By Camille Mojica Rey, PhD
Reviewed by Jeremy Walston, MD





A recently discovered gene that increases the risk of Type 2 diabetes has given scientists new hope of understanding the genetics behind the disease. That knowledge may someday lead to new drugs or treatment options. However, the researchers who discovered this gene say that screening for mutations would not be practical until they learn more about how the gene influences diabetes risk.

More on Type 2 Diabetes

The New Gene: Calpain-10

“Nobody in his right mind would have thought that calpains were linked to Type 2 diabetes,” said Dr. Robert Scherwin, M.D., a Yale researcher and vice-president of the American Diabetes Association.

Although specifics about which proteins Calpain-10 regulates are not known, the finding reveals a biochemical pathway never before considered important in the disease. “Nobody in his right mind would have thought that calpains were linked to Type 2 diabetes,” said Dr. Robert Scherwin, M.D., a Yale researcher and vice-president of the American Diabetes Association.

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Calpain-10 Provides Insight Into Type 2 Diabetes

Until now, genetic information about Type 2 diabetes has been quite meager, Dr. Scherwin said. Genetic abnormalities in the most logical pathways – ones that involve insulin receptors or key signaling molecules – have yet to be implicated in causing the disease, he added.

However, now that scientists know one place to look, they may be able to unravel at least part of the genetic mystery behind the disease.

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Versions of the Gene Increase Risk

In the case of Calpain-10, having a slightly different version of the gene is what increases the risk of developing diabetes. The double-stranded DNA that makes up a gene can be off by just one nucleotide, resulting in what is called a single nucleotide polymorphism (SNP). Although this change does not affect the protein made by the Calpain-10 gene, some SNPs reduce the amount of protein that is produced. Researchers still don’t know how this decrease in protein increases a person’s risk for diabetes.

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More on General Overview of Genetics

Ethnic Groups Differ in the Incidence of Risky Versions

The researchers studying a group of Mexican-Americans in South Texas found that several SNPs in the Calpain-10 gene by themselves increased the risk of diabetes. A combination of two particular SNPs increased the risk three-fold. They calculated that the combination accounted for 14 percent of the diabetes found in that population They also studied European populations and found that although the SNPs were much less common, the same combination also tripled the risk.

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Screening Is a Long Way Off

Traits that can easily be measured, such as obesity, are more reliable predictors of who gets diabetes than mutations in Calpain-10.

“For people walking into their doctor’s office today, it doesn’t really have any clinical implications,” Cox said. Even months from now, knowing that someone carries the risky versions of the gene will be of little use, she added.

Diabetes is a complicated disease in which many genetic and environmental factors are thought to combine in such a way as to bring on the disease. Screening for the variations of Calpin-10 would be useless right now because they are rare and do not accurately predict presence of the disease, only increased likelihood.

Cox and others point out that traits we can easily measure, such as obesity, are much more reliable predictors of who gets the disease. Even if doctors found high-risk genes, they could only prescribe changes in diet and exercise – which are already what doctors recommend to people at risk for the disease.

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Potential for Better Treatment

The discovery of Calpain-10 may lead to individualized treatment of diabetes based on genetics.

The ADA’s Scherwin is hopeful that the future of diabetes treatment will be forever changed by this study’s results. He predicts the discovery of the link between Calpain-10 and diabetes is the first step to characterizing a pathway that can be the target of new drugs.

In addition, and equally as important, the discovery of Calpain-10 may lead to individualized treatment of diabetes based on genetics.

“Right now, our treatment approach is one-size-fits-all,” Scherwin said. “But, we can develop strategies down the road for treating different groups in different ways.” For example, a doctor may recommend different treatment strategies for a family that carries a Calpain-10 mutation than for families that carry a different risk factor.

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References

Baier, L. J., et al. (2000). A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest, 106, R69-73.

Horikawa, Y., et al. (2000). Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet, 26, 163-75.

Personal Communication (2000). Robert Scherwin, MD, Vice-President of the American Diabetes Association. C.N.H. Long Professor of Medicine in the Section of Endocrinology, Department of Internal Medicine at Yale University. Member of the FDA Advisory Committee for Endocrinologic and Metabolic Drugs.

Personal Communication (2000). Nancy Cox, PhD, Associate Professor in the Departments of Human Genetics and Medicine at the University of Chicago. Co-author of one study that identified SNPs in Calpain-10 that increase the risk for Type 2 diabetes.