The Diabetes Research Group has as its remit the improvement of outcomes in diabetes care from the bench through the bedside to the community. It comprises several inter-related research Groups:
The Research Groups interact with each other and with colleagues in the Nutritional Sciences section of the Division, developing a focus on understanding the pathophysiology of Type 2 diabetes and obesity, and applying that knowledge to new preventive and therapeutic interventions.
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.
The group have also pioneered research into the effect of triglyceride structure on postprandial lipid metabolism. More recently we have been investigating the effect of different types of fat and food structure on the release of gut hormones that promote insulin secretion and have effects on satiety.
Over the years, we have acquired a high level of expertise in carrying out dietary intervention trials. Our current goal is to determine the optimum dietary intervention on the cardiovascular disease risk factors associated with the metabolic syndrome. We are investigating whether maternal obesity can programme the offspring to develop metabolic syndrome. We are particularly interested in why obesity causes metabolic syndrome in some people and not others.
In vivo function of zinc-alpha2 glycoprotein (ZAG)
ZAG is believed to participate in the chronic weight loss and muscle wasting exhibited by certain cancer patients. ZAG's true in vivo function is as yet undetermined although given that the protein binds long chain fatty acids, it is likely that ZAG participates in lipid homeostasis. Using a series of biochemical and molecular biology based techniques attempts are being made to identify and characterize ZAG's cell surface receptor. Possible clinical applications of this research would be the development of drugs that inhibit or modulate ZAG:receptor binding, thus reducing or eliminating the drastic weight loss exhibited by some cancer patients during physiologically demanding therapies.
1. Effect of diet-gene interaction on lipid profile and insulin sensitivity in large intervention studies (in collaboration with Prof Tom Sanders).
My main interest is in dietary influence on expression of the peroxisome proliferator-activated receptor genes, PPARα and PPARγ and the PPARγ target gene adiponectin ADIPOQ. Adiponectin enhances insulin sensitivity and protects against cardiovascular disease and suboptimal levels predispose to development of the metabolic syndrome. We have explored the effect of dietary fatty acid interaction with PPARG and PPARA gene variants on plasma lipids in the RISCK study, a randomised control trial in which a high intake of saturated fat was replaced with monounsaturated fats or carbohydrates. We found significant interaction between dietary fatty acid intake, ADIPOQ gene variants and age as a determinant of serum adiponectin concentration, with possible utility for targeted dietary therapy for reducing risk of late-onset disease. Interaction between the intake ratio of polyunsaturated:saturated fatty acids and PPARG gene variants and between dietary fat, PPARA and PPARG gene variants in determination of plasma lipids has also been shown. Ongoing investigations are centred on interaction between genetic variants and intake of n3-PUFA from fish oil in the MARINA study. We have completed studies on n-3 PUFA interaction with ADIPOQ variants which parallel similar age-dependent relationships found with MUFA intake in the RISCK study. Ongoing investigations concern the fatty acid desaturase genes FADS1 and FADS2, and variants are strongly associated with activity in the n-6 and n-3 PUFA synthetic pathways. We are currently investigating the impact of FADS SNP variant and haplotype carriage on plasma fatty acid proportions in response to intake of n-3 PUFA. The aim is to provide evidence of genetic susceptibility to disturbances of plasma fatty acids and lipids that predispose to metabolic and cardiovascular disease and to identify those who may benefit most from dietary modification.
2. PPARγ function in mitigation of lipodystrophic effects of anti-retroviral therapy (in collaboration with Dr Anne Mullen).
The use of anti-retroviral therapy can lead to HIV-associated lipodystrophy syndrome (HALS). There is some evidence that the activity of PPARγ is down-regulated by anti-retroviral drugs. Pharmacological PPARγ ligands such as rosiglitazone, have shown positive effects on HALS in some RCTs. We aim to investigate whether pre-treatment of cultured adipocytes with PUFAs alters the level of activated PPARγ extracted from cells exposed to anti-retrovirals. Promising results in vitro are expected to lead to human trials.
AlSaleh A, Sanders TAB, O’Dell SD (2012). Effect of interaction between PPARG, PPARA and ADIPOQ gene variants and dietary fatty acids on plasma lipid profile and adiponectin concentration in a large intervention study. Proc Nutr Soc. 71:141-53.
AlSaleh A, Frost GS, Griffin BA, Lovegrove JA, Jebb SA, Sanders TAB, O’Dell SD(2011). PPARγ2 gene Pro12Ala and PPARα gene Leu162Val SNPs interact with dietary intake of fat in determination of plasma lipid concentrations. J Nutrigenetics Nutrigenomics 4:355-367
AlSaleh A, O’Dell SD, Frost GS, Griffin BA, Lovegrove JA, Jebb SA, Sanders TAB (2011). Interaction of PPAR-γ2 gene Pro12Ala single nucleotide polymorphism with dietary intake of fatty acids in determination of plasma lipids in subjects at cardiometabolic risk. J Lipid Res. 52:2298-2303.
AlSaleh A, O'Dell SD, Frost GS, Griffin BA, Lovegrove JA, Jebb SA, Sanders TA (2011) Single nucleotide polymorphisms at the ADIPOQ gene locus interact with age and dietary intake of fat to determine serum adiponectin in subjects at risk of the metabolic syndrome. Am J Clin Nutr 94:1-8.
Lee AK, Kyriakou T, Weston AJ, O'Dell SD (2010) Functional single nucleotide polymorphism in acetyl-CoA carboxylase ACACB gene promoter. DNA Cell Biol 29:703-12.
Lee AK, Mojtahed-Jaberi M, Kyriakou T, Aldecoa-Otalora Astarloa E, Arno M, Marshall NJ, Brain SD, O'Dell SD (2010) Effect of high-fat feeding on expression of genes controlling availability of dopamine in mouse hypothalamus. Nutrition 26: 411-422.
Liu G, Riese H, Spector TD, O'Dell SD, Stolk R, Snieder H (2009). Bivariate genetic modeling of the response to an oral glucose tolerance challenge: A gene-environment interaction approach. Diabetologia 52:1048-1055.
Goyenechea E, Collins LJ , Parra D, Abete I, Crujeiras AB, O'Dell SD, Alfredo Martínez J. (2009) The -11391 G/A polymorphism of the adiponectin gene promoter is associated with metabolic syndrome traits and the outcome of an energy-restricted diet in obese subjects. Horm Metab Res 41:55-61.
In addition, we use proteomic techniques to study the effects of trauma and alcohol on protein turnover and tissue repair, and the effects of oxidative stress on these processes.
Research in the Diet and Gastrointestinal Health Group is funded by the European Union, the BBSRC, industry and various medical research charities.
We discovered and characterised several genes involved in iron homeostasis including Dcytb (ferric-reductase), ferroportin (iron exporter) and HCP1/PCFT (haem importer). We demonstrated that hepcidin inhibits intestinal iron transport through down-regulation of DMT1 and ferroportin.
We study molecules involved in cellular zinc homeostasis; the control of cellular zinc ion fluxes in signalling, antioxidant and stress (glucocorticoid) responses; and how cellular metal ions are buffered and compartmentalized.
A particular strength is our multidisciplinary approach:
Collaborations: London Iron Metabolism Group; Zinc-UK; several national and international institutes, including University College London, Institute Cochin, Paris, and National Institute of Nutrition and Seafood Research, Norway.
Funding: BBSRC, MRC (NC3Rs), NERC, EU and Industry.
Dietary iron intake is a key homeostatic step in iron metabolism, and a deficiency or excess absorption of iron is associated with disorders in a significant proportion of the UK population. The spectrum of these ailments ranges from iron deficiency anaemia (insufficiency in the diet) and hereditary haemochromatosis (dysregulatory absorption) to colorectal carcinogenesis (mutagenic and genotoxic propensities). Iron is present in diets in two forms: non-haem iron derived from cereals and vegetables and haem iron derived from animal protein. Investigating iron bioavailability from foods and in supplemental iron is an approach towards the treatment and the prevention of iron deficiency anaemia. Non-haem iron in food iron is reduced to the ferrous (Fe2+) ion prior to uptake by duodenal enterocytes. This is achieved by luminal ascorbate and the duodenal iron-regulated ferric reductase protein (Dcytb, Cybrd1). The regulation of Dcytb under different modulators of iron absorption is an active research area in our laboratory. On-going projects include the interactions of ascorbic acid with Dcytb in the generation of reducing equivalents in the process of ferrireduction. The involvement of Hif 2α in the expression and regulation of Dcytb is also being investigated and explored.
While many advances have been made in understanding how non-haem iron is absorbed, understanding of how haem is taken up has lagged behind. Dietary haem iron from animal products is much more bioavailable than non-haem iron and therefore can provide a relatively larger amount of iron to the body. The mechanism of its absorption remains a major question in the field of iron research. My research interest in this area involves the elucidation of potential haem transport proteins in the gastrointestinal tract.
Hepcidin is a 25-amino acid peptide that regulates systemic iron homeostasis. It binds to ferroportin and induces its internalisation and degradation, thereby decreasing iron export from enterocytes. The effects of iron and flavonoids on the regulation and expression of hepcidin in cell culture and mice models of iron disorders are also areas of my research interest.
Subsequently I undertook a series of cross-sectional studies to measure intramyocellular lipid storage in human subjects characterised by insulin resistance or sensitivty, for example type 2 diabetic subjects, vegan subjects and subjects undergoing weight loss.
Furthermore, I performed human intervention studies to investigate the effects of low glycaemic index dietary manipulations on insulin sensitivity and intramyocellular lipid. This work showed that intramyocellular lipid storage is elevated in insulin resistant subjects compared to insulin sensitive subjects. Dietary manipulations were shown to impact on insulin sensitivity and muscle lipid storage but not in a dependent manner.
My postdoctoral research at Imperial College involved running a large multi-centre, dietary intervention trial; the RISCK trial, in which the effects of dietary manipulations of quantity and quality of dietary fat and carbohydrate on insulin sensitivity and cardiovascular risk were investigated in 650 subjects.
Cellular metal ion homeostasis requires multiple proteins for transport, sensing, chaperoning, and other functions in a network of tightly controlled interactions and with full integration into metabolism and signaling. The metal-regulatory proteins employ specific molecular mechanisms. One mechanism is the sulfur-ligand centered reactivity in zinc/thiolate coordination environments. Sulfur donors confer redox activity on the otherwise biologically redox-inert zinc ion. This coupling between zinc and redox metabolism provides a way of controlling zinc binding and protein functions.
Fundamental insights into the control of transition metal ion homeostasis will lead to an understanding of the pharmacological activity and toxic actions of metal ions, and aid in developing strategies for optimizing human health and for preventing, diagnosing, and treating human diseases.