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UCD Team Makes Breakthrough in Slowing the Spread of Diabetes

Science Today - The Irish Times, 6th June 2002

Research at University College Dublin may open up new treatments for type II diabetes, a disease on the increase across the world. Dick Ahlstrom reports.

Scientists at University College Dublin are trying to unlock the biochemical steps that lead to type II diabetes. The work could lead to novel ways of tackling this difficult disease.

The work is timely given the rapid growth in the number of people developing type II diabetes. There are about 100,000 cases in the Republic and 200 million worldwide. Yet these numbers are expected to double within the next 20 years as a result of environmental, lifestyle and dietary choices in the 21st century, says Dr Philip Newsholme, of UCD's Department of Biochemistry within the Conway Institute of Biomolecular and Biomedical Research.

Diabetes is a disease in which the body loses its ability to regulate levels of sugar in the bloodstream. The hormone, insulin, handles sugar control, but diabetics don't produce enough insulin to keep sugar levels balanced.

There are two main forms of the disease. Type I diabetes tends to emerge during childhood and requires daily insulin injections. With this form of the disease, the islet beta-cells that make insulin die off.

Type II arises much later in life and is usually controlled by strict regulation of the diet and tablets. The beta-cells in this form don't die off but lose the ability to produce enough insulin. "Nobody knows in type II diabetes what goes wrong with the beta-cells," says Newsholme. "They simply become dysfunctional."

He decided to look at the biochemistry of the beta-cell and three years ago joined in a study with Prof Peter Flatt, head of the University of Ulster's diabetes research group. They won a North-South research co-operation grant from the Health Research Board. "It has established a co-operative link between our two labs," says Newsholme.

"We wanted to understand how nutrients stimulate insulin production from the beta-cells. They normally respond to nutrients, particularly glucose by increasing insulin production."

The cells react to everything in the diet, however, not just glucose. The research team, which included Dr Lorraine Brennan, decided to follow up a finding from 10 years earlier suggesting that certain amino acids, nutrients in food, could increase insulin production.

"The effect of the amino acids have been largely unexplained so far," he says. The earlier study described a synergistic effect with insulin production boosted significantly by amino acids. "We wanted to see what this synergy was all about."

The team used beta-cell lines provided by Prof Flatt's group for a series of in vitro studies. Cells were exposed to sugar as glucose and the amino acid L-alanine for an hour and then killed. The products of cell metabolism were then analysed using nuclear magnetic resonance (NMR).

NMR is more familiar as an imaging technique in medical diagnostics. But the technology can also be used in biological research, for measuring concentrations of molecules in solution. UCD received a grant from the Wellcome Trust to buy the NMR biological analysis system, which is the only one of its kind on this island, says Newsholme.

The system uses carbon-13 as a reference substance. Concentrations of the various metabolites are calculated on the basis of C-13 content as the carbons transfer from one to the next. "You can follow the major products that have come as a result of metabolism," says Newsholme.

The synergistic effect of L-alanine was immediately apparent in the findings but still contained a surprise. The beta-cells secreted five times more insulin if the amino acid was present, but 20 times more if both L-alanine and glucose were present in vitro. The team published their findings on June 1st in one of the world's leading journals for research into this disease, Diabetes.

The research group hopes to bring its findings forward by using an in vitro, cell-based model of type II diabetes to study the enzymatic steps as the beta-cells respond to glucose. "In Type II you do have a failure in these pathways," says Newsholme.

Having a detailed understanding of these steps should unearth new drug targets for the control of the disease. Exposure to sustained, high glucose levels seems to switch the beta-cells off. If the trigger for this could be found, perhaps a drug could block this and turn the beta-cells back on.

The L-alanine work should help the team "identify which enzymatic steps are important for insulin secretion", explains Newsholme.

© The Irish Times