Dr Katharina Wallis

Title: GLUCAGON LIKE PEPTIDE 2 –
measurement, mechanisms of release
and clinical relevance in intestinal failure

Project Start Date: 1 April 2004

Completion Date: January 2007

Summary:

This work is part of an ongoing research project at Imperial College London, which is due to be completed in April 2008.

When major segments of bowel have been removed surgically or are damaged by disease the remaining bowel can adjust to a certain degree by increasing its capacity to absorb the necessary nutrients. This process is called intestinal adaptation. For reasons that are not yet completely understood, the magnitude of this adaptive response can vary greatly. An important factor appears to be which part of the bowel has been removed and the length of the remaining bowel. In some cases however, the length of the residual bowel is inadequate to maintain overall nutrition, leading to a condition that is described as intestinal failure. Without medical intervention, patients with intestinal failure become malnourished and dehydrated. In these patients, intravenous feeding can be life-saving but, for many, it is a difficult and stressful procedure which often causes complications. In a small group of patients these complications may ultimately lead to the need for bowel transplantation. For the clinicians it is often extremely difficult to predict, which patients will recover better from such surgery and which patients will remain on intravenous feeding indefinitely.

Glucagon like peptide 2 (GLP-2) is a naturally occurring hormone (or chemical messenger) that is released from specialized cells (called L-cells) within the bowel. GLP-2 is involved in regulating bowel growth and an important facilitator of repair following bowel injury or disease. Animal studies have suggested that the amount of this hormone in the blood stream is closely related to the ability of the bowel to recover after surgery. Moreover, when GLP-2 is used as treatment, it can increase the area of the intestinal lining (or mucosal mass) and improve its efficiency of fluid and electrolyte absorption. It is thought that the natural release of GLP-2 from the bowel is stimulated by food ingestion, however it is not yet fully understood which substances are directly responsible for its discharge from the secretory cells. It is also unknown what influence certain constitutional factors, like body weight, have on the natural release of GLP-2.

My research aims are to:

1. establish a reliable method of measuring GLP-2 in blood and tissue samples.
2. determine the blood level of GLP-2 in a variety of patient groups with and without digestive problems and thus deepen the understanding of how GLP-2 is released and what role it might play in the recovery from bowel injury and disease.
3. address the question whether measuring GLP-2 with a simple blood test could provide clinicians with a reliable tool for predicting patient recovery from intestinal failure.
4. investigate the influence of various dietary factors on the release of GLP-2.

The results of the research are as follows:

1. Radioimmunoassay (RIA). RIA is a sensitive method to measure substances, such as GLP-2, that occur in only minute amounts in the blood. Measurement of GLP-2 to date it is only performed in a few laboratories worldwide. I have established this method at the RIA laboratory at Imperial College. This involved extensive testing and adaptation of various aspects of the measurement technique to ensure that reliable test results are being produced and to aid understanding and interpretation of these results.
2. and 3.      Measurement of GLP-2 in patients: I have measured fasting and meal stimulated blood levels of GLP-2 in various subject groups: healthy lean individuals, obese individuals, patients with intestinal failure and patients undergoing certain types of weight loss operations that involve surgical shortening of the bowel. These measurements have recently been completed and the results await detailed analysis. Early results indicate that there is no difference of GLP-2 release between lean and obese individuals. In patients with intestinal failure, a large variety of GLP-2 concentrations has been found. This is probably due to the fact that different parts of bowel had to be removed. It is therefore likely that greater patient numbers are needed in order to determine whether the measurement of GLP-2 is a helpful tool of predicting whether patients will recover from intestinal failure. Weight loss surgery appears to cause an increase in GLP-2 release following food ingestion. This might cause changes in the bowel structure that enable the bowel to maintain normal function.

4. Stimulation of GLP-2 release: I have investigated the release of GLP-2 from artificially grown cells (called GLUTag cells) that serve as a model for the naturally GLP-2 secreting L-cells in response to various nutritional stimuli.  This work is in progress. Early results indicate that Glutamine (an amino acid) and bile acids exert some of their effects on the bowel through the release of GLP-2. Glutamine is known to be an important source of energy for the gut and has been used as a therapeutic supplement in patients with intestinal failure. A positive effect of Glutamine on GLP-2 secretion (which has not previously been shown) is highly relevant, as it might explain the positive effect of Glutamine on gut function.

Because intestinal failure is a chronic condition that might require intensive treatment over many years, it is crucial to define a realistic prognosis, enabling the patient to arrange his or her personal life and allowing healthcare professionals to plan further treatment and allocate health care resources.

Identifying the stimulants and pathways that lead to natural GLP-2 release is an important step in the development of targeted therapies aimed at facilitating bowel recovery following digestive disease or bowel surgery.

It is expected that this research will be expanded in the future, to include a greater variety of conditions with structural or functional impairment of the human intestine such as chronic inflammation of the bowel.