Vitamin-D-Binding Protein Contributes to the Maintenance of α Cell Function and Glucagon Secretion

Viloria, Katrina; Nasteska, Daniela; Briant, Linford J.B.; Heising, Silke; Larner, Dean P.; Fine, Nicholas H. F.; Ashford, Fiona; Xavier, Gabriela da Silva; Ramos, Maria Jiménez; Hasib, Annie; Cuozzo, Federica; Fox, Jocelyn E. Manning; MacDonald, Patrick E.; Akerman, İldem; Lavery, Gareth G.; Flaxman, Christine S.; Morgan, Noel G.; Richardson, Sarah J.; Hewison, Martin; Hodson, David J.

doi:10.1016/j.celrep.2020.107761

Cited by 24 publications

(28 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whether these results are associated with the beta cell de-differentiation seen in T2DM is not known, but it will be interesting to confirm findings in human samples. DBP is also expressed in delta cells, confirmed using both RNA-seq (Adriaenssens et al, 2016) and immunohistochemistry (Viloria et al, 2020), although its downstream functions are unknown. Cell-specific manipulation of DBP in the islet compartment will therefore be integral to any approaches targeting DBP as a diabetes treatment, perhaps using molecular addresses specific to alpha cells.…”

Section: Other Islet Targets For Dbpmentioning

confidence: 87%

“…Despite the known (potent) biological functions of DBP, an effect on alpha cell physiology has only recently been examined. Using DBP-null mice, we were able to show that loss of DBP results in major alpha cell impairments (Viloria et al, 2020) (Figure 3). Mice deleted for DBP displayed reductions in insulin-and low glucose-stimulated glucagon release.…”

Section: Dbp As An Alpha Cell Regulatormentioning

confidence: 99%

“…Using phalloidin to stain F-actin fibrils, loss of DBP was found to increase the density of polymerised F-actin fibrils, with a concomitant decrease in G-actin monomer abundance (Viloria et al, 2020) ( Figure 3B). Suggesting that these changes in F-actin and G-actin are associated with changes in actin-dependent processes, distribution and size of glucagon granules was found to be altered in DBP-null alpha cells.…”

Section: Dbp As a Novel Intracellular (And Extracellular) Actin Regulmentioning

confidence: 99%

See 2 more Smart Citations

Vitamin D binding protein/GC‐globulin: a novel regulator of alpha cell function and glucagon secretion

Viloria

Hewison

Hodson

2021

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

The contribution of glucagon to type 1 and type 2 diabetes has long been known, but the underlying defects in alpha function are not well-described. During both disease states, alpha cells do not respond appropriately to stimuli, leading to dysregulated glucagon secretion, impaired glucose tolerance and hypoglycaemia. The mechanisms involved in this dysfunction are complex, but possibly include changes in alpha cell glucose-sensing, alpha cell de-differentiation, paracrine feedback, as well as alpha cell mass. However, the molecular underpinnings of alpha cell failure are still poorly understood. Recent transcriptomic analyses have identified vitamin D binding protein (DBP), encoded by GC/Gc, as an alpha cell signature gene. DBP is highly localised to the liver and alpha cells and is virtually absent from other tissues and cell types under non-pathological conditions. While the vitamin D transportation role of DBP is well characterised in the liver and circulation, its function in alpha cells remain more enigmatic. Recent work reveals that loss of DBP leads to smaller and hyperplastic alpha cells, which secrete less glucagon in response to low glucose concentration, despite vitamin D sufficiency. Alpha cells lacking DBP display impaired Ca 2+ fluxes and Na + conductance, as well as changes in glucagon granule distribution. Underlying these defects is disassembly of alpha cell F-actin and sequestration of G-actin monomers, highlighting a novel intracellular actin scavenging role for DBP in islets.

show abstract

Section: Other Islet Targets For Dbpmentioning

confidence: 87%

Section: Dbp As An Alpha Cell Regulatormentioning

confidence: 99%

Section: Dbp As a Novel Intracellular (And Extracellular) Actin Regulmentioning

confidence: 99%

See 1 more Smart Citation

Vitamin D binding protein/GC‐globulin: a novel regulator of alpha cell function and glucagon secretion

Viloria

Hewison

Hodson

2021

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, transgenic mice overexpressing VDR in beta cells are protected against streptozotocin-induced diabetes and exhibit preserved beta-cell mass, along with reduced islet inflammation [142]. Interestingly, a recent study [143] showed that DBP is highly expressed in murine and human alpha cells, and loss of DBP gives rise to alterations in alpha-cell number and size, electrical activity and glucagon secretion in vitro and in vivo. Additionally, authors found reduced expression levels of DBP in islets of donors with late-onset or long-standing T1D [143].…”

Section: Role Of Vitamin D In Autoimmune Diabetes: T1d and Ladamentioning

confidence: 99%

Combination of vitamin D and dipeptidyl peptidase-4 inhibitors (VIDPP-4i) as an immunomodulation therapy for autoimmune diabetes

Pinheiro

Diniz

et al. 2021

International Immunopharmacology

View full text Add to dashboard Cite

Type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) represent the most common types of autoimmune diabetes and are characterized by different age of onset, degrees of immune-mediated destruction of pancreatic beta cells and rates of disease progression towards insulin dependence. Several immunotherapies aimed to counteract autoimmune responses against beta cells and preserve beta-cell function are currently being investigated, particularly in T1D. Preliminary findings suggest a potential role of combination therapy with vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors (VIDPP-4i) in preserving beta-cell function in autoimmune diabetes. This manuscript aims to provide a comprehensive overview of the immunomodulatory properties of vitamin D and DPP-4 inhibitors, as well as the rationale for investigation of their combined use as an immunomodulation therapy for autoimmune diabetes.

show abstract

“…), a-and islet-cell lineage transcription factors (MAFB, FEV, NKX2.2, NEUROD1), G-protein coupled receptors known to impact a-cell function (GIPR, SSTR1, FFAR1, GPR119), and secreted factors implicated in islet function or development (LOXL4, WNT4, UCN3, IL16). Significant negative correlates were less abundant but included the vitamin D binding protein (GC) which is known to regulate a-cell Na + currents (Viloria et al, 2020). GSEA for KEGG Although a-cell lineage markers correlate with Na + current activity, the high degree of overlap in the Na + current properties between human a-and b-cells make it impossible to use Na + currents alone to interrogate shifts in human a-cell phenotypes.…”

Section: Electrophysiological Fingerprint Modelling Links Human A-cell Behavior and Cell Phenotypementioning

confidence: 99%

Heterogenous impairment of α-cell function in type 2 diabetes is linked to cell maturation state

Dai

Camunas-Soler

et al. 2021

Preprint

View full text Add to dashboard Cite

In diabetes, glucagon secretion from pancreatic α-cells is dysregulated. We examined α-cells from human donors and mice using combined electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses α-cell exocytosis by reducing P/Q-type Ca2+ channel activity, and this is disrupted in type 2 diabetes (T2D). Upon high-fat-feeding of mice, α-cells shift towards a β-cell-like electrophysiologic profile in concert with an up-regulation of the β-cell Na+ channel isoform Scn9a and indications of impaired α-cell identity. In human α-cells we identify links between cell membrane properties and cell surface signalling receptors, mitochondrial respiratory complex assembly, and cell maturation. Cell type classification using machine learning of electrophysiology data demonstrates a heterogenous loss of electrophysiologic identity in α-cells from donors with T2D. Indeed, a sub-set of α-cells with impaired exocytosis is defined by an enrichment in progenitor markers suggesting important links between α-cell maturation state and dysfunction in T2D.

show abstract

Vitamin-D-Binding Protein Contributes to the Maintenance of α Cell Function and Glucagon Secretion

Cited by 24 publications

References 63 publications

Vitamin D binding protein/GC‐globulin: a novel regulator of alpha cell function and glucagon secretion

Vitamin D binding protein/GC‐globulin: a novel regulator of alpha cell function and glucagon secretion

Combination of vitamin D and dipeptidyl peptidase-4 inhibitors (VIDPP-4i) as an immunomodulation therapy for autoimmune diabetes

Heterogenous impairment of α-cell function in type 2 diabetes is linked to cell maturation state

Contact Info

Product

Resources

About