title: Raldh3 expression in diabetic islets reciprocally regulates secretion of insulin and glucagon from pancreatic islets.
abstract: We have previously reported that obesity-induced diabetes developed in high-fat diet (HFD)-fed BDF1 mice. This is caused by insufficient insulin response to an excess glucose load. In this study, we have shown that the enhanced expression of retinaldehyde dehydrogenase 3 (Raldh3) causes functional disorders of pancreatic islets in diabetic mouse models. In the pancreatic islets of HFD-induced diabetic BDF1 mice and spontaneously diabetic C57BL/KsJ(db/db) mice, gene expression analysis with oligonucleotide microarray revealed a significant increase in Raldh3 expression. Exposure to a culture medium containing a higher glucose concentration (25 mM) significantly increased Raldh3 expression in murine MIN6 and alphaTC1 clone 9 cells, which derived from the α and β-cells of pancreatic islets, respectively. Overexpression of Raldh3 reduced the insulin secretion in MIN6 cells, and surprisingly, increased the glucagon secretion in alphaTC1 clone 9 cells. Furthermore, the knockdown of Raldh3 expression with siRNA decreased the glucagon secretion in alphaTC1 clone 9 cells. Raldh3 catalyzes the conversion of 13-cis retinal to 13-cis retinoic acid and we revealed that 13-cis retinoic acid significantly reduces cell viability in MIN6 and alphaTC1 clone 9 cells, but not in cells of H4IIEC3, 3T3-L1, and COS-1 cell lines. These findings suggest that an increasing expression of Raldh3 deregulates the balanced mechanisms of insulin and glucagon secretion in the pancreatic islets and may induce β-cell dysfunction leading to the development of type 2 diabetes.
authors.affiliation: Research and Development Planning Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. shimamura.mitsuru.f2@daiichisankyo.co.jp
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shimamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Karasawa
authors.forename: Sachiko
authors.initials: S
authors.lastname: Sakakibara
authors.forename: Akira
authors.initials: A
authors.lastname: Shinagawa
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D005934:Glucagon / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015474:Isotretinoin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D050697:Retinal Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D007328:Insulin; D005934:Glucagon; D050697:Retinal Dehydrogenase; C508905:retinaldehyde dehydrogenase 3, mouse; D015474:Isotretinoin