More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic β-cell signaling

Songyuan Chen, Atsushi Ogawa, Makoto Ohneda, Roger H Unger, Daniel W Foster, J. Denis McGarry

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164 Citations (Scopus)

Abstract

We sought to explore the emerging concept that malonyl-CoA generation, with concomitant suppression of mitochondrial carnitine palmitoyltransferase I (CPT I), represents an important component of glucose-stimulated insulin secretion (GSIS) by the pancreatic β-cell (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney JT, Corkey BE: Malonyl-CoA and long-chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 267:5802-5810, 1992). Accordingly, pancreases from fed rats were perfused with basal (3 mM) followed by high (20 mM) glucose in the absence or presence of 2 mM hydroxycitrate (HC), an inhibitor of ATP-citrate (CIT) lyase (the penultimate step in the glucose → malonyl-CoA conversion). HC profoundly inhibited GSIS, whereas CIT had no effect. Inclusion of 0.5 mM palmitate in the perfusate significantly enhanced GSIS and completely offset the negative effect of HC. In isolated islets, HC stimulated [1- 14C]palmitate oxidation in the presence of basal glucose and markedly obtunded the inhibitory effect of high glucose. Directional changes in 14C incorporation into phospholipids were opposite to those of 14CO2 production. At a concentration of 0.2 mM, 2-bromostearate, 2-bromopalmitate and etomoxir (all CPT I inhibitors) potentiated GSIS by the pancreas and inhibited palmitate oxidation in islets. However, at 0.05 mM, etomoxir did not influence insulin secretion but still caused significant suppression of fatty acid oxidation. The results provide more direct evidence for a pivotal role of malonyl-CoA suppression of CPT I, with attendant elevation of the cytosolic long-chain acyl-CoA concentration, in GSIS from the normal pancreatic β-cell. They also raise the possibility that the tested CPT I inhibitors act, in part, by generating non-metabolizable acyl-CoA species that mimic the effects of natural acyl-CoAs in triggering insulin release.

Original languageEnglish (US)
Pages (from-to)878-883
Number of pages6
JournalDiabetes
Volume43
Issue number7
StatePublished - 1994

Fingerprint

Malonyl Coenzyme A
Carnitine O-Palmitoyltransferase
Glucose
Insulin
Acyl Coenzyme A
Palmitates
Pancreas
ATP Citrate (pro-S)-Lyase
Citric Acid
Phospholipids
Esters
Fatty Acids
Food

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

Cite this

More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic β-cell signaling. / Chen, Songyuan; Ogawa, Atsushi; Ohneda, Makoto; Unger, Roger H; Foster, Daniel W; McGarry, J. Denis.

In: Diabetes, Vol. 43, No. 7, 1994, p. 878-883.

Research output: Contribution to journalArticle

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AU - Unger, Roger H

AU - Foster, Daniel W

AU - McGarry, J. Denis

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