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Disease and treatment

Researchers stimulate the body to combat diabetes and obesity

Diabetes and obesity are currently treated with the substances the body cannot produce in sufficient amounts. The dream of enabling the body to restore the production of insulin has now moved a step forward. Danish researchers have successfully modulated the cell composition of cells in the intestines of mice, resulting in increased gut hormone production and increased glucose tolerance. The results offer new hope for helping the body to combat diabetes and obesity itself.

The inner layer of people’s approximately 9-metre gut is coated with cells that play a vital role in their health and well-being. The cells secrete at least 10 different hormones essential for our metabolism: in particular, glucagon-like peptide (GLP-1), which increases insulin secretion and reduces body weight. This is why modern therapies to combat diabetes are based on GLP-1. Danish researchers have now discovered a method of increasing the body’s own gut hormone production.

“Instead of treating the symptoms by artificially providing insulin or GLP-1, for example, we try to influence the secretory cells in the intestine. Using this method, we succeeded in increasing the production of GLP-1 and thereby improved insulin production and glucose tolerance in mice. However, we need to further develop the drug we used in the treatment before we can test an actual treatment in humans, but our research shows that the strategy is possible,” explains a main author, Natalia Petersen, Assistant Professor, Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

The body can solve the problems

GLP-1 is produced by L cells in the intestine, and this directly affects the secretion of insulin. This explains why people with diabetes have been successfully treated for decades with drugs that stimulate the body’s GLP-1 receptors. This treatment also promotes weight loss, which is why it is an effective strategy against type 2 diabetes and obesity. Nevertheless, the researchers investigated a new strategy because they hoped to induce the body to produce the hormones itself.

“The intestine’s secretory L cells are replaced every 4–5 days. We therefore looked for drugs that can influence the cell replacement process. We have been working on this for more than 3 years. The trick is to make such therapy both effective and safe. Remodelling cells in the intestine should produce sufficient hormones to have therapeutic effects and should not cause cell damage or excessive cell growth. Intestinal cell renewal is a fine balance, and the rho-associated coiled coil–containing protein kinase – ROCK – inhibitor can influence this without making drastic changes but sufficiently increase GLP-1 in cells to see the effect on glucose tolerance.

Actually, our search took us in completely different directions because we found a drug stem cell researchers use in their experiments. The drug is known to modulate cells’ position and to increase cell survival. However, an interesting side-effect was a significant increase in the numbers of secretory cells in the gut.”

The researchers therefore decided to investigate drug Y-27632 more closely by treating both healthy mice and ones that had diabetes with the drug. The result was a revelation: the numbers of GLP-1-producing L cells increased significantly.

“The drug had a noticeable effect on both the healthy mice and the ones with diabetes. They produced more GLP-1, and this led to an increase in the production of insulin and thus improved glucose tolerance. The major advantages of the treatment are that it only needs to be given once or twice a week and that the body itself produces the hormones – instead of receiving them artificially.”

A long-term revolution

The researchers do not yet fully understand the mechanism behind the major effect Y-27632 had on the mice’s metabolism. Our results indicate that this drug reversibly slows down the generation of new cells but also preserves stem cells and produces more gut hormone cells.

“The drug influences two enzymes – ROCK1 and ROCK2 – that apparently play a role in controlling cell differentiation in the gut. However, more research on these mechanisms is required before we can begin developing and testing an actual treatment.”

Although this new strategy may seem to be a wonderful strategy, the researchers believe that much work is still required to achieve the goal. The problem with Y-27632 is that it may have major effects on many other cells in the body.

“The strategy appears correct and the effects are clear, but we need to know more about what other effects the drug has so that we can develop a much more specific drug candidate. But if this is successful, it may revolutionize the treatment of diabetes and obesity in the long term.”

Inhibiting RHOA signaling in mice increases glucose tolerance and numbers of enteroendocrine and other secretory cells in the intestine” has been published in Gastroenterology. The study is based on collaboration between researchers from the Novo Nordisk Foundation Center for Basic Metabolic Research, the Biotech Research and Innovation Centre and the Novo Nordisk Foundation Center for Stem Cell Research.

Natalia Petersen
Assistant Professor
My research interest is to search for new treatment strategies for type 1 and 2 diabetes. Using cell- and organoid-based systems, ex-vivo pancreatic islet studies and animal models, I aim to discover new pharmacological targets to improve the insulin effect and to translate the findings into human research. My aim is to develop the new concept of pharmacological “tailoring” of the intestinal epithelium to increase the secretion of intestinal hormones for treatment of type 2 diabetes and, potentially, other metabolic diseases. Using the intestinal organoid platform for studies on enteroendocrine cells, I have shown that differentiation of intestinal endocrine cells can be enhanced by targeting early secretory progenitors (for example, using gamma-secretase inhibitors). In type 2 diabetic mice, such modulation of intestinal epithelium results in increased incretin secretion and improved glucose tolerance. Currently, I am investigating the roles of nutrient stimuli, signals generated by gut microbiota and cell-to-cell communication in directing enteroendocrine differentiation.