Variant of a common protein plays a primary role in Type 2 diabetes and obesity

Scientists in France and the United States report that a variant of a common protein plays a primary role in Type 2 diabetes and obesity, key features of the "insulin resistance syndrome" that affects more than 50 million people in this country and a similar number in Europe.

Incidence of the syndrome, also linked to coronary artery disease, high blood pressure and high cholesterol, is soaring in the United States and other developed countries. Some clinicians and researchers refer to the syndrome as the metabolic syndrome.

The new research result, based on a very large genetic study of French families, is reported in the August issue of Nature Genetics.

The study identifies a target protein for potential drugs to restore the body's ability to respond to insulin, says Dr. Ira Goldfine, a co-author of the study whose UCSF research team first detected the protein, known as PC-1, in abnormally high amounts in diabetes patients 10 years ago.

The same 1995 paper showed that the PC-1 protein inactivates another protein, called the insulin receptor, which binds insulin. Other work in the lab showed that when this inactivation occurs, it prevents insulin from regulating metabolism of glucose in diabetic people.

The new discovery opens up the possibility of developing drugs to prevent or reverse the potentially deadly insulin resistance syndrome, says Goldfine, professor of medicine at UCSF.

Evidence from many investigators indicates that the insulin resistance syndrome is caused by the body's inability to use insulin efficiently, often leading to obesity, high blood pressure, high cholesterol, and Type 2 diabetes. This syndrome doubles heart attack and stroke risk, and triples the likelihood of early death from either cause.

The new research was led by David Meyre and Philippe Froguel, leading French scientists in research on the genetics of obesity and diabetes, based at the Pasteur Institute's CNRS Institute of Biology in France. UCSF co-author along with Goldfine is Betty Maddux, a UCSF diabetes researcher who has collaborated with Goldfine on several key PC-1 studies.

The human genetics study involved an extensive analysis of the variations in the PC-1 gene in a family population study of more than 3,000 people. The scientists found that a common variant of the PC-1 gene, when coupled with other small changes in the PC-1 gene, was very strongly associated with insulin resistance, Type 2 diabetes, childhood obesity, and adult obesity. The genetics researchers zeroed in on single changes in the sequence of "letters" that make up the DNA coding for the PC-1 gene. In a variant of the PC-1 gene called the q allele, they found that two such mutations, known as SNPS, increase production of the protein in both cells and in the blood (SNP stands for single nucleotide polymorphism).

The finding is the strongest evidence yet that PC-1 is a cause of insulin resistance, Type 2 diabetes, and obesity in many patients, according to Goldfine and the French scientists. Since Goldfine's 1995 report, a number of researchers have focused on different aspects of the link between the PC-1 protein and Type 2 diabetes as well as the related insulin-resistance syndrome. This year, studying mice that over-expressed PC-1 in tissues, Goldfine found evidence of the protein's role in diabetes, reported in the February issue of the journal Diabetes.

The medical needs of people with insulin resistance syndrome now account for about 40 percent of all money spent on adult medications in the United States, according to a recent study. Overeating and inactivity strongly contribute to the syndrome, but the prime cause appears to be genetic. Although the insulin resistance syndrome and Type 2 diabetes affect a very large number of people, its specific metabolic causes have not previously been identified. The current study suggests that abnormalities of the PC-1 gene may be playing a key role in causing this syndrome, the scientists say.