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

Nam Ho Jeoung, Yasmeen Rahimi, Pengfei Wu, W. N Paul Lee, Robert Harris

Research output: Contribution to journalArticle

21 Citations (Scopus)

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. PDHK2deficiency caused higher PDHcomplex 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 of the PDH complex by both PDHK2 and PDHK4.

Original languageEnglish
Pages (from-to)829-839
Number of pages11
JournalBiochemical Journal
Volume443
Issue number3
DOIs
StatePublished - May 1 2012

Fingerprint

Hypothermia
Ketosis
Knockout Mice
Fasting
Insulin
Pyruvate Dehydrogenase Complex
Glucose
Ketone Bodies
Hypoglycemia
Isotopes
Blood Glucose
Fluxes
Gluconeogenesis
Insulin Resistance

Keywords

  • Glucose
  • Heart
  • Hypothermia
  • Ketoacidosis
  • Liver
  • Pyruvate dehydrogenase complex (PDH complex)
  • Pyruvate dehydrogenase kinase (PDHK)
  • Skeletal muscle

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice. / Jeoung, Nam Ho; Rahimi, Yasmeen; Wu, Pengfei; Lee, W. N Paul; Harris, Robert.

In: Biochemical Journal, Vol. 443, No. 3, 01.05.2012, p. 829-839.

Research output: Contribution to journalArticle

Jeoung, Nam Ho ; Rahimi, Yasmeen ; Wu, Pengfei ; Lee, W. N Paul ; Harris, Robert. / Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice. In: Biochemical Journal. 2012 ; Vol. 443, No. 3. pp. 829-839.
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