LONDON - The discovery of a handful of individuals who have a mutation that simultaneously affects their control of blood glucose and blood pressure could spur attempts by pharmaceutical companies to develop new drugs to treat both diabetes and hypertension.

Researchers in Cambridge, UK, have identified three people with mutations in their gene encoding the molecule peroxisome proliferator-activated receptor gamma (PPAR gamma). In recent years, this molecule has been found to be the major target of the class of antidiabetic drugs called the thiazolidinediones, and many major pharmaceutical companies are developing compounds targeting it. This latest discovery confirms that this line of research is going in the right direction.

There are two main forms of diabetes. In Type I diabetes, the beta cells of the pancreas are destroyed and the insulin they normally secrete must be replaced. In Type II diabetes, there is both insulin resistance, in which the body fails to respond appropriately to a given amount of insulin, and some degree of damage to the beta cells.

The thiazolidinediones are used to treat Type I diabetes, improving the body's sensitivity to insulin. They reduce levels of blood glucose and reduce blood pressure.

The three patients in whom mutations in PPAR gamma have been identified had Type II diabetes with both severe insulin resistance and high blood pressure. Results of the examination of their PPAR gamma gene are reported in the Dec. 23, 1999, issue of Nature, in a letter titled "Dominant negative mutations in human PPAR gamma associated with severe insulin resistance, diabetes mellitus and hypertension."

Stephen O'Rahilly, professor of metabolic medicine at the Department of Medicine and the Department of Clinical Biochemistry at Addenbrooke's Hospital in Cambridge, and senior author of the letter, told BioWorld International: "We knew that the thiazolidinedione drugs lowered glucose and improved insulin sensitivity, and that they activated PPAR gamma, but it was still possible that these two actions were not related. Our results now confirm that PPAR gamma is the mechanism by which the thiazolidinediones have their effect, and provides strong support for the development of pharmaceutical ligands to PPAR gamma for the treatment of not only diabetes but, potentially, even high blood pressure."

The early onset and severity of the high blood pressure in the three patients studied make it "inconceivable," O'Rahilly said, that it was not linked to their mutation. "PPAR gamma therefore obviously has a role to play in the regulation of blood pressure. Given that half the patients with Type II diabetes have hypertension, an agent that would simultaneously improve glucose levels and improve blood pressure would be very attractive."

O'Rahilly and his colleagues have been studying a large group of patients with severe insulin resistance and trying to find some of the genes involved. They knew that the thiazolidinedione drugs could bind PPAR gamma, and therefore decided to search for mutations in the gene for PPAR gamma among their patients.

Accordingly, they sequenced this gene in 85 unrelated people, and found missense mutations in two of them. The first patient, a 56-year-old female, had developed gestational diabetes during two pregnancies. After the second pregnancy, she continued to require treatment with insulin and it was difficult to control her diabetes even with very high doses. She had also developed severe pre-eclampsia in both pregnancies, with hypertension diagnosed at the age of 37. Her son was diagnosed with high blood pressure and diabetes at the age of 27.

Both had the same mutation affecting the ligand-binding domain of PPAR gamma. Testing of other family members showed that none of them had the mutation and that it had arisen as a de novo mutation in the mother.

The second patient identified in the group being studied at Addenbrooke's was a young woman whose hypertension had been diagnosed at the age of 15. By 17, she had developed Type II diabetes. Her mutation, which was different to that identified in the other two cases, also involved the ligand-binding domain of PPAR gamma.

The researchers failed to find similar mutations in 230 alleles from Caucasian controls, or 84 alleles from controls of other ethnic groups.

O'Rahilly said, "We started with an interest in finding genes for insulin resistance and ended up finding mutations in PPAR gamma, a molecule which is of huge interest because of these antidiabetic drugs which appear to act on it. But little was known about what PPAR gamma normally does, and we have now found that it is critically important for the control of glucose homeostasis in humans, and also critically important for the control of normal blood pressure."

The finding is particularly interesting, he added, because several groups of researchers who have attempted to make knock-out mice lacking PPAR gamma had failed to obtain illuminating results. Mice lacking both copies of the gene died in utero, while those with only one copy of it seemed completely normal. "This is an unusual case," O'Rahilly said, "where we have learned something from humans before we have been able to learn it from mice - so often it is the other way around."

In an accompanying News and Views article in the same issue of Nature, titled "Insulin resistance and obesity," Michael Schwartz and Steven Kahn, of the Department of Medicine at the University of Washington, speculate whether too much PPAR gamma can cause obesity. They pose the question of whether the insulin resistance associated with human obesity results from impaired PPAR gamma signaling in the absence of a mutation, before concluding that "continued study of this important molecule could yield new approaches to the treatment of diseases such as obesity and diabetes, which take such an important toll on human health."

The Cambridge group now hopes to study the three patients in much greater detail. In particular, they want to find out if they can treat their insulin resistance more effectively, perhaps by treatment with the thiazolidinediones.

"Our study suggests that, paradoxically, they may respond very well to these drugs," O'Rahilly said. "This is because we have found that their mutant receptors, although being impaired in their ability to bind thiazolidinediones, are in fact capable of responding to pharmacological concentrations of these drugs. Thus, we hope that this will also be the situation in vivo, when the drugs are given to the diabetic patients."