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Clore Laboratory: Research
Diabetes, Obesity and Metabolic Research
Current Research Areas
- Fetal origins of metabolic disease
- Islet cell proliferation
- Proteomic approaches to the discovery of novel molecular targets
- Peptidergic control of insulin secretion
- Plant treatments for syndrome X (metabolic syndrome), obesity and diabetes
- Thermogenic receptors in muscle and adipose tissue
- Transcriptional factors associated with insulin sensitivity and lipid metabolism
- Leptin signalling in peripheral tissues
- Appetite control
- Target validation and pioneer therapeutics for metabolic disease
Overview
This internationally recognised research group, housed in the purpose-built Clore Laboratory at the University of Buckingham, has interests in molecular genetics, biochemistry, pharmacology, nutrition and the physiology of metabolic diseases, particularly diabetes and obesity.
The Clore Laboratory is led by Professors Mike Cawthorne and Jon Arch, researchers with a track record in drug discovery, including beta3-adrenoceptor agonists for obesity, orexin and MCH-antagonists and the insulin sensitiser drug rosiglitazone. Mike Cawthorne was awarded the 2001 Society for Medicines Research award for drug discovery in recognition of his work on the discovery of rosiglitazone.
Type 2 diabetes affects more than 120 million people worldwide and the number is expected to at least double over the next 10 years. In Europe, 5-10% of the adult population have diabetes. In the United States, diabetes is the sixth highest cause of death by disease, with an estimated 16 million Americans affected. The incidence rates in many countries in the Middle East, the Indian subcontinent, South East Asia and South America are considerably higher than in Europe and North America, and in some cases are reaching epidemic levels.
Diabetes increases the risk of death from cardiovascular disease such as stroke, coronary heart disease and atherosclerosis. Diabetes is also the leading cause of adult-onset blindness, kidney failure, non-traumatic limb loss, and loss of neurosensory function.
Obesity is strongly linked with type 2 diabetes but it also impacts on many other diseases, particularly cardiovascular disease. Obesity is one of the fastest growing epidemics in the world, affecting both developed and developing countries. It is estimated that the costs of obesity represent approximately 6-8% of the direct healthcare budgets of developed countries. Obesity is not simply a matter of overeating; understanding obesity involves understanding the interaction of genes and diet and the complex neuroendocrine matrix that regulates energy balance.
The Clore Laboratory, University of Buckingham, has developed a sufficient critical mass of researchers to be able to study type 2 diabetes and obesity from the gene through to whole-body physiology. Our goal is to define new molecular targets that could be sites for novel pharmacology and to examine the therapeutic potential of pioneering agents acting at appropriate molecular targets.
Fetal origins of metabolic disease
There is growing evidence that the metabolic programming that leads to the development of obesity, diabetes, hypertension and other aspects of metabolic disease in adult life might be acquired in utero. It has been demonstrated that small-for-date babies are much more prone to develop metabolic disease in later life. Studies are ongoing to define the metabolic programming changes that occur in early life during periods of growth retardation that subsequently lead to the development of metabolic disease in adult life, following periods of overconsumption of high fat diets.
Islet cell proliferation
Pioneering studies are being undertaken to examine factors that regulate islet cell mass as a potential novel approach to the treatment of diabetes.
Proteomic approaches to the discovery of novel molecular targets
In conjunction with the University of Geneva and Proteome Sciences plc, the Clore Laboratory is undertaking studies with novel experimental paradigms to identify new molecular targets associated with insulin resistance, pancreatic islet function and obesity. The proteomic technique involves identifying the differentially expressed proteins in diseased and normal tissues using two-dimensional electrophoresis and mass spectrometry.
Peptidergic control of insulin secretion
Studies are being undertaken on somatostatin and GLP-1 (glucagon-like peptide-1). Somatostatin is a paracrine hormone having effects on many biological systems in many organs in the body. There are five somatostatin receptors; studies have been conducted to demonstrate the nature of the receptors involved in pancreatic hormone secretion. Furthermore, in collaboration with academic and industrial research groups, subtype selective somatostatin analogues are being identified and their role in preventing the development of type 2 diabetes is being explored.
GLP-1 is a hormone secreted by the gut that has a powerful effect on insulin secretion and is a potential treatment for type 2 diabetes. However, it is very rapidly degraded in living systems to a biologically inactive form. In collaboration with an industrial partner, the Clore Laboratory is examining synthetic GLP-1 analogues as potential treatments for type 2 diabetes. In particular, detailed studies are being undertaken on the mechanism by which GLP-1 modulates insulin secretion and biosynthesis in cultured systems, and the relevance of these to the long-term control of blood glucose in diabetic subjects.
In a separate programme, the effect of novel dipeptidyl peptidase IV inhibitors on diabetic control is being investigated.
Plant treatments for syndrome X (metabolic syndrome), obesity and diabetes
More than half of the diabetics in the world are treated by plant-based therapies. Studies are being undertaken to examine the mechanism of action of key plant-based treatments for these diseases and to evaluate their therapeutic potential compared with synthetic drugs. Studies are also in progress to discover new plant-based therapeutics as both pharmaceuticals and nutriceuticals.
Thermogenic receptors in muscle and adipose tissue
Stimulating thermogenesis remains a therapeutic goal in the worldwide fight to treat and prevent obesity. In addition to exercise, energy can be wasted by non-shivering thermogenesis. Studies at the Clore Laboratory are focusing on the identification of the role of uncoupling proteins and various beta-adrenoceptor subtypes in skeletal muscle and adipose tissue. A novel receptor that is functionally coupled to increased oxidative metabolism is being characterised. In addition, the interaction of this oxidative pathway with mitochondrial uncoupling proteins is being examined.
Transcriptional factors associated with insulin sensitivity and lipid metabolism
New agents to improve insulin sensitivity are being developed by pharmaceutical companies. These agents affect the transcription of insulin-responsive genes through activation of nuclear hormone receptors. Proof of principle studies are being conducted on pioneer therapeutics together with more fundamental studies to identify the mechanism of action of these pioneer compounds. In separate studies, the mechanisms by which dietary lipids alter insulin sensitivity are being investigated.
Leptin signalling in peripheral tissues
Leptin, the product of the ob gene, is secreted from adipose tissue and acts on central receptors to affect feeding and energy expenditure. It is hypothesised that leptin is a primary adipostat signal. The Clore Laboratory has shown also that leptin has effects on a number of peripheral tissues, including pancreatic islets, skeletal muscle and intestinal epithelial cells. In pancreatic islets leptin inhibits insulin secretion. Current studies are examining leptin signalling processes in pancreatic islets and the possibility that leptin may have islet protective effects.
Appetite control
Studies are being undertaken on a number of centrally and peripherally acting peptidergic and non-peptidergic agents that influence appetite. These studies are designed to explore the basic mechanisms of appetite control as well as to identify potential new therapeutics.
Target validation and pioneer therapeutics for metabolic disease
The Clore Laboratory has particular skills in evaluating the therapeutic potential of pioneering therapies in the area of metabolic disease. This includes the validation of molecular targets through the use of phenotypic and biochemical evaluation of transgenic and knockout mice.