By Dean A. Haycock

Special To BioWorld Today

Anyone expecting simplicity in biology is quickly disillusioned. The interplay of environmental factors, multiple genes, individual differences and a myriad of interacting biomolecules is enough to make physicists grateful they don't work in such a confusing field.

Type II diabetes is a good example. Its genetic basis has long remained illusive and the disease is characterized by not one, but two, important defects. The first is a lack of responsiveness by cells in the periphery to insulin, a condition known as insulin resistance. The second is a failure of the pancreas to compensate for insulin resistance by increasing insulin secretion.

No one could point to a single flaw on the molecular level to account for both of these disease features. Until now.

The link between the two, according to a paper in the Feb. 26, 1998, issue of Nature, may lie with the IRS. IRS, or insulin-receptor substrates, are proteins that carry signals conveyed by insulin to various cellular targets.

One such protein, IRS-2, has now been linked to both insulin resistance and insulin secretion in a paper titled "Disruption of IRS-2 causes Type 2 diabetes in mice," written by Morris White, an associate investigator of the Howard Hughes Medical Institute, associate professor of biological chemistry at Harvard Medical School, in Boston, and a senior investigator at the Joslin Diabetes Center, also in Boston, and his collaborators.

"The idea that dysfunction of one protein could give both defects at the same time really consolidates the view of the disease," White said.

Insulin resistance prevents cells from efficiently using insulin. Since insulin normally allows cells to take up glucose, lack of insulin results in high blood sugar, or hyperglycemia. In many cases, the body compensates adequately for insulin resistance by increasing the secretion of insulin from cells in the pancreas called b-cells. This compensatory response prevents hyperglycemia.

"Insulin resistance is virtually always a precursor to adult diabetes. However, many people are insulin resistant, but never progress to diabetes. The key factor appears to be the ability of the insulin-producing ß cells to expand and compensate with sufficient insulin secretion," said Joseph Avruch, of the diabetes unit, department of medicine and the department of molecular biology at Massachusetts General Hospital and Harvard Medical School.

It is only when pancreatic b-cells fail to increase their output of insulin that blood sugar rises to dangerous levels and patients develop diabetes Type II.

Findings Surprised Researchers

Previous animal models failed to completely mimic this situation. It is not difficult to produce animals that demonstrate insulin resistance. Knocking out the gene for IRS-1, one of four or more IRS proteins, retards growth and produces mild insulin resistance in mice. It does not, however, prevent the pancreas from compensating by increasing insulin release. As a result, IRS-1 knockouts do not generally develop hyperglycemia.

IRS-2 knockout mice, in sharp contrast, are both considerably insulin resistant and surprisingly incapable of increasing insulin output in compensation. In fact, while other animal models of diabetes are characterized by increased cell mass in the pancreas, the IRS-2 knockout mice show decreased b-cell mass. Not surprisingly IRS-2, but not IRS-1, is found in b-cells.

These findings show IRS-2 is involved both in insulin use by cells and with the mechanism, b-cell compensation, that allows the body to produce more insulin in response to the onset of insulin resistance in muscle and liver cells.

"In one way I was surprised and in another way it was something I had been looking for for 10 years," White said of the discovery. "I've always thought that Type II diabetes is really a rather prevalent disease; it is not uncommon. There are maybe 7 million to 10 million Americans with Type II diabetes and many more who aren't diagnosed. So the question was always in my mind: How could multiple genes — which is the common view right now because gene-hunters can't find the 'diabetes gene' — come together in a single person so frequently?"

White was surprised the discovery happened this year and notes that it wasn't made through the standard "gene-hunting approach."

"It was done by 'grind-and-crank.' Purify the protein. Find out how it works. Knock it out. Look at it. And it gave us a result that makes a lot of sense," White said.

The similarities between the pathology seen in mice lacking the IRS-2 gene and in humans with Type II diabetes suggest that abnormalities of IRS-2 gene functioning may be linked to the disease in humans.

Potential Drugs May Try Boosting IRS-2

"The obvious implications are two. In the short term, the corresponding human gene should be carefully checked for mutations in diabetics. The longer-term implication comes from the clue provided as to what kind of extracellular signals, and what kind of intracellular apparatus, is important for b-cell compensation," Avruch said.

White and his team are now looking for IRS-2 mutations in patients. Studies of populations in Denmark and the U.S. have revealed no mutations so far. The gene seems to be extremely stable, according to White.

"When you look at function of IRS-2 in Type II diabetics, it is reduced. We don't exactly know what environmental or nutritional factors will impact IRS-2 function, but we suspect that its regulation will somehow contribute to the disease," White told BioWorld Today.

Preclinical studies in White's laboratory are directed at shoring up the findings presented in the Nature paper.

"For instance, if we put IRS-2 back into b-cells, and only b-cells, will that be enough to cure the disease?" White asked.

Possible therapeutic targets arising from this work include the identification of drugs that could enhance the expression of IRS-2 in b-cells, muscle and liver.

"I think that could go a long way toward helping Type II diabetic patients," White said, "because you would reduce the resistance in the peripheral tissue and you would help b-cells survive and compensate for whatever resistance remained."

Another possible goal would be the identification of transcription factors that regulate IRS-2 production in b-cells and peripheral tissue. *