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

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.

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.

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.