Cerulenin, an inhibitor of protein acylation, selectively attenuates nutrient stimulation of insulin release: a study in rat pancreatic islets.
Nutrients such as glucose stimulate insulin release from pancreatic beta-cells through both ATP-sensitive K+ channel-independent and -dependent mechanisms, which are most likely interrelated. Although little is known of the molecular basis of ATP-sensitive K+ channel-independent insulinotropic nutrient actions, mediation by cytosolic long-chain acyl-CoA has been implicated. Because protein acylation might be a sequel of cytosolic long-chain acyl-CoA accumulation, we examined if this reaction is engaged in nutrient stimulation of insulin release, using cerulenin, an inhibitor of protein acylation. In isolated rat pancreatic islets, cerulenin inhibited the glucose augmentation of Ca2+-stimulated insulin release evoked by a depolarizing concentration of K+ in the presence of diazoxide and Ca2+-independent insulin release triggered by a combination of forskolin and phorbol ester under stringent Ca2+-free conditions. Cerulenin inhibition of glucose effects was concentration dependent, with a 50% inhibitory concentration (IC50) of 5 microg/ml and complete inhibition at 100 microg/ml. Cerulenin also inhibited augmentation of insulin release by alpha-ketoisocaproate, a mitochondrial fuel. Furthermore, cerulenin abolished augmentation of both Ca2+-stimulated and Ca2+-independent insulin release by 10 micromol/l palmitate, which causes palmitoylation of cellular proteins. In contrast, cerulenin did not attenuate insulin release elicited by nonnutrient secretagogues, such as a depolarizing concentration of K+, activators of protein kinases A and C, and mastoparan. Glucose oxidation, ATP content in islets, and palmitate oxidation were not affected by cerulenin. In conclusion, cerulenin inhibits nutrient augmentation of insulin release with a high selectivity. The finding is consistent with a prominent role of protein acylation in the process of beta-cell nutrient sensing.
Yajima
H
H
Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Matsumoto, Japan.
Komatsu
M
M
Yamada
S
S
Straub
S G
SG
Kaneko
T
T
Sato
Y
Y
Yamauchi
K
K
Hashizume
K
K
Sharp
G W
GW
Aizawa
T
T
D000215:Acylation / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D002118:Calcium / Q000502:physiology; D002569:Cerulenin / Q000494:pharmacology*; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D009994:Osmolar Concentration; D010084:Oxidation-Reduction / Q000187:drug effects; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D007329:Insulin Antagonists; D011506:Proteins; D002569:Cerulenin; D019308:Palmitic Acid; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium