Expression of Thyroid Hormone Receptor Isoform α1 in Pancreatic Islets

Abstract

Thyroid hormone receptors (TR) mediate the action of thyroid hormones. Genetic studies revealed that the individual TR isoforms possess different functions. In the present paper we studied the expression of the isoforms TRα1 and TRβ1 in the murine pancreatic islet. TRα1 and TRβ1 mRNA transcripts and proteins were detected in islets using reverse transcription-polymerase chain reaction and Western blotting analyses, respectively. In immunohistochemical studies individual cells in the periphery of islets were labelled using an anti-TRα1 antibody. No labelled cells were detected in the exocrine pancreas. A similar staining pattern was obtained with an anti-glucagon antibody, but not with an anti-insulin antibody, which suggests that TRα1 is mainly expressed in α-cells. In order to address a potential function of TRα1 in this cell type, the regulation of glucagon gene expression by triiodothyronine was studied in a glucagon-producing cell line by Northern blot analysis and transient transfection assays using glucagon promoter luciferase fusion gene constructs. In these assays, triiodothyronine did not regulate the glucagon mRNA level or the glucagon promoter activity. The predominant localization of TRα1 in pancreatic α-cells suggests that this receptor isoform mediates a specific, yet unknown, function of thyroid hormones in this cell type.

Key words

Thyroid hormone - receptor - pancreas - diabetes mellitus - glucagon

References

• 1 Cortizo A M, Chazenbalk G D, de Gagliardino E E, Garcia M E, Pisarev M A, Gagliardino J J. Thyroid hormone binding and deiodination by pancreatic islets: relationship with the in vitro effect upon insulin secretion.  Acta Endocrinol. 1987;  116 66-72
• 2 Fernandez-Mejia C, Davidson M B. Regulation of glucokinase and proinsulin gene expression and insulin secretion in RIN-m5 F cells by dexamethasone, retinoic acid, and thyroid hormone.  Endocrinology. 1992;  130 1660-1668
• 3 Forrest D, Vennström B. Functions of thyroid hormone receptors in mice.  Thyroid. 2000;  10 41-52
• 4 Forrest D, Erway L C, Ng L, Altschuler R, Curran T. Thyroid hormone receptor β is essential for development of auditory function.  Nature Genet. 1996;  13 354-357
• 5 Forrest D, Sjöberg M, Vennström B. Contrasting developmental and tissue-specific expression of a and b thyroid hormone receptor genes.  EMBO J. 1990;  9 1519-1528
• 6 Fragner P, Ladram A, Aratan de Leon S. Triiodothyronine down-regulates thyrotropin-releasing hormone (TRH) synthesis and decreases pTRH-(160 - 169) and insulin release from fetal rat islets in culture.  Endocrinology. 1999;  140 4113-4119
• 7 Grzeskowiak R, Amin J, Oetjen E, Knepel W. Insulin responsiveness of the glucagon gene conferred by interactions between proximal promoter and more distal enhancer-like elements involving the paired-domain transcription factor Pax6.  J Biol Chem. 2000;  275 30037-30045
• 8 Hellerström C. Growth pattern of pancreatic islets in animals. Volk BW, Wellmann KF The Diabetic Pancreas. London; Bailliére Tindall 1977: 61-97
• 9 Hinata S, Nishi S, Matsukage T, Funai T, Ichiyama A, Yoshimi T. Regulation of glucokinase gene expression in cultured rat islet cells: The inhibitory effects of T3 and glucagon, and the stimulatory effect of glibenclamide.  Diabetes Res. 1994;  26 13-23
• 10 Knepel W, Chafitz J, Habener J F. Transcriptional activation of the rat glucagon gene by cyclic AMP-responsive element in pancreatic islet cells.  Mol Cell Biol. 1990;  10 6799-6804
• 11 Knepel W. Transcriptional control of pancreatic islet hormones gene expression.  Exp Clin Endocrinol. 1993;  101 39-45
• 12 Lee J T, Lebenthal E, Lee P C. Regulation of rat pancreatic nuclear triiodothyronine receptor by glucocorticoid.  Pancreas. 1991;  6 96-103
• 13 Murata Y. Multiple isoforms of thyroid hormone receptor: An analysis of their relative contribution in mediating thyroid hormone action.  Naoya J Med Sci. 1998;  61 103-115
• 14 Schmoll D, Walker K S, Alessi D R, Grempler R, Burchell A, Guo S, Walther R, Unterman T G. Regulation of glucose-6-phosphatase gene expression by protein kinase Bα and the forkhead transcription factor FKHR.  J Biol Chem. 2000;  275 36324-36333
• 15 Taniyama M, Kusano S, Miyoshi Y, Nakamura H, Kaihara M, Tobe T, Tomita M, Katagiri T, Ban Y. Mild resistance to thyroid hormone receptor beta.  Exp Clin Endocrinol Diabetes. 1996;  104 339-343
• 16 Wikström L, Johannsson C, Saltó C, Barlow C, Campos Barros A, Baas F, Forrest D, Thorén P, Vennström B. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor α1.  EMBO J. 1998;  17 455-461