Researchers find defective gene that impairs insulin secretion

Researchers find defective gene that impairs insulin secretion
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First Published: Thu, Nov 19 2009. 09 30 PM IST

Updated: Thu, Nov 19 2009. 09 30 PM IST
Bangalore: Have we finally found the diabetes gene?
An international team of researchers reports in Friday’s issue of Science that they have discovered a new gene as well as pinned down, for the first time, the mechanism by which its defect impairs insulin secretion, leading to type 2 diabetes. More importantly, the researchers treated the genetic defect with drugs that are approved for treating hypertension and erectile dysfunction, suggesting that the new genes are potential candidates for developing therapies in future.
The discovery is significant because even though nine genes have been identified so far to be instrumental in the adult onset diabetes, a metabolic disorder reaching epidemic levels, particularly in India, none has been linked to the precise mechanism by which the disease develops.
“The authors have presented a very significant finding in type 2 diabetes; it’s a complete study in the sense that it maps out the gene as well as shows the molecular function apart from verifying the disease causing locus in human patients,” says Avadhesha Surolia, director of the National Institute of Immunology in New Delhi.
This is an important finding especially when we do not have a clear idea as to why some people or families are more predisposed to develop diabetes, says Anoop Misra, director and head, department of diabetes and metabolic diseases, Fortis Hospitals, in the Capital.
One of the highlights of the research is the use of inbred rats with inherited susceptibility to the disease. The culprit gene, Adra2a, helps to suppress insulin secretion, and the researchers found it was significantly overexpressed in the inbred rats. They also found that a particular genetic sequence in the human version of the Adra2a gene is associated with reduced insulin secretion and increased risk of type 2 diabetes.
Since environmental and population variability affect the genetic make-up, lead authors of the study—Erik Renstrom and Anders Rosengren from Lund University Diabetes Centre in Sweden—say but for the inbred rats, it would have been difficult to identify Adra2a using only human genetics.
Till date, one of the strongest diabetic associations has been found in TCF7L2 gene, which also links through reduced insulin secretion. Mutation in any of these nine genes might lead to type 2 diabetes and the age of onset will decrease if more than one such mutation coexists, says Surolia.
“It is unlikely that any single gene can explain all type 2 diabetes, as it is a polygenic disease with multiple genes with rather modest effect sizes being involved,” says V. Mohan, chairman and chief diabetologist at Dr Mohan’s Diabetes Specialities Centre in Chennai, also a WHO collaborating centre for non communicable diseases prevention and control.
And even though Renstrom and colleagues showed that the drugs can counteract the adverse effects of this genetic defect, Dr Mohan says extrapolating this to large human studies isn’t easy.
In a country that currently has 50.8 million diabetics, going up to about 9% of the population by 2030, according to the International Diabetic Federation, studies to pinpoint any particular gene having a dominant role in the development of this disease haven’t been quite successful. So, Fortis’ Misra believes these findings may be important for Indian population. “Investigations are needed to see whether this defect may partly explain heightened tendency of Asian Indians to develop diabetes.”
Renstrom and Rosengren say their study of the Caucasian sample shows that Adra2a gene is involved in about 40% of type 2 diabetes cases. “So, clearly Adra2a is not the sole explanation for the disease. Further studies in other populations would be important,” they wrote in an email.
Currently, type 2 diabetes treatment pretty much follows the one-size-fits-all approach—the same therapy is being given to everyone with increased plasma glucose. But in reality, say experts, the molecular disease mechanism varies between individuals.
Through this study, says Surolia, authors have opened the door to personalized medicine. In future, patients may be checked for this particular defect and treated specifically with approved drugs.
Till that happens, says Misra, diet and lifestyle factors can largely overcome genetic advantage or disadvantage. In October, the medical journal Lancet published an extensive study showing that lifestyle intervention can delay type 2 diabetes by up to 10 years.
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First Published: Thu, Nov 19 2009. 09 30 PM IST