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Old gene’s new tricks shed light on diabetes

December 07, 2015


By Jovana Drinjakovic

To Dr. Daniel Drucker, who is both an endocrinologist and a scientist, diabetes is more than a disease – it is a puzzle to be solved. Now his latest research into a little-known hormone has uncovered a major missing link in our understanding of the disease and opened the door to improving available treatments.

  Both young (8 weeks old) and mature (20 weeks old) mice have different sets of genes that are active in the pancreases of the normal animals (WT) versus the mutants that lack the TCF7 gene (TCF7 -/-).
Dr. Drucker and his colleagues at the Lunenfeld-Tanenbaum Research Institute (LTRI) have found a surprising connection between a hormone that is produced in the gut and TCF7 – a gene previously only known to work in the immune system - in the development of diabetes.

The study is published online December 7 in Nature Medicine, a leading journal in biomedical research.

When you think of hormones and diabetes, insulin is the first to spring to mind. Released from specialized cells in the pancreas after a meal, its job is to instruct our tissues to absorb sugar from the bloodstream before it becomes toxic. When this process fails, that’s when diabetes occurs.

In comparison, hormones produced by the gut have received less attention, despite their large number (there are about 100 of them) and the vital roles they play in how the body responds to food. Among them are the incretins, named for their ability to increase the release of insulin following a meal.

Dr. Drucker’s earlier work revealed the importance of glucagon-like peptide (GLP-1), the most studied incretin hormone, in boosting insulin release and controlling appetite, which has led to new treatments for diabetes and obesity. His latest study reveals an unexpected role for a lesser-known incretin, called glucose-dependent insulinotropic polypeptide (GIP).

GIP is also released from the gut after we eat, and acts in the pancreas where it activates a molecular cascade promoting the release of insulin. To understand in detail how this happens, the research team engineered a mouse to lack the GIP receptor gene in the insulin-producing beta cells in the pancreas, rendering them effectively numb to GIP.

When the researchers looked at the patterns of genes that were switched on or off, in the absence of GIP action, they were in for a surprise. They found that the TCF7 gene – well known for its role in creating immune cells – was markedly turned down in beta cells. This suggested that TCF7 could play a role in both the immune and endocrine systems, a bit like having a cruise liner captain who also pilots space shuttles on the side.

So what is TCF7 doing in the pancreas? And how is it linked to diabetes?

To answer these questions, Dr. Drucker and his colleagues investigated a different mouse that specifically lacks the TCF7 gene. This strain of mice had been created almost a decade ago as a tool to study the immune system. When Dr. Drucker’s team began to examine these animals they soon found that they exhibited all the hallmarks of diabetes.

“These mice were a metabolic mess. They had rapid development of diabetes, big problems with beta cell survival, and could not secrete adequate insulin in response to glucose or high fat meals. Nobody had ever discovered this before,” said Dr. Drucker.

While these experiments established a link between TCF7 and diabetes in mice, it remained unclear if this was also the case in humans. In collaboration with Dr. Paul MacDonald’s group from the University of Alberta, the researchers measured TCF7 in pancreatic beta cells from diabetic human subjects and found the same clear connection.

Indeed, the findings in human pancreas samples aligned perfectly with the animal data. “TCF7 levels were turned on by GIP in normal beta cells, yet TCF7 levels were markedly lower in cells from diabetic subjects. Moreover, experimental reduction of TCF7 function increased the death of human beta cells” says Dr. Drucker.

The researchers went on to show that in both mice and humans, TCF7 regulates the function and survival of beta cells by controlling the activity of many other genes, providing a new window into understanding the function and survival of beta cells.

In effect, Dr. Drucker’s team have uncovered a new molecular pathway - from GIP in the gut, to TCF7 in the pancreas – which runs along a route that is different to that followed by the more-studied incretin GLP-1. “Dan’s group have a remarkable track record in uncovering new roles for this class of hormones and their latest work shows how much more there is to be discovered”, noted Jim Woodgett, LTRI Director. “This newly discovered connection opens up a whole new approach for potential therapies for diabetes”.

New discoveries take time and a lot of luck to be translated into patient impact, but there’s also a tangible medical potential in this discovery because drugs that mimic the GIP could be combined with the already available GLP-1-based medicines to further improve treatment for obesity and diabetes.







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