glucagon secretion from α-cells largely remain unresolved. Therefore, we studied the regulation of glucagon secretion from αTC1-6 (αTC1 clone 6) cells and compared it with insulin release from INS-1 832/13 cells. We found that INS-1 832/13 and αTC1-6 cells respectively secreted insulin and glucagon concentration-dependently in response to glucose. In contrast, tight coupling of glycolytic and mitochondrial metabolism was observed only in INS-1 832/13 cells. Although glycolytic metabolism was similar in the two cell lines, TCA (tricarboxylic acid) cycle metabolism, respiration and ATP levels were less glucose-responsive in αTC1-6 cells. Inhibition of the malate-aspartate shuttle, using phenyl succinate (PhS), abolished glucose-provoked ATP production and hormone secretion from αTC1-6 but not INS-1 832/13 cells. Blocking the malate-aspartate shuttle increased levels of glycerol 3-phosphate only in INS-1 832/13 cells. Accordingly, relative expression of constituents in the glycerol phosphate shuttle compared with malate-aspartate shuttle was lower in αTC1-6 cells. Our data suggest that t...Continue Reading

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Citations

Sep 22, 2015·The Journal of Clinical Investigation·Alan D Attie
Mar 17, 2016·Biochimica Et Biophysica Acta·Thierry Brun, Pierre Maechler
Sep 2, 2016·Physiological Reviews·David G Nicholls
Mar 3, 2020·Frontiers in Endocrinology·Farzad Asadi, Savita Dhanvantari
Jul 22, 2019·Journal of Molecular Biology·Peter Spégel, Hindrik Mulder
Dec 7, 2021·Molecular Metabolism·Naoya MuraoSusumu Seino

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