BioWorld International Correspondent

LONDON - After years of searching, researchers finally have identified a new genetic mutation that causes an insulin-resistant form of adult-onset diabetes in humans. The mutant gene encodes a molecule that plays a crucial role in the insulin-signaling pathway.

The discovery reinforces the importance of the signaling that takes place inside the cell once insulin has locked onto its cell-surface receptor. By pinpointing a signaling molecule that is essential for human insulin action, the work also will be of interest to those in the pharmaceutical industry who are seeking drugs to treat insulin resistance and prevent its adverse metabolic effects.

Stephen O'Rahilly, professor of clinical biochemistry and medicine at the University of Cambridge in the UK, told BioWorld International: "This is the first clear example of a human form of insulin-resistant diabetes that is due to a defect in insulin's ability to signal in the cell. This is something that has been sought for many years. Our work also unequivocally proves that this family of molecules is essential for human insulin action."

That information will be valuable for the pharmaceutical industry, he added, because a better understanding of how insulin works in humans is a key factor in devising drugs that will make insulin work better.

A report of the study appears in the May 28, 2004, issue of Science in an article titled "A Family with Severe Insulin Resistance and Diabetes Due to a Mutation in AKT2."

In Type II diabetes, which normally develops in adulthood, the pancreas produces plenty of insulin, but the cells of the body fail to respond to it, so blood sugar levels remain high. That phenomenon is known as insulin resistance. Treatments for Type II diabetes therefore are focused on enhancing the action of insulin.

O'Rahilly first collected the samples used in the study 13 years ago, from a British family in which Type II diabetes was inherited. The first individual to be studied was a woman, now 34, who developed diabetes at the age of 30. She is not obese. Her mother (also not obese), her maternal grandmother and a maternal uncle all had higher than normal blood levels of insulin, and the mother and maternal grandmother developed diabetes in their late 30s.

Analysis showed that all the affected members of the family had a single base change in the gene encoding a molecule called AKT2.

Three other close relatives studied by O'Rahilly and his team were all normal, with normal fasting levels of glucose and insulin, and did not have the mutation. Nor was the mutation present in the DNA of 1,500 Caucasian controls from the UK.

Experiments in cells showed that the mutant form of the enzyme was incapable of phosphorylating its downstream substrates, and that the presence of some mutant AKT2 in cells interfered with the functioning of the normal AKT2 in those cells. In liver and fat cells expressing mutant AKT2, insulin was unable to exert its normal actions.

O'Rahilly said: "AKT2 was already known to be involved in how insulin works, but no mutations in it had been found before which contributed to any human disease. We have proved unequivocally in this study that this mutation in AKT2 was the cause of severe insulin resistance and diabetes in this family."

Unfortunately for the family, the discovery of the mutation is unlikely to help treat their diabetes, although they now will be able to have genetic counseling.

Surprisingly, the existing mouse model that lacks the gene encoding AKT2 is not severely affected. Those mice do have resistance to insulin and a proportion of them go on to develop diabetes. "But they are nothing like as severely affected as this family we studied," O'Rahilly said. "So we would like to understand more about how this particular mutation in AKT2 affects insulin metabolism. We plan to do this both in cellular models and by creating our own animal model. We want to know how this change in just one copy of the gene can have such a devastating effect on insulin action, because we think this might tell us something important about how these signaling networks work in the cells."

The group also is planning to investigate whether more common variants of the AKT2 gene affect someone's risk of diabetes. "Possibly there are less severe variants, perhaps affecting the expression levels of this gene, which contribute to the commoner forms of insulin resistance," O'Rahilly said.