Scientists have identified the first genetic defect linked to insulin resistance, a precursor to most of the 15 million cases of adult diabetes in the United States. The research helps clarify the murky understanding of what causes insulin resistance and diabetes. It identifies a target -- the gene's abnormal protein -- for potential new drugs to treat both conditions.
The research, published in the September issue of the journal Diabetes, is a collaboration between scientists at the University of California, San Francisco (UCSF) and in Italy.
About 60 million people in the U.S. and a similar number in Europe are insulin resistant, a condition in which the body's insulin cannot efficiently metabolize the sugar, glucose. Most of these people are not diabetic because the pancreas is able to secrete extra amounts of insulin. But one in four insulin-resistant people -- about 15 million Americans -- develop adult diabetes when they become unable to maintain normal insulin and glucose levels. Adult, or type 2, diabetes is by far the most common form of the disease.
Several natural proteins have been implicated in insulin resistance, including a protein called PC-1, produced in abnormally high concentrations by many insulin-resistant people. Since it blocks insulin's ability to stimulate cells' use of the sugar, glucose, PC-1 has been considered a prime suspect in insulin resistance.
In the research reported today, the scientists mapped all the instruction-bearing regions of the human PC-1 gene and discovered that a single DNA "letter," or nucleotide, out of more than 2,500, sometimes takes an alternate form. This form -- which they called the Q allele -- is about three times more common among insulin-resistant people and more than twice as frequent among adult diabetics than in people with normal insulin function, they discovered.
This research marks the first time any gene for the common form of insulin resistance has been completely mapped.
"By zeroing in on the protein coded by this newly discovered variant, along with the more common form of PC-1, drug designers may be able to target a far higher proportion of insulin-resistant people," said Ira Goldfine, MD, professor of medicine and physiology at UCSF and co-author of the paper in Diabetes. Senior author on the paper and leader of the Italian researchers is Vincenzo Trischitta, MD; lead author is Antonio Pizzuti, MD. Both are scientists in the endocrinology research unit of the Istituto Scientifico Ospedale Casa Sollievo della Sofferenza in San Giovanni Rotondo, Italy.
People who are insulin resistant, but not diabetic, suffer a range of health threats including lowered HDL ("good") cholesterol levels and a greatly increased risk of hypertension and coronary artery disease. Because of its inherent health hazards and its link to diabetes, insulin resistance is known among endocrine researchers as the "secret killer."
Diabetics face a much higher than normal risk of heart disease, kidney failure, leg amputations, blindness and nerve disease. Their condition must be strictly controlled, but current medications are not completely effective. The condition has proven to be a particularly difficult disease to cure in large part because its underlying causes are a shifting mix of many factors.
"While the expression of some diseases like cystic fibrosis are controlled by just one gene, diabetes is likely to be affected by several," Goldfine says. "Moreover, both insulin resistance and the subsequent development of diabetes are moderated by exercise, weight loss and hormone levels. These lifestyle and related factors can affect the expression of genes." Indeed, the disease has been called "the geneticist's nightmare."
In June, at the annual meeting of the American Diabetes Association, Goldfine and UCSF researcher Betty Maddux reported that introducing antibodies to PC-1 in cell cultures -- in effect "turning off" PC-1 -- increased insulin's effectiveness. They also demonstrated precisely where PC-1 interferes with cells' insulin receptors, which are essential for normal insulin function.
These results and those reported today contribute to the conclusion that PC-1 is not just associated with insulin resistance, but plays a role - perhaps the key role - in causing the condition.
The findings help convince Goldfine that PC-1 interacts with insulin receptors at the cell's surface and prevents these receptors from being activated normally.
"The insulin key goes into the receptor lock, but PC-1 seems to keep the lock from turning," he suggests.
PC-1 is a normal protein in most tissues, Goldfine points out, and is probably involved in bone metabolism. It appears to be associated with insulin resistance in two ways: when it is present in excess amounts in its normal form and, as the new research reveals, when it is present in its variant form.
A change in one out of 2600 nucleotide "letters" in the gene's coding region -- a switch from an A to a C -- caused a substitution of one amino acid (from lysine to glutamine) among many hundreds that make up the PC-1 protein. This variant of the PC-1 protein has a two to three times greater inhibitory effect on the insulin receptor than does the more common form, the team found. The study's results do not explain all cases of insulin resistance. About 20 percent of people with the insulin resistance condition show neither elevated levels of normal PC-1 nor the Q allele form. And about 20 percent of people with elevated levels of PC-1, or with the Q allele form of PC-1, are not insulin resistant.
Goldfine and colleagues are continuing to study insulin-resistant people to learn more about how PC-1 inhibits cells' insulin receptors.
Co-authors on the new report, along with Goldfine, Trischitta and Pizzuti, include Lucia Frittitta, Roberto Baratta and Riccardo Vigneri, scientists at the Instituto di Medicina Interna, Endocrinologia e Malattie Metaboliche, Universita di Catania, Italy; Alessandra Argiolas, Tonio Ercolino and Vittorio Tassi, who are colleagues of Trischitta and Pizzuti at the Institute Scientifico Ospedale Casa Sollievo in Italy; and Licia Iacoviello at the Instituto Mario Negri SUD, Chieti, Italy. Also: Maura Bozzali and Guglielmo Scarlato of the Instituto di Neurologia, Universitia di Milano.
Antonio Pizzuti also has an appointment at the Instituto di Neurologia.
The research was funded in part by the American Diabetes Association, the Juvenile Diabetes Foundation, and the Italian Department of Public Health.
NOTE: To receive a faxed copy of the Diabetes paper, call Wallace Ravven (415) 476-2557.
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