Tranilast Inhibits Glucose-induced Insulin Secretion from Pancreatic β-Cells

Abstract

Tranilast, N-(3,4-demethoxycinnamoyl)-anthranilic acid, is an anti-allergic agent identified as an inhibitor of mast cell degranulation. Recently, tranilast was shown to decrease albuminuria in a rat model of diabetic nephropathy and to ameliorate vascular hypertrophy in diabetic rats, suggesting that it may be clinically useful in the treatment of diabetic complications. However, the effects of tranilast on glucose tolerance have not been elucidated. Thus, the aim of this study is to investigate the effect of tranilast on insulin secretion in pancreatic β-cells. Treatment with tranilast significantly suppressed insulin secretion in INS-1E cells and rat islets induced by 16.7 mmol/l glucose. Furthermore, tranilast inhibited tolbutamide-induced insulin secretion. Treatment with tranilast increased ⁸⁶Rb⁺ efflux from COS-1 cells in which pancreatic β-cell-type ATP-sensitive K⁺ (K_ATP) channels were reconstructed and suppressed the cytosolic ATP/ADP ratio in INS-1E cells. Interestingly, treatment with tranilast enhanced glucose uptake in INS-1E cells. In the present study, we demonstrated that tranilast inhibited glucose- and tolbutamide-induced insulin secretion through the activation of K_ATP channels in pancreatic β-cells.

Key words

ATP - ATP-sensitive K⁺ channels - INS-1E - insulin secretion - islet - tranilast

References

• 1 Wiederkehr A, Wollheim CB. Implication of mitochondria in insulin secretion and action.  Endocrinology. 2006;  147 2643-2649
• 2 Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T. Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion.  Science. 1999;  283 981-985
• 3 Erecinska M, Bryla J, Michalik M, Meglasson MD, Nelson D. Energy metabolism in islets of Langerhans.  Biochim Biophys Acta. 1992;  1101 273-295
• 4 Deeney JT, Prentki M, Corkey BE. Metabolic control of b-cell function.  Semin Cell Dev Biol. 2000;  11 267-275
• 5 Ashcroft FM, Gribble FM. ATP-sensitive K⁺ channels and insulin secretion: their role in health and disease.  Diabetologia. 1999;  42 903-919
• 6 Azuma H, Banno K, Yoshimura T. Pharmacological properties of N-(3′,4′-dimethoxycinnamoyl) anthranilic acid (N-5′), a new anti-atopic agent.  Br J Pharmacol. 1976;  58 483-488
• 7 Inagaki N, Kawasaki H, Nagai H. High rate of IgE-mediated hista-mine release from rat mesenteric mast cells.  Exp Anim. 2001;  50 187-190
• 8 Komatsu H, Kojima M, Tsutsumi N, Hamano S, Kusama H, Ujiie A, Ikeda S, Nakazawa M. Mechanism of inhibitory action of tranilast on the release of slow reacting substance of anaphylaxis (SRS-A) in vitro: effect of tranilast on the release of arachidonic acid and its metabolites.  Jpn J Pharmacol. 1988;  46 53-60
• 9 Chand N, Perhach  Jr  JL, Diamantis W, Sofia RD. Heterogeneity of calcium channels in mast cells and basophils and the possible relevance to pathophysiology of lung diseases: a review.  Agents Actions. 1986;  17 407-417
• 10 Nie L, Oishi Y, Doi I, Shibata H, Kojima I. Inhibition of proliferation of MCF-7 breast cancer cells by a blocker of Ca²⁺-permeable channel.  Cell Calcium. 1997;  22 75-82
• 11 Pfeiffer A, Schatz H. Diabetic microvascular complications and growth factors.  Exp Clin Endocrinol Diabetes. 1995;  103 7-14
• 12 Yamada H, Tajima S, Nishikawa T, Murad S, Pinnell SR. Tranilast, a selective inhibitor of collagen synthesis in human skin fibroblasts.  J Biochem (Tokyo). 1994;  116 892-897
• 13 Suzawa H, Kikuchi S, Ichikawa K, Koda A. Inhibitory action of tranilast, an anti-allergic drug, on the release of cytokines and PGE₂ from human monocytes-macrophages.  Jpn J Pharmacol. 1992;  60 85-90
• 14 Mifsud S, Kelly DJ, Qi W, Zhang Y, Pollock CA, Wilkinson-Berka JL, Gilbert RE. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy.  Nephron Physiol. 2003;  95 83-91
• 15 Soma J, Sugawara T, Huang YD, Nakajima J, Kawamura M. Tranilast slows the progression of advanced diabetic nephropathy.  Nephron. 2002;  92 693-698
• 16 Inagaki N, Gonoi T, Clement JPt, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. Reconstitution of I_KATP: an inward rectifier subunit plus the sulfonylurea receptor.  Science. 1995;  270 1166-1170
• 17 Lam NT, Cheung AT, Riedel MJ, Light PE, Cheeseman CI, Kieffer TJ. Leptin reduces glucose transport and cellular ATP levels in INS-1 b-cells.  J Mol Endocrinol. 2004;  32 415-424
• 18 Elsner M, Tiedge M, Guldbakke B, Munday R, Lenzen S. Importance of the GLUT2 glucose transporter for pancreatic b cell toxicity of alloxan.  Diabetologia. 2002;  45 1542-1549
• 19 Koyama S, Takagi H, Otani A, Suzuma K, Nishimura K, Honda Y. Tranilast inhibits protein kinase C-dependent signalling pathway linked to angiogenic activities and gene expression of retinal microcapillary endothelial cells.  Br J Pharmacol. 1999;  127 537-545
• 20 Spiecker M, Lorenz I, Marx N, Darius H. Tranilast inhibits cytokine-induced nuclear factor κB activation in vascular endothelial cells.  Mol Pharmacol. 2002;  62 856-863
• 21 Miyachi Y, Imamura S, Niwa Y. The effect of tranilast of the generation of reactive oxygen species.  J Pharmacobiodyn. 1987;  10 255-259
• 22 Noma A. ATP-regulated K⁺ channels in cardiac muscle.  Nature. 1983;  305 147-148
• 23 Niki I, Ashcroft FM, Ashcroft SJ. The dependence on intracellular ATP concentration of ATP-sensitive K-channels and of Na,K-ATPase in intact HIT-T15 beta-cells.  FEBS Lett. 1989;  257 361-364
• 24 Niki I, Ashcroft SJ. Possible involvement of protein phosphorylation in the regulation of the sulphonylurea receptor of a pancreatic b-cell line, HIT T15.  Biochim Biophys Acta. 1991;  1133 95-101

Correspondence