Diabetes Research

Novel candidate biomarkers of diabetic nephropathy, Mitochondrial dysfunction in oxidative stress disorders

Another problems with islet transplantation is that the side effects of the anti-rejection drugs (immunosuppression) outweigh the benefits of improved glucose control in most patients. Therefore, most patients are not suitable for islet transplantation therapy and therefore must rely on insulin injections to control their diabetes. Microencapsulation of islets may allow transplantation of islets in the absence of immunosuppression. The islets are encapsulated in alginate, a polysaccharide derived from seaweed. The alginate forms a network around the islets, which is tight enough to prevent immune cells from making contact with the islets and killing them. The alginate network is, however, open enough to allow the diffusion of nutrients into the capsule and insulin out from the capsule. Therefore this can allow transplantation in the absence of immunosuppression therapy.

Diabetes and reproductive function: effects of kisspeptin and pregnancy on islet function.

Pregnancy and β-cell proliferation

During normal healthy pregnancy insulin sensitivity decreases and the insulin-secreting β-cells in the islets of Langerhans increase in number in response. Under normal physiological conditions β-cells proliferate at an extremely low rate and pregnancy is one of the few physiological states in which β-cells proliferate much more rapidly and islet size increases significantly. Gestational diabetes occurs when the mother is unable to increase insulin release sufficiently to compensate for insulin resistance, possibly caused by insufficient beta-cell proliferation. The mechanisms that cause this increase in proliferation are currently poorly understood and a better understanding would be extremely valuable for the treatment of both gestational diabetes and type 2 diabetes. My current research involves the use of in vitro and in vivo models to investigate the control of islet structure and function during pregnancy, and examining whether these physiological mechanisms could be used therapeutically to stimulate β-cell proliferation.

Kisspeptin and the regulation of islet function

Kisspeptin is a recently-discovered molecule that is found, along with its receptor, in a few areas of the human body – the hypothalamic area of the brain, the placenta and the endocrine pancreas. One important function of kisspeptin in the brain is to control when the process of puberty starts, but the function(s) of kisspeptin in the placenta and the pancreas are mostly unknown. I have previously shown that both kisspeptin and its receptor are expressed within pancreatic islets and that kisspeptin potentiates glucose-induced insulin release, both in vitro and in vivo. I am now investigating the physiological role of the kisspeptin system in islets. Given the vital role of kisspeptin in other tissues in regulating reproductive function I am particularly interested in a possible role of kisspeptin in regulating islet function during states such as puberty and pregnancy.

The aim of the research is to understand the molecular basis and anatomical pathways involved in leptin and insulin action and the role of the immune system and inflammation in obesity and the metabolic syndrome using both in vitro and in vivo models.

Autoimmunity in Type 1 diabetes: Type 1 diabetes is the result of the destruction of insulin-secreting pancreatic beta cells by a process in which autoimmune recognition of beta cell proteins is implicated. My research group has long-standing interests in the identification and characterisation of beta cell targets of the autoimmune response in Type 1 diabetes, with the view of developing strategies to identify individuals at risk for disease, and to apply antigen specific immune intervention to prevent disease progression in high-risk subjects. My group was the first to detect circulating autoantibodies to a tyrosine phosphatase-like protein, IA-2, in diabetic patients, and this antibody marker is now widely used for the prediction and diagnosis of disease. We have subsequently identified a region of the IA-2 molecule that is very commonly recognised by both ciirculating autoantibodies and T-cells in Type 1 diabetes. We are currently investigating the relationships between T- and B-cell responses to this and other regions of the IA-2 molecule, and the potential for this region to form the basis of antigen-specific vaccination protocols to prevent disease.

Development and function of pancreatic beta cells: IA-2 is a tyrosine phosphatase-like protein localised to secretory granules of pancreatic beta cells, as well as to secretory vesicles of a number of other neuroendocrine organs, including the pituitary. Our recent studies have shown that IA-2 is an important regulator of beta cell secretory granule content and insulin secretion. IA-2 is poorly expressed in fetal life, but is up-regulated after birth, in parallel with increases in islet insulin secretion in response to glucose. We are currently interested in understanding the changes in beta cell gene expression that occur during the functional maturation of pancreatic beta cells during their development, and the influences of hormones and environmental factors, particularly diet, on the development and function of the endocrine pancreas. These studies will aid our understanding of how early exposure to environmental factors can influence susceptibility to Type 1 and Type 2 diabetes later in life.

Experimental medicine programme in diabetes

Hypoglycaemia unawareness: pathogenesis and prevention

Up to 50% of people with established type 1 (insulin dependent) diabetes mellitus lose their ability to recognise the onset of a falling blood glucose concentration and so are at greatly increased risk of severe hypoglycaemia, in which confusion, abnormal behaviour, coma , seizure and, very rarely, death, occur because of inadequate glucose supply to the brain. This damages quality of life, with impact on the patient and his or her family and friends. Professor Amiel demonstrated defective stress responses to hypoglycaemia, which are reversible by strict hypoglycaemia avoidance. She also showed abnormal brain responses, with failure to activate aversive pathways or de-activate hedonic brain pathways in hypoglycaemia unaware patients, helping explain the difficulties people face in changing behaviour to avoid future hypoglycaemia. Currently, her group uses techniques ranging from semi-structured interviewing to collaborative neuroimaging, seeking to discover which of the abnormal brain responses to hypoglycaemia in unawareness are inducible and reversible, and which are innate and potentially useful as a biomarker of risk. A parallel clinical workstream focuses on optimising patient education to avoid hypoglycaemia and the use of new technologies in insulin delivery and glucose sensing (pumps and sensors) to improve hypoglycaemia protection, in a stepped programme that culminates in islet transplantation and cell therapy for type 1 diabetes patients.

Studies in insulin resistance, type 2 diabetes and obesity.

Prof Amiel’s group are also applying physiological investigative techniques such as insulin clamping, stable isotope measurement of substrate turnover and brain and other organ imaging to questions related to type 2 diabetes, in which insulin resistance plays a role. Current studies include use of different modalities of brain imaging to look at the impact of insulin resistance, insulin sensitization, and weight reducing treatments such as gastric bypass on the central mechanisms of appetite control. With liaison psychiatrist, Prof Khalida Ismail, the group run the South London Diabetes study, recruiting people with newly diagnosed diabetes into research, with a particular interest in understanding ethnic and other socio-demographic influences on the metabolic abnormalities that cause type 2 diabetes.