HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 286/4/E560    most recent 00561.2002v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (42) Citing Articles via Google Scholar Google Scholar Articles by Lupi, R. Articles by Del Prato, S. Search for Related Content PubMed PubMed Citation Articles by Lupi, R. Articles by Del Prato, S.

Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR₂ in the modulation of insulin secretion

¹Department of Endocrinology and Metabolism, Metabolic Unit, and ²Department of Oncology, Surgical Unit, University of Pisa, 56100 Pisa, Italy

Submitted 23 December 2002 ; accepted in final form 12 November 2003

Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: , and (subdivided into ₁ and ₂). Recently, the presence of PPAR has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPAR mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPAR agonist are not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from nonobese adult donors. The presence of PPAR mRNAs was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24 h to either 22.2 mmol/l glucose and/or 0.25, 0.5, or 1.0 mmol/l long-chain fatty acid mixture (oleate to palmitate, 2:1). PPAR and, to a greater extent, total PPAR and PPAR₂ mRNAs were expressed in human islets, whereas PPAR mRNA was not detected. Compared with human adipose tissue, PPAR mRNA was expressed at lower levels in the islets, and PPAR at similar levels. The expression of PPAR₂ mRNA was not affected by exposure to 22.2 mmol/l glucose, whereas it decreased markedly and time dependently after exposure to progressively higher free fatty acids (FFA). This latter effect was not affected by the concomitant presence of high glucose. Exposure to FFA caused inhibition of insulin mRNA expression, glucose-stimulated insulin release, and reduction of islet insulin content. The PPAR agonists rosiglitazone and 15-deoxy--^12,14prostaglandin J₂ prevented the cytostatic effect of FFA as well as the FFA-induced changes of PPAR and insulin mRNA expression. In conclusion, this study shows that PPAR mRNA is expressed in human pancreatic islets, with predominance of PPAR₂; exposure to FFA downregulates PPAR₂ and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPAR agonists can prevent these effects.

pancreatic islets; peroxisome proliferator-activated receptors; polymerase chain reaction; messenger ribonucleic acid; lipotoxicity; glucotoxicity; prostaglandin; free fatty acids

This article has been cited by other articles:

				J. Takada, M. H. Fonseca-Alaniz, T. B. F. de Campos, S. Andreotti, A. B. Campana, M. Okamoto, C. d. N. Borges-Silva, U. F. Machado, and F. B. Lima Metabolic recovery of adipose tissue is associated with improvement in insulin resistance in a model of experimental diabetes J. Endocrinol., July 1, 2008; 198(1): 51 - 60. [Abstract] [Full Text] [PDF]

				A. Gastaldelli, E. Ferrannini, Y. Miyazaki, M. Matsuda, A. Mari, and R. A. DeFronzo Thiazolidinediones improve beta-cell function in type 2 diabetic patients Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E871 - E883. [Abstract] [Full Text] [PDF]

				N. Welsh, M. Cnop, I. Kharroubi, M. Bugliani, R. Lupi, P. Marchetti, and D. L. Eizirik Is There a Role for Locally Produced Interleukin-1 in the Deleterious Effects of High Glucose or the Type 2 Diabetes Milieu to Human Pancreatic Islets? Diabetes, November 1, 2005; 54(11): 3238 - 3244. [Abstract] [Full Text] [PDF]

				R. L. Hull, Z.-P. Shen, M. R. Watts, K. Kodama, D. B. Carr, K. M. Utzschneider, S. Zraika, F. Wang, and S. E. Kahn Long-Term Treatment With Rosiglitazone and Metformin Reduces the Extent of, but Does Not Prevent, Islet Amyloid Deposition in Mice Expressing the Gene for Human Islet Amyloid Polypeptide Diabetes, July 1, 2005; 54(7): 2235 - 2244. [Abstract] [Full Text] [PDF]

				S. Del Guerra, R. Lupi, L. Marselli, M. Masini, M. Bugliani, S. Sbrana, S. Torri, M. Pollera, U. Boggi, F. Mosca, et al. Functional and Molecular Defects of Pancreatic Islets in Human Type 2 Diabetes Diabetes, March 1, 2005; 54(3): 727 - 735. [Abstract] [Full Text] [PDF]

				E. Santini, P. Fallahi, S. M. Ferrari, A. Masoni, A. Antonelli, and E. Ferrannini Effect of PPAR-{gamma} Activation and Inhibition on Glucose-Stimulated Insulin Release in INS-1e Cells Diabetes, December 1, 2004; 53(suppl_3): S79 - S83. [Abstract] [Full Text] [PDF]

				J. Matsui, Y. Terauchi, N. Kubota, I. Takamoto, K. Eto, T. Yamashita, K. Komeda, T. Yamauchi, J. Kamon, S. Kita, et al. Pioglitazone Reduces Islet Triglyceride Content and Restores Impaired Glucose-Stimulated Insulin Secretion in Heterozygous Peroxisome Proliferator-Activated Receptor-{gamma}-Deficient Mice on a High-Fat Diet Diabetes, November 1, 2004; 53(11): 2844 - 2854. [Abstract] [Full Text] [PDF]