By Wallace Ravven

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

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

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

“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.