Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice.

The Biochemical Journal
Nam Ho JeoungRobert A Harris

Abstract

The importance of PDHK (pyruvate dehydrogenase kinase) 2 and 4 in regulation of the PDH complex (pyruvate dehydrogenase complex) was assessed in single- and double-knockout mice. PDHK2 deficiency caused higher PDH complex activity and lower blood glucose levels in the fed, but not the fasted, state. PDHK4 deficiency caused similar effects, but only after fasting. Double deficiency intensified these effects in both the fed and fasted states. PDHK2 deficiency had no effect on glucose tolerance, PDHK4 deficiency produced only a modest effect, but double deficiency caused a marked improvement and also induced lower insulin levels and increased insulin sensitivity. In spite of these beneficial effects, the double-knockout mice were more sensitive than wild-type and single-knockout mice to long-term fasting, succumbing to hypoglycaemia, ketoacidosis and hypothermia. Stable isotope flux analysis indicated that hypoglycaemia was due to a reduced rate of gluconeogenesis and that slightly more glucose was converted into ketone bodies in the double-knockout mice. The findings establish that PDHK2 is more important in the fed state, PDHK4 is more important in the fasted state, and survival during long-term fasting depends upon regulation o...Continue Reading

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Citations

Nov 12, 2013·Reviews in Endocrine & Metabolic Disorders·Nam Ho JeoungRobert A Harris
Feb 12, 2013·American Journal of Physiology. Heart and Circulatory Physiology·David G CotterPeter A Crawford
Mar 5, 2015·Molecular Metabolism·Christopher NogiecMary-Elizabeth Patti
Aug 8, 2015·Metabolomics : Official Journal of the Metabolomic Society·Qing-Yi LuWai-Nang Lee
Jul 1, 2015·Diabetes & Metabolism Journal·Nam Ho Jeoung
Jul 9, 2014·Diabetes & Metabolism Journal·In-Kyu Lee
Aug 29, 2018·American Journal of Physiology. Endocrinology and Metabolism·Kristoffer SvenssonSimon Schenk
Nov 30, 2018·The Journal of Biological Chemistry·Alla KlyuyevaKirill M Popov
Dec 21, 2013·The Journal of Biological Chemistry·Shih-Chia TsoDavid T Chuang
Sep 4, 2020·The Journal of Biological Chemistry·Dipsikha BiswasThomas Pulinilkunnil
Oct 4, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·James T LynchSimon T Barry
Mar 28, 2021·Developmental Cell·Lia Heinemann-YerushalmiElazar Zelzer

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