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

Vitamin-D-binding protein (DBP) or group-specific component of serum (GC-globulin) carries vitamin D metabolites from the circulation to target tissues. DBP is highly localized to the liver and pancreatic α cells. Although DBP serum levels, gene polymorphisms, and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α cell morphology, α cell function, and glucagon secretion. Deletion of DBP leads to smaller and hyperplastic α cells, altered Na+ channel conductance, impaired α cell activation by low glucose, and reduced rates of glucagon secretion both in vivo and in vitro. Mechanistically, this involves reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects are also seen in β cell and δ cell function. Immunostaining of human pancreata reveals generalized loss of DBP expression as a feature of late-onset and long-standing, but not early-onset, type 1 diabetes. Thus, DBP regulates α cell phenotype, with implications for diabetes pathogenesis.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.D.J.H. was supported by MRC ( MR/N00275X/1 and MR/S025618/1 ) and Diabetes UK ( 17/0005681 ) project grants. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). L.J.B.B. was supported by a Sir Henry Wellcome Postdoctoral Fellowship ( Wellcome Trust ; 201325/Z/16/Z ) and a Junior Research Fellowship from Trinity College, Oxford . P.E.M. was funded by a foundation grant from the Canadian Institutes of Health Research (grant 148451 ). G.G.L. was supported by a Wellcome Trust Senior Research Fellowship ( 104612/Z/14/Z ). N.G.M. and S.J.R. were supported by Diabetes UK ( 15/0005156 and 16/0005480 ), MRC ( MR/P010695/1 ), and JDRF ( 2-SRA-2018-474-S-B ) project grants. We thank Dr. Deirdre Kavanagh and COMPARE for microscopy assistance. Human pancreas sections were provided by the Alberta Diabetes Institute IsletCore at the University of Alberta in Edmonton, with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN), and other Canadian organ procurement organizations.published version, accepted version, submitted versio

Sulfation pathways in the maintenance of functional beta-cell mass and implications for diabetes

Diabetes type 1 and type 2 are widely occurring diseases. In spite of a vast amount of biomedical literature about diabetic processes in general, links to certain biological processes are only becoming evident these days. One such area of biology is the sulfation of small molecules, such as steroid hormones or metabolites from the gastrointestinal tract, as well as larger biomolecules, such as proteins and proteoglycans. Thus, modulating the physicochemical propensities of the different sulfate acceptors, resulting in enhanced solubility, expedited circulatory transit, or enhanced macromolecular interaction. This review lists evidence for the involvement of sulfation pathways in the maintenance of functional pancreatic beta-cell mass and the implications for diabetes, grouped into various classes of sulfated biomolecule. Complex heparan sulfates might play a role in the development and maintenance of beta-cells. The sulfolipids sulfatide and sulfo-cholesterol might contribute to beta-cell health. In beta-cells, there are only very few proteins with confirmed sulfation on some tyrosine residues, with the IRS4 molecule being one of them. Sulfated steroid hormones, such as estradiol-sulfate and vitamin-D-sulfate, may facilitate downstream steroid signaling in betacells, following de-sulfation. Indoxyl sulfate is a metabolite from the intestine, that causes kidney damage, contributing to diabetic kidney disease. Finally, from a technological perspective, there is heparan sulfate, heparin, and chondroitin sulfate, that all might be involved in next-generation beta-cell transplantation. Sulfation pathways may play a role in pancreatic beta-cells through multiple mechanisms. A more coherent understanding of sulfation pathways in diabetes will facilitate discussion and guide future research.<br/

Birmingham Environment for Academic Research:Case studies volume 3

This collection of case studies was brought together to showcase the extent and diversity of research that is supported by the University of Birmingham’s Environment for Academic Research (BEAR). BEAR is a collection of contemporary IT resources designed to help research. The following case studies demonstrate how BEAR services such as the Research Data Store (RDS), BEAR software and the University supercomputer BlueBEAR are integral to the progression of important research across disciplines.BlueBEAR is a key component of BEAR, providing compute power and specialist applications free to enable staff and students to delve deeper into their research. Upgraded in 2023, the cluster includes many large memory nodes and a GPU service alongside standard compute nodes. Alongside BlueBEAR, the RDS is a popular choice amongst researchers to securely store their working research data. As of publication, more than 5000 researchers across all five colleges were actively using BlueBEAR and/or the RDS. In this volume, we showcase case studies representing diverse research from every college. From estimating snow coverage to modelling second language acquisition, we show how BEAR services are enabling exciting and important research across the university