1, 25-Dihydroxyvitamin D3 enhances glucose-stimulated insulin secretion in mouse and human islets: a role for transcriptional regulation of voltage-gated calcium …
L Kjalarsdottir, SA Tersey, M Vishwanath… - The Journal of steroid …, 2019 - Elsevier
The Journal of steroid biochemistry and molecular biology, 2019•Elsevier
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 …
(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 …
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-D3 (1,25D3) 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 1,25D3 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 1,25D3 in human and mouse islets and contains a conserved VDRE in intron 7. Results from GSIS assays suggest that 1,25D3 might upregulate a variant of R-type VGCC that is resistant to chemical inhibition.
Conclusion
These results suggest that the role of 1,25D3 in regulating calcium influx acts through the R-Type VGCC during GSIS, thereby modulating the capacity of beta cells to secrete insulin.
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