Role of the Vitamin D Receptor in Insulin Secretion and Beta Cell Function




Kjalarsdottir, Lilja

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1,25-dihydroxyvitamin D3 (VitD) is a ligand for the Vitamin D Receptor (VDR, NR1I1), which is a member of the family of Nuclear Hormone Receptors (NHR). Previously, the Repa lab identified VDR as the fourth most abundant NHR in mouse islets based on mRNA levels, also, VDR is clearly present in human islets [1]. In the past years multiple epidemiological studies have implicated Vitamin D deficiency in the development of Type 2 Diabetes, however no reports have described any mechanism(s) linking VitD status with pancreatic islet function. Therefore, my studies have focused on the role of Vitamin D and VDR in islet biology. Preincubation of isolated mouse and human islets with Vitamin D results in enhanced glucose-stimulated insulin secretion (GSIS). This response is VDR-dependent, as no VitD-mediated change in GSIS is observed in islets obtained from Vdr-null mice. However, VitD causes no changes in gene expression of any of the major islet hormones, nor does it change glucose uptake into primary beta cells. VitD does however increase glucose-stimulated calcium uptake, suggesting that VitD affects transcription of genes involved in calcium flux into the beta cell. To identify molecular mechanisms linking VDR activity to increased insulin secretion and increased glucose-stimulated calcium uptake, we performed global gene expression profiling by microarray in mouse and human islets. These studies identified multiple genes associated with islet function, calcium transport and insulin secretion. One of these genes is the R-type voltage-gated calcium channel, CaV2.3, which is highly upregulated by VitD in human and mouse islets. We identified a strong VDR binding element within intron 7 of the Cav2.3 gene that is conserved in mouse and man. With previous reports linking Cav2.3 activity with Type 2 Diabetes, our findings support a role for vitamin D signaling in the regulation of CaV2.3 and calcium uptake to enhance glucose-stimulated insulin secretion by beta cells of the endocrine pancreas. A second VDR target gene we identified in the islet is klotho, a key regulator of phosphate homeostasis. We clearly establish that klotho mRNA and protein are detected in beta cells of mouse islets, at levels sufficient to mediate signal transduction pathways via klotho’s role as a co-receptor for FGF23. By analysis of islets from Klotho-/- mice, we also show that the sialidase activity of klotho may modulate the membrane localization of GLUT-2 to affect glucose-stimulated insulin secretion. In summary, my studies suggest that vitamin D status may impact the beta cell’s capacity to sense glucose levels and respond appropriately to secrete the anabolic hormone, insulin. Future studies involving beta cell-selective deletion of VDR, klotho, and Cav2.3 are now warranted, to elucidate the contribution of islet vitamin D signaling pathways in glucose homeostasis in vivo. The results of studies for my dissertation research provide a needed mechanistic approach, which complements the current clinical and observational reports that exist, regarding potential roles for Vitamin D in the progression of Diabetes. In addition, our identification of numerous Vitamin-D regulated genes of the human and mouse islet can form the basis for future hypothesis-driven research efforts to identify novel therapeutic targets to affect insulin secretion and beta cell function.

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