Pancreatic GnRH Is Essential for Constitutive Expression of Insulin in Islet β Cells

Presentation Number: LB MON 76
Date of Presentation: April 3rd, 2017

Mitsumori Kawaminami*, Ryota Terashima and Shiro Kurusu
Kitasato University, Aomori, Japan

Abstract

While GnRH is a principal neurohormone regulating gonadotrophin secretion, it is expressed also in peripheral tissues including pancreas. Peripheral action of GnRH is so far not clear. As GnRH stimulates the expression of annexin A5 (ANXA5), a member of annexin family 12 proteins, in the gonadotroph and peripheral cells, e.g. luteal cells, Leydig cells and mammary epithelial cells (1, 2, 3), ANXA5 could be utilized as a biomarker of GnRH action. In the present study, to seek a novel action site of GnRH and its function, the distribution of ANXA5 was examined in GnRH deficient mutant hypogonadal mouse (hpg). Immunohistochemistry for ANXA5 presented lower expression of ANXA5 in the anterior pituitary tissues of hpg as reported by us recently (4). We examined pancreas and found lower expression of ANXA5 in the pancreatic islet of hpg. Majority of islet cells were ANXA5 positive suggesting that β cells were the target of pancreatic GnRH. Surprisingly, immunohistochemistry demonstrated diminished expression of insulin in the islet of hpg. ANXA5 and insulin mRNA were confirmed to be both lower than those of wild mice in the pancreas of hpg. GnRHa administration (1 μg/day for 7days) to male hpg mice increased intensity of both ANXA5 and insulin immunostaining in the islet and decreased blood sugar significantly. Clonal cell line of β cell, MIN6, was used to see the direct effect of GnRH in vitro. GnRHa (10-9 M) increased both ANXA5 and insulin mRNA expression after 3 h incubation. As the promoter region of GnRH gene was reported to contain androgen responsive element, we examined the effect of castration on GnRH and ANXA5 expression. Wild adult mice were orchidectomized and pancreas was collected one week later. GnRH and ANXA5 mRNA were both increased by orchidectomy. Getting together, present study first demonstrate that ANXA5 can be used as a biomarker of GnRH action in the pancreas and show that pancreatic GnRH affects the constitutive expression of insulin. Functional relationship between androgen and pancreatic GnRH-ANXA5-insulin is suggested.

Reference:(1) Kawaminami et al., Endocrinology 2003 Aug;144(8) 3625-31 (2) Yao and Kawaminami J Reprod Dev 2008 Aug;54(4) 259-64 (3) Rieanrakwong et al., Endocrinology 2016 Jul;157(7) 2750-8 (4) Yonezawa et al., Endocr J 2015 62(12) 1127-32

 

Nothing to Disclose: MK, RT, SK