Fasting and decreased B cell sensitivity: important role for fatty acid-induced inhibition of PDH activity

Am J Physiol. 1996 Jun;270(6 Pt 1):E988-94. doi: 10.1152/ajpendo.1996.270.6.E988.


Fasting inhibits glucose-induced insulin secretion. We investigated the role of a glucose fatty acid cycle for such inhibition and its molecular basis in pancreatic islets from 48-h fasted rats. The fasting-impaired insulin response to 27 mM glucose was restored by 41% with a carnitine palmitoyltransferase I inhibitor, etomoxir. Etomoxir also restored (by 50%) impaired glucose oxidation in islets from fasted rats and increased the ratio of oxidation to glycolytic flux from 33 to 43%. Fasting decreased total pyruvate dehydrogenase (PDH) activity (active, unphosphorylated plus inactive, phosphorylated form) by 29%, as well as the percentage of active form (54 +/- 5 vs. 79 +/- 2% in fed rats, P < 0.001). Fasting increased islet PDH kinase activity as follows: PDH-bound activity by 36% and free (not PDH bound) PDH kinase by 70%. Fasting failed to affect PDH kinase content when assayed by an enzyme-linked immunoabsorbent assay with antibodies raised against 45 kDa PDH kinase alpha-chain. We conclude that fasting impairs B cell function to a major extent through the operation of a glucose fatty acid cycle and that decreased PDH activity resulting from increased specific activity of PDH kinase constitutes an important molecular mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Culture Techniques
  • Enzyme Inhibitors / pharmacology
  • Epoxy Compounds / pharmacology
  • Fasting
  • Fatty Acids / physiology*
  • Glucose / metabolism
  • Glucose / pharmacology
  • Glycolysis / drug effects
  • Insulin / metabolism
  • Islets of Langerhans / physiology*
  • Male
  • Oxidation-Reduction / drug effects
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
  • Rats
  • Rats, Sprague-Dawley
  • Succinates / pharmacology


  • Enzyme Inhibitors
  • Epoxy Compounds
  • Fatty Acids
  • Insulin
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex
  • Succinates
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Glucose
  • etomoxir
  • monomethyl succinate