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20 Genes Confirmed as Diabetes Genes: DZD Sheds Light on Diabetes Pathogenesis

Massive obesity increases the risk for type 2 diabetes. However, not every fat person develops the disease, because the susceptibility for type 2 diabetes in humans is to a substantial part inherited. It is not yet fully understood which gene variants play a role here. By aligning human GWAS results with two mouse models for type 2 diabetes, a team of scientists led by Annette Schürmann of the DZD partner, the German Institute of Human Nutrition (DIfE), has now confirmed 20 genes as diabetes genes and has classified them according to their function. Four of these genes are important for the regenerative capacity of the insulin-producing cells of the pancreas. The study provides important clues about the pathomechanisms of the disease. A report of the researchers’ findings has now been published in the journal Diabetes (DOI:10.2337/db14-0425) .

 

Just like humans, mice vary in their susceptibility to type 2 diabetes. There are fat mice that are diabetes prone and fat mice that despite their obesity do not develop diabetes. New Zealand obese mice with a genetic predisposition to obesity develop insulin resistance due to their excessive weight and as a consequence develop type 2 diabetes. In contrast, B6-ob/ob mice – despite obesity and beginning insulin insensitivity – do not develop diabetes, since their insulin-producing beta cells are protected from disease-related deterioration and even proliferate to provide the body with sufficient insulin. Since humans and mice are genetically similar, the two mice strains can be used as a model system to elucidate which gene variants make people susceptible to diabetes or protect against the disease.

Genes in beta cells vary in how they are regulated
In the present study, the researchers led by Schürmann first compared the above mentioned mouse strains with respect to their genetic traits. They found that in the beta cells of the two strains more than 2,000 genes show differences in how they are regulated. To transfer these insights to the human disease, the scientists subsequently aligned these diabetes-relevant mouse genes with 106 human diabetes candidate genes known from genome-wide association studies. Although these genes are associated with type 2 diabetes, their function in diabetes pathogenesis still remains unclear.
Twenty of the examined genes were associated with type 2 diabetes both in humans and in the mouse model system. “Our results not only confirm the relevance of some human genes for type 2 diabetes. They also provide a manageable list of genes that can now be investigated in more detail in human and mouse studies,” said Annette Schürmann, principal investigator of the study. “This list is a distinct advantage, because it provides a basis on which we can explore the gene functions and underlying molecular mechanisms under controlled conditions,” Schürmann pointed out. Such studies are often not possible on humans for ethical and practical reasons.

Results useful for new strategies of prevention and treatment
“As our research shows, four of the investigated genes play a role in the regenerative capacity and the growth of the beta cells and could determine whether diabetes breaks out or not,” said Oliver Kluth, first author of the study. “Further research on the cellular function of the confirmed diabetes genes will not only give us deep insight into the pathogenic mechanisms of the disease, but will also lead us to new strategies of diabetes prevention and therapy,” added Hans-Georg Joost, former scientific director of the DIfE and co-author of the study.

 

Original publication:
Oliver Kluth, Daniela Matzke, Gunnar Schulze, Robert W. Schwenk, Hans-Georg Joost, Annette Schürmann: Differential transcriptome analysis of diabetes resistant and sensitive mouse islets reveals significant overlap with human diabetes susceptibility genes. Diabetes 2014, http://diabetes.diabetesjournals.org/content/early/2014/07/22/db14-0425.abstract


Background Information:
* To carry out genome-wide association studies (GWAS), two groups of subjects are needed: a control group (i.e. “normal” or usually healthy) and a group that shows the phenotype of interest, i.e. the disease or a special feature. DNA samples are taken from both groups. In the subsequent analysis, the researchers look for genetic differences between the two groups. If one genetic marker is more frequent in the group of the phenotype of interest, this means that there is an association. However, a genome-wide association study does not say anything about the context of the phenotype with the particular form of expression of a gene – it is a mere association. The causal relationship can only be explored after the identification of such “candidate genes” with molecular biological and biochemical methods (Source: Wikipedia).