AJP - Endocrinology and Metabolism, Vol 270, Issue 6 E988-E994, Copyright © 1996 by American Physiological Society
Fasting and decreased B cell sensitivity: important role for fatty acid-induced inhibition of PDH activity
Y. P. Zhou, D. A. Priestman, P. J. Randle and V. E. Grill
Department of Molecular Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
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.
