Funded Research

Obesity in pregnancy has adverse effects on both mother and baby and predisposes them to heart diseases later in life. Women of child-bearing age, pregnant, lactating and women adhering to vegan diet are at much higher risk of B12 deficiency, and their offspring are at elevated risk of low birth weight and preterm birth. This led to significant interest in understanding the maternal diet during pregnancy. My research showed that pregnant women with low B12 have higher sugar and fat levels in the blood and develop more body fat, which are signs of higher risk for heart diseases in later life. However, the causal reason is unknown.

B12 is one of the key micronutrients turning the biological switch on/off for the methylation process, which is responsible for efficient functioning of small RNA molecules called microRNA that control genes and cellular process. Here I propose that when B12 levels are deficient, the methyl groups normally added to the microRNA are reduced. This results in dysfunctional microRNAs which could profoundly change gene/protein products and contribute to disease development.

The aim is to characterise the methylation sites and identify the gene targets of microRNAs at the tissue level caused by low B12 using advanced technologies. This approach will identify new pathways affected and detect new targets that could enable tailored therapies in specific patient subgroups to treat diabetes. Benefits are anticipated to enhance the potential for the individualized health care and management of patients with diabetes during pregnancy.

All forms of diabetes are characterised by a chronically elevated level of blood glucose (chronic hyperglycaemia), which results from insufficient secretion of insulin from the β-cells of the pancreas. Type 2 diabetes (T2D) is a progressive disease in which elevated blood glucose gradually damages the β-cell so that they release even less insulin, which leads to higher blood glucose levels and therefore further β-cell damage. At time of T2D diagnosis, it is often found that an individual’s capacity to produce adequate amounts of insulin in order to maintain healthy blood glucose levels has declined by as much as 50%. This inexorable decline in β-cell function leads to devastating secondary complications, such as heart, eye and kidney disease.

Although the current therapeutic strategies available for T2D can reduce blood glucose either by enhancing insulin release (sulphonylureas, GLP-1 receptor agonists) or by increasing glucose clearance from the blood (insulin, metformin), none of these therapies provide any long-term benefit with regard to maintaining β-cell health and insulin secretion. In people without diabetes, a rise in blood glucose causes glucose from the blood to be taken up by the β-cell where it is broken down by metabolism to produce a molecule called ATP, which is needed to stimulate insulin release. In contrast, when blood glucose is chronically elevated, too much glucose is metabolised by the β-cell and eventually causes ‘blockages’ in the metabolic pathway. These ‘blockages’ mean that glucose can no longer be metabolised to produce enough ATP to cause insulin secretion. Thus, this proposal will investigate if the β-cell can be protected against the detrimental effects of chronic hyperglycaemia by lowering the amount of glucose which is metabolised by the cell down to the same level as which occurs in people without diabetes. This novel approach will prioritise maintaining, or restoring, β-cell health and insulin secretion which will greatly reduce the risk of developing debilitating secondary complications.

Poor nutrition and population ageing are the main contributors to the current global epidemic of obesity and type-2 diabetes. A pathological process underlying the development of these conditions is chronic inflammation of the adipose tissue. There are two main types of adipose tissue: white adipose tissue that stores energy in the form of fat, and brown adipose tissue that contains a unique type of mitochondria (cellular organelles that produce energy), which can dissipate the energy from fat and glucose as heat. Inflammation affects both the white adipose tissue and the brown adipose tissue. Our research has shown that dietary fatty acids activate innate immune signalling pathways associated with inflammation and it aims to demonstrate that certain innate immune pathway components can be manipulated in a manner that promotes the energy dissipating activity of the brown adipose tissue. This demonstration would provide proof-of-principle that pharmacological interventions altering the activity of innate immune inflammatory pathways can be used therapeutically to promote energy expenditure in a way that reduces body weight, improves insulin sensitivity and prevents or ameliorates type 2 diabetes.