Lilja Kjalarsdottir1, Sarah A Tersey2, Mridula Vishwanath3, Jen-Chieh Chuang4, Bruce A Posner3, Raghavendra G Mirmira5, Joyce J Repa6. 1. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, United States. Electronic address: lilja@usa.com. 2. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. 3. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, United States. 4. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, United States. 5. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, United States; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States. 6. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, United States; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, United States. Electronic address: joyce.repa@utsouthwestern.edu.
Abstract
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.
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.
Authors: Sue Lynn Lau; Rebecca A Stokes; Beverly Ng; Kim Cheng; Roderick Clifton-Bligh; Jenny E Gunton Journal: PLoS One Date: 2022-06-17 Impact factor: 3.752
Authors: Lilian Cristina Mendoza; Jürgen Harreiter; Gernot Desoye; David Simmons; Juan M Adelantado; Alexandra Kautzky-Willer; Agnieszka Zawiejska; Ewa Wender-Ozegowska; Annunziata Lapolla; Maria G Dalfra; Alessandra Bertolotto; Roland Devlieger; Fidelma Dunne; Elisabeth R Mathiesen; Peter Damm; Lisse Lotte Andersen; Dorte Moller Jensen; David Hill; Mireille Nicoline Maria van Poppel; Rosa Corcoy Journal: Nutrients Date: 2022-08-09 Impact factor: 6.706