Fasting and decreased b-cell sensitivity: important role for fatty
acid-induced inhibition of pyruvate dehydrogenase activity.
Zhou, Yun-Ping, David A. Priestman, Philip J. Randle, and Valdemar E.
Grill.
Department of Molecular Medicine, The Endocrine & Diabetes Unit,
Karolinska Institute, Karolinska Hospital, S-171 76, Stockholm,
Sweden, Nuffield Department of Clinical Biochemistry, Radcliffe
Infirmary, University of Oxford, Oxford, OX2 6HE, UK, Department of
Medicine, Endocrine section, University of Trondheim, N-7006
Trondheim, Norway
APStracts 3:0027E, 1996.
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 per cent active form (54
+/- 5 vs 79 +/- 2 % in fed rats, P<0.001). Fasting increased
islet PDH kinase activity: PDH-bound by 36% and free (not PDH-bound)
PDH kinase by 70%. Fasting failed to affect PDH kinase content when
assayed by an ELISA with antibodies raised against 45 kD PDH kinase
O-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.
Received 21 August 1995; accepted in final form 16 January 1996.
APS Manuscript Number E401-5.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 February 96