Four Genes Influence the Ability of Insulin-Producing Cells to Divide

Within the framework of a cooperative project funded by the German Center for Diabetes Research (DZD), a team of scientists led by Annette Schürmann of the German Institute of Human Nutrition (DifE) has identified four genes that in obese mice influence the ability of the insulin-producing cells to divide, depending on the carbohydrate intake.

All four genes are located on chromosome 1. In their previous studies on mice as well as on humans, the researchers had linked this chromosome to diabetes. “Our current findings provide deep insight into the mechanisms underlying the pathogenesis of diabetes and show how complex they are,” said lead author Oliver Kluth of the DIfE.
The team of researchers which also includes scientists of Helmholtz Zentrum München at the University of Tübingen and physicians from the University Hospital Tübingen, have now published their results in the journal PLOS Genetics (Kluth et al. 2015; DOI:10.1371/journal.pgen.1005506);

The hormone insulin stimulates fat and muscle cells to receive glucose from the blood in order to provide themselves with energy. In people with type 2 diabetes, however, the signaling effect of insulin is disrupted. Doctors refer to this as insulin resistance.In the initial stage of the disease, the body tries to compensate for this insulin insensitivity of the cells by releasing more insulin than normal via the beta cells of the pancreas. As the disease progresses, these cells become increasingly fatigued and die off over time, resulting in a lack of insulin.This is due to increased levels of glucose and fatty acids in the blood, but genetic predisposition also appears to play a role for the life span of the beta cells.In order to elucidate the molecular mechanisms that are critical in the presence of insulin resistance for the ability of the insulin-producing cells to divide and identify genes that play a role here, the scientists compared the physiological changes and gene expression of the beta cells of two different mouse strains in vivo und in vitro.Both the New Zealand obese (NZO) mouse and the B6-ob/ob mouse have a natural tendency to be overweight, but only the NZO mouse strain is prone to diabetes – a phenomenon that can also be observed in humans because not every obese person is equally susceptible to the disease.Up to the age of 18 weeks the animals received a high-fat, but carbohydrate-free diet, through which both mouse strains gained a lot of weight. Their blood glucose levels did not increase during this period. If the mice were then given carbohydrates to eat, after a few days the blood glucose levels increased noticeably in the diabetes-prone NZO mice. Moreover, in these animals the carbohydrate diet led to the death of the beta cells by apoptosis (programmed cell death). The beta cells of the other mouse strain, however, were not only protected from dying, their number increased even further. The associated increased insulin production normalized these animals’ blood glucose levels, which initially were also elevated. Thus, these animals did not develop diabetes. “As can be assumed from our data, the different reaction of the beta cells is due to four genes. Studies on isolated beta cells show that increased expression of the genes Lefty1, ApoA2 and Pcp4l1 stimulates cell division and ultimately protects the B6-ob/ob mice against diabetes. In contrast, increased expression of the Ifi202b gene had just the opposite effect in the NZO mice,” said the biochemist Kluth. “In humans, too, at least some of the genes we identified appear to play a role in diabetes. As human studies conducted by our cooperation partners show, two different variants of the human gene Lefty1 are associated with altered insulin secretion,” added study director Schürmann. “Furthermore, in study participants in Utah, researchers observed a link between type 2 diabetes and variants of human APOA2 gene,” the scientist went on to say.“It is useful for our research to identify genes that play a role in both mice and humans,” said Kluth. In this way we can study the gene function and the molecular mechanisms underlying glucotoxicity* and diabetes pathogenesis on the mouse model in more detail and under controlled conditions. Due to ethical and practical reasons, such studies on people are often impossible.

Background information:

* Elevated blood glucose levels have a toxic effect on many tissues.
Scientists refer to this as glucotoxicity.