Vitamin D regulates insulin pathway and glucose metabolism in zebrafish ( Danio rerio )

Abstract

1,25‐dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D (VD) metabolite, is a steroid hormone playing an important role in many physiological functions in addition to maintaining mineral homeostasis. In this study, we explored the mechanism that the VD regulated insulin pathway and glucose metabolism in zebrafish in vitro and in vivo. Our results show that 1,25(OH)2D3 significantly enhances the expression of insulin receptor a (insra), insulin receptor substrate 1 (irs1) and glucose transporter 2 (glut2), and promotes glycolysis and glycogenesis, while suppressing gluconeogenesis in zebrafish liver cell line (ZFL) under the condition of high glucose (20 mM), instead of the normal glucose (10 mM). Moreover, consistent results were obtained from the zebrafish fed with VD3‐deficient diet, as well as the cyp2r1−/− zebrafish, in which endogenous VD metabolism is blocked. Furthermore, results from dual‐luciferase reporting system exhibited that 1,25(OH)2D3 directly activated the transcription of insra, rather than insrb in zebrafish by binding to vitamin D response element (VDRE) located at −181 to −167 bp in the promoter region of insra. Importantly, the 1,25(OH)2D3 treatment significantly alleviated the symptoms of hyperglycemia in diabetic zebrafish. In conclusion, our study demonstrated that VD activates VDRE located in the promoter area of insra in zebrafish to promote insulin/insra signaling pathway, thereby contributing to the maintenance of glucose homeostasis.

Enhanced insulin activity achieved in VDRa/b ablation zebrafish

“…However, significant upregulation of insulin transcriptional and AKT activation have been seen in the liver of the present vdra -/-;vdrb -/zebrafish. A previous study, in which diet-supplemented vitamin D 3 could promote insulin signaling supports this speculation (11). Moreover, significant enhancement of glucose catabolism was also seen in our vdra -/-;vdrb -/zebrafish.…”

“…Insights into the physiological actions of 1a,25(OH) 2 VD 3 in zebrafish have been gradually achieved from recent studies in several deficient zebrafish models (5)(6)(7)(8)(9)(10)(11). Basically, the involvement of 1a,25(OH) 2 VD 3 in mineral ion homeostasis or related craniofacial cartilage development in zebrafish have been only observed in several studies using morpholino-based knockdowns (5,10).…”

“…In zebrafish mutants with deficient in cyp2r1, an enzyme involved in vitamin D 3 activation, fatty acid oxidation in visceral adipose tissue (VAT) is promoted by 1a,25(OH) 2 VD 3 in our laboratory (8). Recently, Shao et al (2022) revealed the role of 1a,25(OH) 2 VD 3 in the regulation of insulin and glucose metabolism with cyp2r1-deficient models (11). These studies indicated the diversity of physiological functions of vitamin D 3 signaling developed over its long evolution.…”

“…Recently, Shao et al. (2022) revealed the role of 1α,25(OH) 2 VD 3 in the regulation of insulin and glucose metabolism with cyp2r1 -deficient models ( 11 ). These studies indicated the diversity of physiological functions of vitamin D 3 signaling developed over its long evolution.…”

Importance of GLUT Transporters in Disease Diagnosis and Treatment

“…By contrast, the low glucose concentration of 10 mM resulted in a very small increase in GLUT2 expression that was within the margin of error. In addition, treating diabetic zebrafish with that vitamin D 3 caused a significant reduction in visible hyperglycemia symptoms, which are growth retardation and the body being curved rather than straight [ 99 ].…”