Obesity is a major cause of morbidity and premature mortality.
A programme of basic research has demonstrated novel hypothalamic neuropeptides that powerfully regulate satiety. The most potent of these, glucagon-like peptide-1 (GLP-1), is being studied in humans to assess the effect on both food intake and other metabolic parameters, including blood glucose and insulin concentrations.
A distinct improvement of overall diabetic control and postprandial glucose concentration was demonstrated in initial studies. However, the effect lasts only about an hour.
A longer acting preparation is being pioneered in this unit using a naturally occurring long acting analogue, exendin 4. GLP-1 is a hormone normally produced in the gut and released from the lower bowel by long chain fatty acids and carbohydrate in food. By careful choice of dietary components, pilot studies suggest that it will be possible to maximise the endogenous release of GLP-1 and thereby improve carbohydrate tolerance in mild diabetics. In addition, work is ongoing in collaboration with Alizyme PLC to develop and test, on site, a nonpeptide agent which will bind avidly to the GLP-1 receptor and form the basis of a possible new therapeutic principle in type II diabetes mellitus. Investigation of novel appetite regulators such as CART, orexin, Agrp and aMSH has been initiated.
Human infusion studies are being undertaken with a number of other novel regulatory peptides. Leptin, the hormone released by fat and having actions peripherally on metabolism and centrally to inhibit food intake, whilst a large peptide itself, has active fragments. These will be administered to establish proof of principle (action in man as predicted from models) and may form the basis of a new approach to the treatment of diabetes and of obesity. GLP-2, distantly related to GLP-1, is a newly identified endogenous growth factor for the small intestine of rats. GLP-2 is also present in human gut and the growth effect will be examined in man, using crypt cell production rates in small intestinal biopsies.
Once the action is established, it is intended to undertake studies in patients with short intestine syndrome, since these people have been previously postulated to have insufficient of an unknown growth factor to be able to take advantage of the guts amazing ability to grow. It is thus postulated that once a certain bowel length is achieved by administration of exogenous growth factor (GLP-2) the bowel will then become self-sustaining.