Gut Hormone Biology Laboratory
GLP-1 is an incretin hormone and regulates the glucosehomeostasis, while GLP-2 is an intestinotrophic hormone, regulating the size and absorptive capacity of the GI tract. Both hormones are secreted from the intestinal endocrine L-cells upon food intake.
In the group we work with the extra-pancreatic effects of GLP-1 in relation to pulmonary and intestinal diseases. We are interested in the importance of the endogenous secreted hormones and the mechanism of action of the beneficial effects on pulmonary and intestinal diseases. We are also interested in the implication of GLP-2 in colon cancer.
The Gut Hormone Biology Lab is working within three different research areas.
GLP-1 and pulmonary diseases
We have a model of chronic obstructive pulmonary disease (COPD) in mice. We use ovalbumin to sensitize the mice and after ten days we give them inhalations with lipopolysaccharide and ovalbumin, this mediates an acute worsening in their respiratory function.
We measure the pulmonary function in a whole body plethysmograph. We discovered that treatment with GLP-1 had a beneficial effect on COPD and we are working to elucidate the mechanism of action behind this.
Recently we showed that GLP-1 could improve lung function and reduce mortality in a model of murine COPD. GLP-1 is an incretin hormone acting as a secretagogue of insulin and analogues are therefore marketed to treat type 2 diabetes. The effect observed in the COPD model was very surprising.
We hypothesize that the beneficial effects of GLP-1 on pulmonary function is obtained through a secretion of atrial natriuretic peptide (ANP) either from the atrial myocytes or from ANP secreting cells in lung tissue. ANP is a hormone important for the regulation of blood pressure, but has also shown to relax bronchial smooth muscle cells, thereby decreasing airway obstruction. ANP was recently shown to be secreted from atrial myocyte upon GLP-1 stimulation, thereby acting as a second messenger for the cardiovascular effects which has been observed after treatment with GLP-1 analogues. ANP in itself has got a very short half-life and cannot be used as a bronchodilator, but if GLP-1 analogues can be used to stimulate a rapid ANP secretion, GLP-1 analogues can have a therapeutic role in the treatment of acute airway obstruction in exacerbations of pulmonary diseases. This finding can have a major impact on the treatment strategy of e.g. acute exacerbations in COPD, a widespread disease with a high morbidity and mortality.
The project is funded by The Danish Research Council.
Gut hormones and colon cancer
Our group was the first to show that treatment with the intestinotrophic hormone GLP-2 could promote the development of tumors in a model of colonic adenomas in mice. On the other hand we have no idea if the endogenous secreted hormone is implicated in the initiation or promotion of colonic cancers. Using colon cancer cell lines and knock out animals we aim to investigate if the GLP-2 secreting L-cell is implicated in colon cancer.
The present project seeks to unravel a potential role of the entero-endocrine L-cell in development of colon cancer. L-cells are localized in the gut mucosa and produce the hormone GLP-1, which plays an important role for the regulation of blood glucose by stimulation of insulin secretion. Today stable GLP-1 mimics are widely used as treatment for type-2-diabetes. However, due to their peptideogenic nature, these have to be taken by daily injections. Therefore, attempts are carried out to develop a pill that can stimulate the release of the endogenous GLP-1. One such strategy is to stimulate secretion by selective activation of the bile acid receptor TGR5, which is expressed by the L-cell and is thought to underlie bile-acid stimulated GLP-1 secretion.
Currently it is, however, unknown if targeting of the L-cell is a safe approach to treat type-2-diabtes. A cause for worry is that GLP-2 (the ever forgotten sister of GLP-1), which is co-stored and co-secreted with GLP-1, has been shown to increase proliferation of intestinal cells and to promote tumor development in mouse models. Upon its secretion intact (biological active) GLP-2 is metabolized to GLP-2(3-33) which appears to have antagonistic effect on the GLP-2 receptor and therefore inhibits tumors growth. It therefore appears that the balance GLP-2 secretion and the extent to which intact GLP-2 is converted to GLP-2 (3-33) is important for adequate intestinal proliferation but it may also affect the risk of tumor development.
Therefore, we are interested in investigating if stimulation of the L–cell can change the degradation rate of GLP-2. More specifically, this study aims to unravel the mechanism behind bile acid mediated L-cell secretion and the consequences of prolonged bile-acid stimulated L-cell secretion. Indeed, epidemiological studies have repeatedly shown a link between elevated luminal bile acid concentration (often observed in obese and type-2-diabetic subjects) and increased colon cancer incidence. We, therefore, believe that this project will provide important insight into the molecular mechanism behind the increased risk of colon cancer in type 2 diabetic patients and if targeting L-cell secretion by selective TGR5 activation increases the risk for colon cancer development. As a secondary outcome, the project will examine if the metabolite of GLP-2 can inhibit development of cancer cells and thereby be a potential target in new treatment strategies.
Gut hormones and intestinal injury
We think that both hormones are important for protection of the intestinal epithelia upon injury, such as chemotherapy induced mucositis. We have shown that treatment with GLP-1 and GLP-2 can ameliorate the intestestinal injury seen after chemotherapy in mice. When given in combination the effect is additive. We are working to elucidate if the endogenous secreted hormones are important for the intestinal recovery after damage.
We tend to focus our research in this area in the importance of the peptide in chemotherapy-induced mucositis. Chemotherapy-induced mucositis is a frequent complication of anticancer treatment. The disease threatens the effectiveness of therapy because it often leads to dose reduction and impairs patients’ quality of life. We have shown that both GLP-1 and GLP-2 treatment were able to reduce the damages to the intestine seen in mice after injections of chemotherapy.
We know that patients with obesity or diabetes have an impaired secretion of both GLP-1 and GLP-2. We also know that when patients are not eating, the secretion is abolished, and the epithelium gets atrophic. Still it is not seldom to see, that patients with severe nausea after chemotherapy are treated with total parenteral nutrition, which then again will abolish the endogenous secretion of the peptides. Therefore we are investigating if the endogenous hormones are involved in the regenerative processes that occur after the intestinal damage. We have to know if patients needs substitution with the hormones if they have an impaired secretion e.g. diabetes, obesity or are treated with total parenteral nutrition.
We use experimental models of mucositis and the diphtheria toxin conditional knock out mouse, in which we can selectively destroy the GLP-1 and GLP-2 secreting L-cells.
We are involved in a number of collaborations:
- Gubra biotech company
- Associate Professor Jacob Bo Hansen, Department of Biology, Faculty of Science.
- Professor Mogens Helweg-Claesson, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences.
- Professor Palle Bekker Jeppesen, Rigshospitalet, Department og Gastroenterology.
The Gut Hormone Biology Lab has received grants from a number of private and public foundations.
- Danish Council for Independent Research Medical Sciences (FSS)
Hannelouise Kissow is the grant holder.
Case number: DFF 4004-00620B
- The Danish Cancer Society - Valdbjørns Fond
- Aase og Ejnar Danielsen Foundation
- Fonden til Lægevidenskabens Fremme
- Det Lægevidenskabelige Fakultets Fond
- Oda og Hans Svenningsens Fond
- Krista og Viggo Petersen's Fond
- Else og Mogens Wedell-Wedelsborg Fond
- Dagmar Marshall fond
- fabrikant Einer Willumsen Mindelegat
- Københavns Universitets Fond for Kræftforskning