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Diabetes and Obesity within the Division of Metabolic and Vascular Health

Doctor holding insulin syringe

The study of obesity and type-2 diabetes within the Division extends from the molecular to the translational. The depth of the research covered by research group leaders at WMS is complemented by strategic links with the Evans Center for Interdisciplinary Biomedical Research (Boston University School of Medicine) where obesity is a major research interest.

Molecular and Cellular Studies

Dr Mark Christian is elucidating the biochemical processes involved in the formation of lipid droplets, which are central to the development of obesity and the deleterious accumulation of lipids in non-adipose tissues.

Professor Victor Zammit is studying the molecular mechanisms that link hyperglycaemia with hepatic steatosis and dyslipidaemia, which are key aspects of the (pre)diabetic state.

An important class of membrane proteins that control a wide variety of cellular functions are the G-protein coupled receptors (GPCRs). The roles GPCRs in adipose tissue biology, and in particular, the regulation of adipogenesis in white and brown adipocytes are being investigated by Professor Dimitris Gramatopoulos and Dr Harpal Randeva in both humans and rodents.

The differentiation of white and brown adipocytes is investigated by Dr Philip McTernan and Dr Gyan Tripathi, including the elucidation of pathways that contribute towards the different extents to which development of a subclinical inflammatory phenotype occurs in distinct adipose tissue depots with the onset and progression of obesity.

In particular, the role of bacterial lipopolysaccharide in the activation of these pathways in the (pre)diabetic state is being researched in view of the relationship between gut flora, loss of gut mucosal integrity and the development of insulin resistance in humans and animal models.

The basis for the difference in dependence on saturated and unsaturated fatty acids of inflammation in adipose tissue is the subject of the research of Dr Claire Bastie.

Consequences of Hyperglycaemia

Most complications of diabetes are associated with high blood glucose levels. Professor Paul Thornalley and Dr Naila Rabbani are studying how the elevation of methylglyoxal in tissues, and in the circulation, that accompanies hyperglycaemia increases the glycation of specific residues of the apoproteins present in HDL and LDL, and how this alters the properties of these particles e.g. increased atherogenicity of LDL. These studies also extend to the study of the effects of hyperglycaemia on renal tubule thiamine transporters, and their role in the thiamine deficiency associated with diabetes, in collaboration with Dr Daniel Zehnder.

Human trials on the ability of high-dose thiamine supplementation to prevent specific defects in kidney function in diabetes (e.g. microalbuminuria) have also been conducted by this group. The interference of diabetic hyperglycaemia with the molecular interactions between glycans and their receptors (e.g. DC-SIGN) is one of the research interests of Dr Daniel Mitchell.

Whole-Body Human Metabolism

Whole-body calorimetry and NMR imaging of humans are being used within the Human Metabolism Research Unit (HMRU) to determine the effects of different dietary and pharmacological treatments on energy expenditure and fuel-selection by tissues.

This work is being conducted by Dr Tom Barber and Dr Narendra Reddy who are also using the newly-developed technique of IDAEL-Magnetic Resonance Imaging (in collaboration with Professor Charles Hutchinson) to identify individuals who express more brown adipose tissue (which expends energy and may be involved in bodyweight control) as adults. This work is also aimed at providing a source of human white and brown adipose tissue for the cell culture experiments being performed by Drs McTernan and Tripathi (see above).

Diabetes and Related Conditions in Women

PCOS, a multi-faceted (pre)diabetic state linked with insulin resistance, obesity, hepatic steatosis is being investigated by Dr Harpal Randeva. His program of work extends to the impact of obesity during pregnancy on cardiometabolic signatures in both mother and offspring, and also in site specific adipose tissue from mothers.

Gestational diabetes is a condition that is increasing in frequency as the female population of child-bearing age becomes more obese. The interactions between obesity and pregnancy outcomes, and the development of type-2 diabetes by women subsequent to pregnancy, are being studied by Dr Harpal Randeva and Dr Saravanan Ponnusamy, the latter who is also performing trials of the effects of B12 and folic acid supplementation in early pregnancy on the risk of developing gestational diabetes.

The metabolic links between adipose tissue and the placenta under the stress of pregnancy are the focus of research being conducted by Professor Dimitris Grammatopoulos.

Lifestyle and Diabetes

Long-standing prospective studies on the interactions between life-style and pharmacological treatments on health outcomes in diabetics are being conducted in the UK and African populations by Dr Paul O’Hare.