Gut hormone and 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.