Acute and Long-term Effects of Peroxisome Proliferator-activated Receptor-γ Activation on the Function and Insulin Secretory Responsiveness of Clonal Beta-Cells

Abstract

Thiazolidinediones (TZDs) are used as antidiabetic therapy. The purpose of the present study was to examine whether the TZD rosiglitazone has direct actions on pancreatic beta-cells that contribute to its overall effects. Effects of acute and prolonged (48 h) exposure to rosiglitazone, as a model glitazone compound, were assessed in clonal pancreatic BRIN-BD11 beta-cells maintained in standard, glucotoxic and lipotoxic cultures. In acute 20-min incubations, rosiglitazone (0.2–100 μM) did not alter basal or glucose-stimulated insulin secretion. However, rosiglitazone (6.25 μM) enhanced (p<0.001) the acute insulinotropic action of GLP-1. Prolonged exposure to 6.25 μM rosiglitazone in standard media had no effect on cell viability or cellular insulin content, but slightly reduced the insulin secretory response to glucose and alanine (p<0.05). Prolonged (48 h) exposure to glucotoxic or lipotoxic conditions reduced beta-cell viability (p<0.05), cellular insulin content (p<0.001 and p<0.05, respectively), and insulin release in response to glucose and a range of secretagogues. The adverse effect of lipotoxicity on beta-cell viability was prevented by concomitant exposure to 6.25 μM rosiglitazone. Culture with 6.25 μM rosiglitazone further decreased acute insulin release under glucotoxic conditions. However, when insulin secretion was expressed as percentage cellular insulin content, rosiglitazone (6.25 μM) significantly improved many of the adverse effects of gluco- and lipotoxic conditions on insulin secretory responsiveness. The results suggest that despite decrease in cellular insulin content TZDs exert direct beneficial effects on beta-cell viability and function during gluco- or lipotoxicity.

Key words

insulin secretion - rosiglitazone - beta-cell - AMPK - PPAR-γ

References

• 1 Stumvoll M. Thiazolidinediones – some recent developments.  Expert Opin Investig Drugs. 2003;  12 1179-1187
• 2 Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).  J Biol Chem. 1995;  270 12953-12956
• 3 Ye P, Fang H, Zhou X, He YL, Liu YX. Effect of peroxisome proliferator-activated receptor activators on tumor necrosis factor-alpha expression in neonatal rat cardiac myocytes.  Chin Med Sci J. 2004;  19 243-247
• 4 Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline GW, Romanelli AJ, Rossbacher JC, Moore IK, Regittnig W, Munoz DS, Kim JH, Shulman GI. n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner.  Diabetes. 2007;  56 1034-1041
• 5 Wu HT, Chen W, Cheng KC, Yeh CH, Shen KH, Cheng JT. Indomethacin activates peroxisome proliferator-activated receptor γ to improve insulin resistance in cotton pellet granuloma model.  Horm Metab Res. 2010;  42 775-780
• 6 Campbell IW, Mariz S. Beta-cell preservation with thiazolidinediones.  Diabetes Res Clin Pract. 2007;  76 163-176
• 7 Dubois M, Pattou F, Kerr-Conte J, Gmyr V, Vandewalle B, Desreumaux P, Auwerx J, Schoonjans K, Lefebvre J. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells.  Diabetologia. 2000;  43 1165-1169
• 8 Fryer LG, Parbu-Patel A, Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways.  J Biol Chem. 2002;  277 25226-25232
• 9 LeBrasseur NK, Kelly M, Tsao TS, Farmer SR, Saha AK, Ruderman NB, Tomas E. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues.  Am J Physiol Endocrinol Metab. 2006;  291 E175-E181
• 10 Wang X, Zhou L, Shao L, Qian L, Fu X, Li G, Luo T, Gu Y, Li F, Li J, Zheng S, Luo M. Troglitazone acutely activates AMP-activated protein kinase and inhibits insulin secretion from beta cells.  Life Sci. 2007;  81 160-165
• 11 Richards SK, Parton LE, Leclerc I, Rutter GA, Smith RM. Over-expression of AMP-activated protein kinase impairs pancreatic beta-cell function in vivo.  J Endocrinol. 2005;  187 225-235
• 12 Tsuboi T, da Silva Xavier G, Leclerc I, Rutter GA. 5′-AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics.  J Biol Chem. 2003;  278 52042-52051
• 13 Sun G, Tarasov AI, McGinty J, McDonald A, da Silva Xavier G, Gorman T, Marley A, French PM, Parker H, Gribble F, Reimann F, Prendiville O, Carzaniga R, Viollet B, Leclerc I, Rutter GA. Ablation of AMP-activated protein kinase alpha1 and alpha2 from mouse pancreatic beta cells and RIP2. Cre neurons suppresses insulin release in vivo.  Diabetologia. 2010;  53 924-936
• 14 Richardson H, Campbell SC, Smith SA, Macfarlane WM. Effects of rosiglitazone and metformin on pancreatic beta cell gene expression.  Diabetologia. 2006;  49 685-696
• 15 Lamontagne J, Pepin E, Peyot ML, Joly E, Ruderman NB, Poitout V, Madiraju SR, Nolan CJ, Prentki M. Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic beta-cell at submaximal glucose concentrations.  Endocrinol. 2009;  150 3465-3474
• 16 Buettner R, Bettermann I, Hechtl C, Gäbele E, Hellerbrand C, Schölmerich J, Bollheimer LC. Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome.  Horm Metab Res. 2010;  42 769-774
• 17 McClenaghan NH, Barnett CR, Ah-Sing E, Abdel-Wahab YH, O’Harte FP, Yoon TW, Swanston-Flatt SK, Flatt PR. Characterization of a novel glucose-responsive insulin-secreting cell line, BRIN-BD11, produced by electrofusion.  Diabetes. 1996;  45 1132-1140
• 18 Hamid M, McCluskey JT, McClenaghan NH, Flatt PR. Comparison of the secretory properties of four insulin-secreting cell lines.  Endocr Res. 2002;  28 35-47
• 19 Flatt PR, Bailey CJ. Abnormal plasma glucose and insulin responses in heterozygous (ob/+) mice.  Diabetologia. 1981;  20 573-577
• 20 Diani AR, Sawada G, Wyse B, Murray FT, Khan M. Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes.  Am J Physiol Endocrinol Metab. 2004;  286 E116-E122
• 21 Kawasaki F, Matsuda M, Kanda Y, Inoue H, Kaku K. Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice.  Am J Physiol Endocrinol Metab. 2005;  288 E510-E518
• 22 Cox PJ, Ryan DA, Hollis JH, Harris AM, Miller AK, Vousden M, Cowley H. Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans.  Drug Metab Dispos. 2000;  28 772-780
• 23 Winzell MS, Ahrén B. G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes.  Pharmacol Ther. 2007;  116 437-448
• 24 LeClerc I, Rutter GA. AMP-activated protein kinase: a new beta-cell glucose sensor?: Regulation by amino acids and calcium ions.  Diabetes. 2004;  53 S67-S74
• 25 Green BD, Irwin N, Duffy NA, Gault VA, O’Harte FP, Flatt PR. Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1.  Eur J Pharmacol. 2006;  547 192-199
• 26 Derosa G, Maffioli P, Ferrari I, Mereu R, Ragonesi PD, Querci F, Franzetti IG, Gadaleta G, Ciccarelli L, Piccinni MN, D’Angelo A, Salvadeo SA. Effects of one year treatment of vildagliptin added to pioglitazone or glimepiride in poorly controlled type 2 diabetic patients.  Horm Metab Res. 2010;  42 663-669
• 27 Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction.  Endocr Rev. 2008;  29 351-366
• 28 Lenzen S. Oxidative stress: the vulnerable beta-cell.  Biochem Soc Trans. 2008;  36 343-347
• 29 Kanda Y, Shimoda M, Hamamoto S, Tawaramoto K, Kawasaki F, Hashiramoto M, Nakashima K, Matsuki M, Kaku K. Molecular mechanism by which pioglitazone preserves pancreatic beta-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARgamma agonist.  Am J Physiol Endocrinol Metab. 2010;  298 E278-E286
• 30 Blumentrath J, Neye H, Verspohl EJ. Effects of retinoids and thiazolidinediones on proliferation, insulin release, insulin mRNA, GLUT 2 transporter protein and mRNA of INS-1 cells.  Cell Biochem Funct. 2001;  19 159-169
• 31 Schinner S, Krätzner R, Baun D, Dickel C, Blume R, Oetjen E. Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs.  Br J Pharmacol. 2009;  157 736-745
• 32 Gupta D, Jetton TL, Mortensen RM, Duan SZ, Peshavaria M, Leahy JL. In vivo and in vitro studies of a functional peroxisome proliferator-activated receptor gamma response element in the mouse pdx-1 promoter.  J Biol Chem. 2008;  21: 283 32462-32470
• 33 Zeender E, Maedler K, Bosco D, Berney T, Donath MY, Halban PA. Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta.  J Clin Endocrinol Metab. 2004;  89 5059-5066
• 34 Evans-Molina C, Robbins RD, Kono T, Tersey SA, Vestermark GL, Nunemaker CS, Garmey JC, Deering TG, Keller SR, Maier B, Mirmira RG. Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure.  Mol Cell Biol. 2009;  29 2053-2067
• 35 Cnop M, Hannaert JC, Pipeleers DG. Troglitazone does not protect rat pancreatic beta cells against free fatty acid-induced cytotoxicity.  Biochem Pharmacol. 2002;  63 1281-1285
• 36 Kim SH, Abbasi F, Chu JW, McLaughlin TL, Lamendola C, Polonsky KS, Reaven GM. Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals.  Diabetes. 2005;  54 2447-2452

Correspondence