Development and potential reversal of type 2 diabetes: How critical is vitamin A in the regulation of insulin responsiveness and lipid homeostasis?

Lead Research Organisation: Newcastle University
Department Name: Population Health Sciences Institute

Abstract

The rapid increase in number of people affected by type 2 diabetes is matter of grave concern. Diabetes is a world-wide problem and has risen from 108 million in 1980 to 422 million in 2014. In the Philippines, one out of every six Filipino has either pre-diabetes or diabetes. Recent studies have shown that type 2 diabetes develops by excess, yet reversible, fat accumulation in liver and pancreas. There is also some evidence suggesting that vitamin A may contribute to this condition, but the underlying mechanisms are not yet fully understood. Furthermore, it is not yet clear why some people develop type 2 diabetes faster than others, even with a similar liver fat content. The proposed study therefore aims to understand if vitamin A increases the metabolic stress that is caused by a fatty liver, and if changes in vitamin A metabolism could contribute to an increase in liver fat, therefore inducing a vicious cycle of liver fat accumulation and acceleration of the development of diabetes. The study will finally evaluate if diet-induced weight loss among diabetics in the Philippines could improve all aspects of diabetes control, and if a low energy liquid diet is culturally acceptable. Finally, the project may help to develop new prevention strategies to enable the Ministry of Health to reduce the burden of diabetes and its complications in the Philippines.

Technical Summary

According to WHO, the global prevalence of diabetes has increased from 4.7% in 1980 to 8.5% in 2014. In the Philippines, the national prevalence in 2008 was already at 7.2%. Although recent clinical and pathophysiological studies have shown that type 2 diabetes is caused by excess, yet reversible, fat accumulation in liver and pancreas, there is convincing evidence that impaired vitamin A signalling and metabolism contributes to this condition. Indeed, serum retinol binding protein (RBP4) correlates with hepatocyte triglyceride concentrations in both animals and humans, and is associated with increased de novo lipogenesis. Binding of retinol-RBP4, but not apo-RBP4, to STRA6 triggers phosphorylation of STRA6, up-regulation of SOCS3 with subsequent suppression of insulin signalling. Retinoic acid receptor (RAR)-alpha signalling is required to maintain glucose-stimulated insulin secretion in pancreatic beta-cells and adequate mitochondrial beta-oxidation in the liver. The project therefore aims to determine how increased RBP4 augments liver de novo lipogenesis via a range of mechanisms, and to determine whether energy restriction breaks this potential vicious cycle. Finally, the project aims to determine whether: i) diet-induced weight loss among diabetics in the Philippines achieves the same pathophysiological changes as in Causcasians in Newcastle; ii) a low energy liquid diet is culturally acceptable; and iii) if substantial weight loss can deliver a clinically superior overall outcome at 6 months compared with management by current best practice guidelines from the Ministry of Health in the Philippines.

Planned Impact

This study would be the first study in the Philippines to determine whether aberrant vitamin A status exacerbates the risk of diabetes development in LMIC undergoing rapid economic transition. In addition, findings from the study may help to explain the inter-individual differences in the liver fat threshold for diabetes development observed in ongoing studies. More importantly, the clinical study, if successful, would be the first step in confirming if a simple-to-implement energy restriction regime is effective in halting, and in the long term, reducing the high incidence rates of diabetes in the Philippines. The economic and clinical benefit to the Philippines could be far reaching, since most people who develop type 2 diabetes will develop multiple comorbidities which are a considerable burden on the public health system. Since type 2 diabetes cases have been observed at the age of 18 years in the Philippines, the effect upon morbidity and mortality are very great, and reduce life expectancy by 6 years. Furthermore, the National Nutrition Survey (NNS) results are used in crafting and reviewing health and nutrition-related policies and laws in the Philippines, thus offering the opportunity that the results from this study could be used in influencing current policies on type 2 diabetes monitoring and treatment.

Publications

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Description To date, samples from the Newcastle led DIRECT trial have been analysed for retinoids and indicated an important interaction between responders and non-responders to weight loss. This interaction is currently being written up as a publication.
Data from our international partners is unfortunately not yet available due to the on-going COVID-19 pandemic.
Exploitation Route The results by the trial to date are exploratory, there is currently no direct translation of the results into clinical practice. However, once results from the international partners becomes available, there may be some outcomes from this pilot with relevance for clinical practice.
Sectors Agriculture, Food and Drink,Healthcare

 
Description Food and Nutrition Research Institute, Department of Science and Technology, DOST Compound, General Santos Avenue, Bicutan, Taguig City 1631, Metro Manila 
Organisation Food and Nutrition Research Institute (FNRI)
Country Philippines 
Sector Public 
PI Contribution The FNRI will analyse blood samples from the on-going Expanded National Nutrition Survey (ENNS) to explore potential interactions between vitamin A blood concentrations and diabetes risk. The FNRI will also work in collaboration with the University of the Philippines to recruit diabetes and non-diabetes subjects to evaluate the liver and pancreatic fat content of these volunteers using MRI scans combined with blood analysis of important biomarkers.
Collaborator Contribution The FNRI Philippines will carry out a cross-sectional pilot study embedded in the on-going Expanded National Nutrition Survey (ENNS). This study provides the official statistics on food, nutrition and health situation in the country and covers all 17 regions and 79 provinces of the Philippines. As part of the project, stored serum samples drawn from diabetic, pre-diabetic and non-diabetic participants of the ENNS will be analysed for RBP4 and correlated with serum retinol and fasting blood glucose concentrations. The FNRI will in collaboration with the University of the Philippines recruit diabetic (n=20) and non-diabetic (control) volunteers (n=20). To minimise possible confounding by different ethnic groups, the study will recruit Filipinos only. Volunteers will be assessed through anthropometric measurements, will be asked to donate one blood sample, and will undergo a Magnetic Resonance Imaging (MRI) scan to allow the research team to produce fat fraction maps of liver and pancreas to quantify intra-organ triglyceride content and both visceral and subcutaneous fat.
Impact To date, the research partners in the Philippines have been able to obtain ethical approval for the proposed work. However, due to the on-going pandemic, the clinical and laboratory work was not able to commence as yet. We have asked to suspend the grant until July this year, and hope that work can commence in the summer. The Philippines have seen recent increases in COVID-19 cases, but vaccinations have started. We are carefully optimistic that work can commence again in the summer of 2021.
Start Year 2020
 
Description MONASH UNIVERSITY Malaysia 
Organisation Monash University Malaysia
Country Malaysia 
Sector Academic/University 
PI Contribution Monash University Malaysia will help us to understand if the intra-organ fat amount is similar in Asia diabetic patients as it is for European diabetes patients. Newcastle University has set up the collaboration agreement with Monash University Malaysia.
Collaborator Contribution Monach University Malaysia will be recruiting Diabetic (n=20) and non-diabetic (control) volunteers (n=20). Volunteers will be assessed through anthropometric measurements, will be asked to donate one blood sample, and will undergo a Magnetic Resonance Imaging (MRI) scan to allow the research team to produce fat fraction maps of liver and pancreas to quantify intra-organ triglyceride content and both visceral and subcutaneous fat.
Impact To date, Monash University Malaysia has successfully obtained ethical clearance for the planned research activities. Due to the on-going pandemic however, the clinical work has not started. Since the vaccination program has started in Malaysia, we are hopeful however that work can commence in the summer of 2021.
Start Year 2020