Genetic and inherited

 

 

 

 

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Researchers Discover New Genetic Culprit in Type 2 Diabetes

The scientists say their findings offer new insight into the origins of type 2 diabetes, a major public health problem that affects more than 135 million people worldwide. The incidence of type 2 diabetes is on the rise, and it currently accounts for about 90 percent of cases of diabetes. If untreated, type 2 diabetes can cause blindness, kidney and heart disease, stroke, loss of limbs and reduced life expectancy.

The multi-institution research team, which included HHMI investigator Graeme Bell and his colleagues at the University of Chicago, announced their discovery in an article published in the October 2000 Nature Genetics and in a second article published in the October 2000 Journal of Clinical Investigation.

The Nature Genetics report details the scientists' discovery that small genetic variations, called single-nucleotide polymorphisms (SNPs), in the gene for calpain-10 are associated with type 2 diabetes in a long-studied population of Mexican Americans who are susceptible to the disease. The report also implicated the gene in diabetes in an isolated population of people from Finland.

In the Journal of Clinical Investigation article, the scientists showed that a group of Pima Indians at high risk for diabetes also had the calpain-10 polymorphism. This group had insulin resistance and showed reduced levels of calpain-10 gene expression, demonstrating that the polymorphism relates to the disease. That study was also led by co-authors from the National Institutes of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, who were also co-authors on the Nature Genetics paper.

The search for a specific genetic defect underlying type 2 diabetes began after Bell and University of Texas at Houston researcher Craig Hanis led a 1996 screening study that localized a diabetes susceptibility gene in a population of highly diabetes-susceptible Mexican Americans in Texas. That population had been studied by Hanis — a co-author of the Nature Genetics paper — and his colleagues for more than two decades. The screening study statistically linked increased diabetes risk to an unknown gene on chromosome 2, which the scientists named NIDDM1.

"This was the first genome-wide screen for susceptibility genes for type 2 diabetes," said Bell. "It actually demonstrated that one could map susceptibility genes for this disorder." The finding launched Bell, Hanis and their colleagues on a search to pinpoint the specific gene and its variants that caused increased diabetes susceptibility in this population.

"Such an identification had never been done before for a genetically complex disorder such as type 2 diabetes," said Bell. "It was extraordinarily difficult because the gene location is not precisely defined by recombination events, as it is for a single-gene disorder. Rather, it is only a probability that the gene will be in a particular region, so the region that you have to search is much larger than for a single-gene disorder."

By sequencing DNA samples from the Mexican-American population under study and performing statistical analysis on the DNA sequences, the researchers narrowed their search for the gene from a vast region of chromosome 2 to a much more manageable region of 66,000 DNA base pairs. Further analysis led them to SNPs in a previously unknown gene called CAPN10. The gene codes for calpain-10, a protein-snipping enzyme called a protease, said Bell.

"This protease was not on anyone's list of favorite genes for affecting either insulin secretion or insulin action or hepatic glucose production," said Bell. "People were focusing on the insulin receptor and insulin receptor pathway; on insulin-responsive tissues or the secretory mechanism that regulates glucose metabolism of the pancreatic beta cell. They weren't thinking about proteases."

What's more, the SNPs were not even in the protein-coding portions of the CAPN10 gene, but in non-coding regions of the gene called introns. Introns are gene segments that are edited out when a gene is copied to messenger RNA (mRNA) to make the functioning protein. According to Bell, their studies suggest that the SNPs they found somehow decrease the level of CAPN10 expression, thus contributing to the diabetes susceptibility in affected populations. Bell emphasized that an enormous amount of work lies ahead to understand the role of calpain-10 and its variants in diabetes susceptibility.

"Clearly, once we understand more about the pathway, it could lead to new therapeutic approaches for treating diabetes," said Bell. "But we don't know enough about the pathway right now to predict whether or not that realization will come to pass. This discovery is certainly an important piece of the puzzle, but having gotten this far, we now end up with many more challenges ahead," he said.

For example, the researchers would like to understand how the different versions of the gene, or alleles, they found might interact to increase diabetes susceptibility. Their current hypothesis is that diabetes susceptibility is achieved through a "two-hit" effect:

"The two-hit notion is that one allele affects calpain-10 expression in, for example, the pancreatic beta cell," said Bell. "And the other allele would affect expression in an insulin-responsive tissue. Thus, it would require a defect in both tissues to lead to type 2 diabetes."

The CAPN10 expression study in Pima Indians is important, Bell said, "because we demonstrated that variations in CAPN10 do indeed affect expression of the gene in skeletal muscle, as we predicted. Also, individuals who are at greatest risk of diabetes, have lower levels of calpain-10 mRNA in skeletal muscle.

"In addition, the Pima study shows a nice correlation between calpain-10 mRNA levels in skeletal muscle, and glucose metabolism by skeletal muscle. So, it begins to provide some understanding of the mechanism of this defect."

More broadly, Bell said that he hopes that the success of their search for type 2 diabetes susceptibility genes will inspire other scientists to tackle other complex genetic diseases. "Of course, we're still at the beginning, but our success so far with type 2 diabetes means that those investigators looking for genes for asthma, schizophrenia and other disorders that also have a complex genetic basis are going to have a high likelihood of success as well," he said.

Decreased insulin responsiveness of glucose uptake in cultured human skeletal muscle cells from insulin-resistant no diabetic relatives of type 2 diabetic families

 

To investigate the contribution of inherited biochemical defects to the peripheral insulin resistance of type 2 diabetes, we studied cultured skeletal muscle from 10 insulin-resistant no diabetic first-degree relatives of type 2 diabetic families and 6 control subjects. Insulin stimulation of glucose uptake and glycogen synthesis was maximal in myoblasts. Insulin-stimulated glucose uptake (fold-stimulation over basal uptake) was decreased in relative compared with control myoblasts at 0.001 micromole/l (0.93 +/- 0.05 [mean +/- SE] vs. 1.15 +/- 0.06, P < 0.05) and 0.1 micromole/l (1.38 +/- 0.10 vs. 1.69 +/- 0.08, P = 0.025) insulin. Insulin responsiveness was markedly impaired in 5 of the relative myoblast cultures, and in 4 of these, there was an associated increase in basal glucose uptake (76.7 +/- 7.0 vs. 47.4 +/- 5.5 pmol x min(-1) x mg(-1) protein, relative vs. control; P < 0.02). Expression of insulin receptor substrate 1, phosphatidylinositol 3-kinase, protein kinase B, and glycogen syntheses was normal in the relative cultures with impaired insulin responsiveness. Glycogen synthesis was also normal in the relative cultures. We conclude that the persistence of impaired insulin responsiveness in some of the relative cultures supports the role of inherited factors in the insulin resistance of type 2 diabetes and that the association with increased basal glucose uptake suggests that the 2 abnormalities may be linked.

Genetic Defect Is Possible Link to Onset of Type 2 Diabetes

Whether one person is more likely than another to develop diabetes may be "in the genes," Italian and American scientists have found. The researchers identified a genetic defect linked to insulin resistance -- a condition in which the body resists the effects of insulin and which usually precedes onset of type 2 diabetes. The discovery paves the way for genetic tests that could identify people at risk for type 2 diabetes. It may also lead to development of new drugs to restore the body's ability to regulate blood glucose (sugar) levels. The study was reported in a recent issue of Diabetes.

The genetic defect, dubbed the "Q allele," was found two to three times more often among people with insulin resistance or type 2 diabetes than among people with neither condition, report researchers Antonio Pizzuti, MD, and colleagues at the Institute Scientific Ospedale Casa Sollievo della Sofferenza in San Giovanni Rotondo, Italy, and Ira D. Goldfine, MD, of the University of California, San Francisco.

Type 2 diabetes occurs in about 25% of all people who develop insulin resistance, Goldfine tells WebMD. So the discovery could be very important for the prevention and treatment of type 2 diabetes -- and the heart disease and other complications associated with insulin resistance. "If you have insulin resistance, what you do is compensate by making more insulin, and the combination of high insulin and insulin resistance leads to ... hypertension ... abnormal clotting mechanisms, gout, etc.," says Goldfine, director of diabetes and endocrine research at UCSF-Mt. Zion Medical Center. People with type 2 diabetes also often go on to develop conditions associated with high blood glucose levels, Goldfine notes, including kidney failure, eye damage, and nerve damage.

The defect Goldfine and his Italian colleagues describe is a needle in a genetic haystack: the abnormal substitution of a single DNA particle out of 2,600 in the gene PC-1. Yet this one genetic defect has the power to interfere with the ability of insulin to regulate the way cells metabolize glucose.

A researcher who reviewed the study for WebMD says that although the discovery is interesting and might be important, it won't be translated into forms of treatment for some time. "This is not ready for prime time... but it's a very neat observation," says Robert A. Goldstein, MD, PhD, vice-president for research at the Juvenile Diabetes Foundation. "That genotyping [genetic testing] ... could identify people at risk for either type 2 diabetes or [coronary artery disease] is quite interesting."

The research was supported by grants from the American Diabetes Association, Juvenile Diabetes Foundation, and the Italian Department of Public Health.