Modulation of glucocorticoid-induced GAD expression in pancreatic beta-cells by transcriptional activation of the GAD67 promoter and its possible effect on the development of diabetes.
GAD is a pancreatic beta-cell autoantigen in humans and nonobese diabetic (NOD) mice. Modulation of GAD expression in pancreatic beta-cells has been suggested to be associated with the development of autoimmune diabetes. Hormonal changes through environmental stimuli are considered to influence the expression of the disease. We determined whether steroid hormones would modulate the expression of GAD in pancreatic beta-cells. We treated NOD mouse beta-cells (MIN6N8a cells) with various steroids, including testosterone, estradiol, progesterone, and cortisol, and examined the expression of GAD67 mRNA. We found that only cortisol enhanced the expression of GAD67, whereas the other steroid hormones had no effect. When we treated MIN6N8a cells with a synthetic glucocorticoid, dexamethasone, we found that GAD67 mRNA expression was stimulated in a dose- and time-dependent manner. Cells treated with 100 nmol/l dexamethasone for 6 h showed a 10-fold increase in the expression of GAD67 mRNA and an increase in GAD67 protein. The upregulation of GAD67 expression in beta-cells by dexamethasone was found to be due to the transcriptional activation of the GAD67 promoter. We then examined whether dexamethasone would influence the development of diabetes in NOD mice. Injection of dexamethasone into neonatal NOD mice resulted in a significant increase in the expression of GAD67 mRNA in pancreatic beta-cells and the development of insulitis and diabetes. We conclude that glucocorticoid hormones can modulate GAD expression by the transcriptional activation of the GAD promoter and may influence the development of autoimmune diabetes in NOD mice.
Kim
Kyung Soo
KS
Laboratory of Endocrinology, Institute for Medical Sciences, Suwon, Republic of Korea.
Kang
Yup
Y
Choi
Sung E
SE
Kim
Ju Hee
JH
Kim
Hyeon Man
HM
Sun
Beichen
B
Jun
Hee-Sook
HS
Yoon
Ji-Won
JW
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000378:metabolism*; D006854:Hydrocortisone / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D005938:Glucocorticoids; D007527:Isoenzymes; D012333:RNA, Messenger; D003907:Dexamethasone; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D006854:Hydrocortisone