TY - JOUR
T1 - 1,25-Dihydroxyvitamin D 3 enhances glucose-stimulated insulin secretion in mouse and human islets
T2 - a role for transcriptional regulation of voltage-gated calcium channels by the vitamin D receptor
AU - Kjalarsdottir, Lilja
AU - Tersey, Sarah A.
AU - Vishwanath, Mridula
AU - Chuang, Jen Chieh
AU - Posner, Bruce A.
AU - Mirmira, Raghavendra G.
AU - Repa, Joyce J.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/1
Y1 - 2019/1
N2 - Aim: Vitamin D deficiency in rodents negatively affects glucose-stimulated insulin secretion (GSIS) and human epidemiological studies connect poor vitamin D status with type 2 diabetes. Previous studies performed primarily in rat islets have shown that vitamin D can enhance GSIS. However the molecular pathways linking vitamin D and insulin secretion are currently unknown. Therefore, experiments were undertaken to elucidate the transcriptional role(s) of the vitamin D receptor (VDR) in islet function. Methods: Human and mouse islets were cultured with vehicle or 1,25-dihydroxyvitamin-D 3 (1,25D 3 ) and then subjected to GSIS assays. Insulin expression, insulin content, glucose uptake and glucose-stimulated calcium influx were tested. Microarray analysis was performed. In silico analysis was used to identify VDR response elements (VDRE) within target genes and their activity was tested using reporter assays. Results: Vdr mRNA is abundant in islets and Vdr expression is glucose-responsive. Preincubation of mouse and human islets with 1,25D 3 enhances GSIS and increases glucose-stimulated calcium influx. Microarray analysis identified the R-type voltage-gated calcium channel (VGCC) gene, Cacna1e, which is highly upregulated by 1,25D 3 in human and mouse islets and contains a conserved VDRE in intron 7. Results from GSIS assays suggest that 1,25D 3 might upregulate a variant of R-type VGCC that is resistant to chemical inhibition. Conclusion: These results suggest that the role of 1,25D 3 in regulating calcium influx acts through the R-Type VGCC during GSIS, thereby modulating the capacity of beta cells to secrete insulin.
AB - Aim: Vitamin D deficiency in rodents negatively affects glucose-stimulated insulin secretion (GSIS) and human epidemiological studies connect poor vitamin D status with type 2 diabetes. Previous studies performed primarily in rat islets have shown that vitamin D can enhance GSIS. However the molecular pathways linking vitamin D and insulin secretion are currently unknown. Therefore, experiments were undertaken to elucidate the transcriptional role(s) of the vitamin D receptor (VDR) in islet function. Methods: Human and mouse islets were cultured with vehicle or 1,25-dihydroxyvitamin-D 3 (1,25D 3 ) and then subjected to GSIS assays. Insulin expression, insulin content, glucose uptake and glucose-stimulated calcium influx were tested. Microarray analysis was performed. In silico analysis was used to identify VDR response elements (VDRE) within target genes and their activity was tested using reporter assays. Results: Vdr mRNA is abundant in islets and Vdr expression is glucose-responsive. Preincubation of mouse and human islets with 1,25D 3 enhances GSIS and increases glucose-stimulated calcium influx. Microarray analysis identified the R-type voltage-gated calcium channel (VGCC) gene, Cacna1e, which is highly upregulated by 1,25D 3 in human and mouse islets and contains a conserved VDRE in intron 7. Results from GSIS assays suggest that 1,25D 3 might upregulate a variant of R-type VGCC that is resistant to chemical inhibition. Conclusion: These results suggest that the role of 1,25D 3 in regulating calcium influx acts through the R-Type VGCC during GSIS, thereby modulating the capacity of beta cells to secrete insulin.
KW - Calcitriol
KW - Insulin secretion
KW - Islet
KW - Transcriptional regulation
KW - Vitamin D
KW - Voltage-gated calcium channels
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U2 - 10.1016/j.jsbmb.2018.07.004
DO - 10.1016/j.jsbmb.2018.07.004
M3 - Article
C2 - 30071248
AN - SCOPUS:85051052840
SN - 0960-0760
VL - 185
SP - 17
EP - 26
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
ER -