The Effects of Cerulenin, an Inhibitor of Protein Acylation, on the Two Phases of Glucose-Stimulated Insulin Secretion

Straub, Susanne G.; Yajima, Hiroki; Komatsu, Mitsuhisa; Aizawa, Toru; Sharp, Geoffrey W. G.

doi:10.2337/diabetes.51.2007.s91

Cited by 31 publications

(42 citation statements)

References 36 publications

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“…Consistent with the idea that fatty acid synthesis is important for insulin release, inhibitors of acetyl-CoA carboxylase such as TOFA and CP-640186, and of fatty acid synthase, such as triclosan and cerulenin, lowered insulin release from 50% to 90% in both rat pancreatic islets and INS-1 832/13 cells ( Figures 4 and 5). Cerulenin has previously been reported to inhibit insulin release and protein acylation in rat pancreatic islets [42] while only slightly decreasing ATP levels of the islets (15% to 37%) [43].…”

Section: Discussionmentioning

confidence: 94%

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

MacDonald

Dobrzyń

Ntambi

et al. 2008

Archives of Biochemistry and Biophysics

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Pancreatic beta cell mitochondria convert insulin secretagogues into products that support insulin exocytosis. We explored the idea that lipids are some of these products formed from acyl group transfer out of mitochondria to the cytosol, the site of lipid synthesis. There are two isoforms of acetyl-CoA carboxylase, the enzyme that forms malonyl-CoA from which C 2 units for lipid synthesis are formed. We found that ACC1, the isoform seen in lipogenic tissues, is the only isoform present in human and rat pancreatic islets and INS-1 832/13 cells. Inhibitors of ACC and fatty acid synthase inhibited insulin release in islets and INS-1 cells. Carbon from glucose and pyruvate were rapidly incorporated into many lipid classes in INS-1 cells. Glucose and other insulin secretagogues acutely increased many lipids with C 14 -C 24 chains including individual cholesterol esters, phospholipids and fatty acids. Many phosphatidylcholines and phosphatidylserines were increased and many phosphatidylinositols and several phosphatidylethanolamines were decreased. The results suggest that lipid remodeling and rapid lipogenesis from secretagogue carbon support insulin secretion.

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Section: Discussionmentioning

confidence: 94%

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

MacDonald

Dobrzyń

Ntambi

et al. 2008

Archives of Biochemistry and Biophysics

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“…Subsequent studies proposed that protein acylation might be involved in the KATP channel-independent amplification pathway responsible for time-dependent potentiation (TDP) and the second phase of glucose-stimulated insulin secretion [17,18]. Evidence in support of the idea was based originally on the malonyl CoA/long chain acyl CoA hypothesis that postulates a glucose-induced increase in the concentration of long chain acyl CoA in the cytosol [15], and subsequently on the use of cerulenin, a fungal antibiotic and well-known inhibitor of protein acylation [17,18]. The essential findings with cerulenin were that it had no effect on basal insulin secretion but had a powerful inhibitory effect on both phases of glucose-stimulated insulin release.…”

Section: Discussionmentioning

confidence: 99%

“…Cerulenin, a fungal antibiotic that inhibits protein acylation [28,29], has been used to indicate that protein acylation is involved in activities as diverse as Ca 2+ channel modulation [9], internalization [29,30], the stimulation of insulin release [16][17][18][19] and more recently, the inhibition of insulin secretion [20]. In the present study, we show that cerulenin enhanced the peak amplitude of I Ca-L in the range of -40 to +30mV and shifted the maximum of the currentvoltage relationship towards more negative potentials without changing the activation threshold for I Ca-L .…”

Section: Discussionmentioning

confidence: 99%

“…As protein acylation is a reversible process with dynamic cycles of acylation and deacylation [8,14] it is capable of playing a major role in signal transduction. It has been suggested that protein acylation plays a signaling role in the control of glucose-stimulated insulin secretion [15][16][17][18][19] and in the action of inhibitors of secretion such as norepinephrine [20]. In view of the importance of Ca 2+ -channels in the stimulation of insulin secretion [21][22][23][24][25][26] and the observation that Ca 2+ channels in bovine chromaffin cells are acylated [9], we studied the effects of two inhibitors of protein acylation, cerulenin and tunicamycin, on the activity of L-type Ca 2+ -channels in the β-cell line INS 832/13.…”

Section: Introductionmentioning

confidence: 99%

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The inhibitors of protein acylation, cerulenin and tunicamycin, increase voltage-dependent Ca2+ currents in the insulin-secreting INS 832/13 cell

Zhao

Sharp

Straub

2007

Biochemical Pharmacology

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As it has been suggested that protein acylation plays a role in nutrient stimulus-secretion coupling in the pancreatic β-cell, we examined the insulin secreting INS 832/13 β-cell line for evidence that protein acylation was involved. The perforated whole-cell configuration was employed to voltageclamp INS 832/13 cells. Voltage pulses were applied and Ca 2+ -currents measured in the presence and absence of the protein acylation inhibitors cerulenin and tunicamycin. Both inhibitors enhanced the peak amplitude of I Ca,L . Both increased the peak inward current in the range between −40 and +30 mV and shifted the apparent maximum current by 10 mV in the hyperpolarizing direction without affecting the activation threshold of −40 mV. The two drugs had qualitatively and quantitatively similar effects. Steady state activation curves revealed that cerulenin and tunicamycin shifted the activation curves in the hyperpolarization direction. Activation time constants were significantly reduced in the presence of both drugs. The Ca 2+ charge influx was increased by the drugs at all potentials tested. In contrast to these effects on the L-type Ca 2+ channel, the two inhibitors of protein acylation had no effect on the ATP-sensitive K + channel. The results suggest that protein acylation exerts a tonic inhibitory effect on L-type Ca 2+ channel function in the insulin secreting β-cell.

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“…We have recently suggested a role of protein acylation (21,22). Namely, cerulenin, an inhibitor of protein acylation, selectively obliterated nutrient-induced insulin release without metabolic perturbation in the islet cells (21).…”

Section: Molecular Basis Of Nonionic Signalsmentioning

confidence: 99%

Importance of Nonionic Signals for Glucose-Induced Biphasic Insulin Secretion

Aizawa

Sato²,

Komatsu³

2002

Diabetes

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Glucose induces biphasic insulin secretion by the islet ␤-cell. Based on recent knowledge on glucose signaling in the ␤-cell, the underlying mechanisms for this biphasicity could be envisaged as follows. Glucose-induced elevation of cytosolic free Ca 2؉ concentration, which is due to the electrophysiological events that originate in closure of the ATP-sensitive K ؉ (K ATP ) channel, most likely triggers the first phase. The second phase is produced by gradual augmentation and potentiation of Ca 2؉ -triggered insulin release by the K ATP channelindependent, nonionic signals. Protein acylation may be involved in the nonionic signaling. In patients lacking functional K ATP channels, however, the first phase of glucose-induced insulin secretion is clearly retained, casting doubt on the simplistic view outlined above. In this pathological condition, the K ATP channel-independent, most likely nonionic, glucose action alone is sufficient for the first-phase response. Diabetes 51 (Suppl.

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The Effects of Cerulenin, an Inhibitor of Protein Acylation, on the Two Phases of Glucose-Stimulated Insulin Secretion

Cited by 31 publications

References 36 publications

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

The inhibitors of protein acylation, cerulenin and tunicamycin, increase voltage-dependent Ca2+ currents in the insulin-secreting INS 832/13 cell

Importance of Nonionic Signals for Glucose-Induced Biphasic Insulin Secretion

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