04 Jul Vitamin A Derivative May Have Anti-Diabetic Capabilities
MedicalResearch.com Interview with:
Dr. Armisten
Stefan Amisten, PhD
The Oxford Centre for Diabetes, Endocrinology & Metabolism
University of Oxford, Oxford
Diabetes Research Group, Division of Diabetes & Nutritional Sciences
King’s College London, Faculty of Life Sciences & Medicine, London
UK
MedicalResearch.com: What is the background for this study?
Response: Type 2 diabetes is a global epidemic that is causing an increasing medical and financial burden on both individuals and society in general. Type 2 diabetes is characterized by insulin resistance, poor insulin response to blood glucose which leads to chronically elevated blood glucose and damage to the cardiovascular system and other organs, which may ultimately lead to blindness, kidney failure, blindness, toe amputations, cardiovascular disease and premature death. Although a number of drugs are available for the treatment of Type 2 diabetes, no drug is currently able to cure diabetes, as they are only able to slow down the disease progression. There is therefore a need to develop novel therapies to treat Type 2 diabetes.
G-protein coupled receptors (GPCRs) constitute a family of almost 400 cell surface receptors that is the target of a large number of modern medicines. Interestingly, only a small subset of all GPCRs are currently targeted by modern medicines, which means that a large number of GPCRs still have untapped therapeutic potential, largely because they have not been studied in-depth, or because their ligands (i.e. binding partners) have not been identified.
This study is a result of a thorough cataloguing of all G-protein coupled receptors (GPCRs) in human pancreatic islets (Amisten et al. Pharmacol Ther. 2013 Sep;139(3):359-91.), where the receptor GPRC5C was identified as one of the most abundant orphan GPCRs in human islets.
MedicalResearch.com: What are the main findings?
Response: In our study, we investigated the function of GPRC5C, with a focus on how GPRC5C regulates insulin secretion and proliferation and survival of insulin-producing beta cells using a range of novel molecular biology techniques. We found that GPRC5C has strong anti-apoptotic effects and that it also stimulates beta-cell proliferation. Our data also suggests that all-trans-retinoic acid, a metabolite of vitamin A, interacts with GPRC5C through a mechanism that is not completely understood to stimulate beta cell survival and proliferation.
Our experimental data suggests that all-trans retinoic acid, via the GPRC5C receptor, exerts strong anti-diabetes effects that may be important for the development and treatment of diabetes. Interestingly, our findings are supported by animal studies demonstrating that vitamin A deficiency may lead to type-2 diabetes due to pancreatic islet beta-cell loss (i.e. reduced survival and proliferation of beta-cells), which is reversed by the re-introduction of dietary vitamin A (Trasino SE et al. J Biol Chem. 2015 Jan 16;290(3):1456-73).
Although the exact mechanism by which all-trans retinoic acid modulates GPRC5C function is poorly understood, our findings suggest that the GPRC5C receptor might be an attractive target for a novel type-2 diabetes therapy aimed at preserving and restoring functional beta-cell mass, which is reduced in type-2 diabetes and non-existent in type-1 diabetes, via activation of the GPRC5C receptor.
MedicalResearch.com: What should readers take away from your report?
Response: That it is important to understand the basic biology of beta cells in order to find better ways to treat Type 2 diabetes. It is important to study poorly characterized orphan receptors such as GPRC5C, as this may lead to the discovery of unexpected functions and the identification of novel therapeutic target candidates, and that GPRC5C seems to be a key regulator of the survival and proliferation of beta-cells.
Studies on orphan GPCRs has been hampered by a lack of suitable pharmacological tools. However, a number of newly developed molecular biology techniques, such as Lentiviral delivery of shRNAs to knock-down gene expression and CRISPR technologies to inactivate genes, may be used to study the function of orphan receptors even though traditional pharmacological tools such as receptor agonists and antagonists are not available for orphan receptors. Hopefully these methodologies will help accelerate the study of orphan receptors, which may be developed into truly novel drug targets for a number of different diseases.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Our study suggests that GPRC5C and all-trans retinoic acid may be important for the function, proliferation and survival of insulin-producing pancreatic islet beta cells. Further studies are needed to elucidate the mechanism by which all-trans retinoic acid modulates GPRC5C function, and if it is possible to develop novel therapies for type-2 diabetes based on GPRC5C and/or the vitamin A metabolite all-trans retinoic acid.
Our study proves the need to understand other orphan receptors in other conditions, as they may also play important roles. It is important to avoid “herd mentality” by focusing research efforts on well-characterized receptors, as truly novel drug target candidates might otherwise be overlooked.
Disclosures: This study has been supported by Diabetes UK, who awarded me an RD Lawrence Fellowship to study the function of GPRC5C. Without the generous support from Diabetes UK, we would not have been able to complete this project.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Citation:
Stefan Amisten, Israa Mohammad Al-Amily, Arvind Soni, Ross Hawkes, Patricio Atanes, Shanta Jean Persaud, Patrik Rorsman, Albert Salehi. Anti-diabetic action of all-trans retinoic acid and the orphan G protein coupled receptor GPRC5C in pancreatic β-cells. Endocrine Journal, 2017; 64 (3): 325 DOI: 10.1507/endocrj.EJ16-0338
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Last Updated on July 4, 2017 by Marie Benz MD FAAD