Cambridge - In study in Nature Genetics (2014; doi: 10.1038 / ng.2915), the failure of gene that is involved in the transport of insulin in the beta cells surprisingly increases the risk of type 2 diabetes reduced by two thirds. Two pharmaceutical companies want to use the discovery for new diabetes therapy.
Not all people who eat unhealthily, are obese and do little physical exercise develop metabolic syndrome and type 2 diabetes in old age. On the other hand, the disease can also affect slim people without recognizable risk factors. The reason is suspected in genes that either protect against the disease or predispose to it.
The team around David Altshuler of the Broad Institute in Cambridge Massachusetts studied the genetic makeup of 758 elderly people with both extremes of diabetes risk. The researchers limited themselves to gene segments in the vicinity of so-called single nucleotide polymorphisms (SNP), which were associated with the risk of diabetes in previous studies. SNP are just random marker points on the genome. They indicate genetic factors, but as rule there are no “direct hits” from gene mutations that influence the disease in one direction or the other.
Scientists from the pharmaceutical company Pfizer also took part in the study, which began in 2009 involved who hope for new therapeutic approaches for diabetes. Loss-of-function mutations with protective effect are considered stroke of luck: the effects of loss-of-function mutations could then be imitated by active ingredients. In addition, the elucidation of the pathogenetic metabolic pathways offers the opportunity to intervene at one point or another, for example by blocking an enzyme or receptor.
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First, the researchers discovered two older obese participants who did not have type 2 diabetes , mutation in the SLC30A8 gene. The gene contains the genetic information for the transport protein ZnT8, which transports zinc into the beta cell. Zinc is needed there to store insulin. It is unclear how the loss of ZnT8 affects the pathogenesis of type 2 diabetes.
However, it seems certain that the mutations in ZSLC30A8 lead to loss of ZnT8 production. In the targeted analysis of 150,000 people, including those from the database of deCode Genetics from Reykjavik, further loss-of-function mutations were found that were also associated with protection against type 2 diabetes. According to calculations by Altshuler, carriers of loss-of-function mutations have 65 percent lower risk of type 2 diabetes if they lead an unhealthy lifestyle.
This is likely to make ZnT8 the target of drug development in the next few years do. The Pfizer and Amgen corporations (which deCode took over in December 2012) have already announced corresponding research projects to the media. With new antidiabetic drug, however, is expected in 10 to 20 years at the earliest. The prerequisite is that suitable active ingredient is found, which then successfully goes through preclinical and clinical developments.