New research into diabetes at UCD could help deliver improved treatments for Alzheimer's and other neurodegenerative diseases, writes Dick Ahlstrom.
About 100,000 people in this country have diabetes and know it. Another 100,000 probably have this life-threatening disease but are unaware they are at risk. The rapid growth in the numbers presenting with this disease has taken the medical community by surprise. It has become a common hazard of our 21st century lifestyle and our new-found tendency to be overweight.
The disease occurs when the body fails to regulate blood sugar levels properly. This happens either because the body doesn't produce enough insulin, the hormone responsible for controlling sugar levels, or the body can't make proper use of the insulin that is available.
Either way high blood sugar levels play havoc over time with the body's sensitive systems. It does serious damage to the retina, to blood circulation in the limbs and also to the kidneys, so much so that a kidney transplant may represent the ultimate treatment.
Dr Derek Brazil of University College Dublin's Department of Medicine has started a new research project focusing on damage caused by diabetes to the kidney, a condition known as diabetic nephropathy (ND). It affects about 30 per cent of all diabetics and he wants to understand why it hits some and not others and whether there is a genetic component to it.
Working from UCD's Conway Institute, he will build on recently published research that showed insulin is important not just in ND but also in protecting normal brain cell development. He and colleagues at the Joslin Diabetes Centre, Harvard Medical School in Boston published their findings last August in the Journal of Neuroscience.
"Neurons need a lot of energy," explains Brazil. "It was never known whether insulin had an effect in the brain." The research group studied mice that lacked IRS-2, a key protein essential for insulin production and action in the body.
They found that mice with a lack of IRS-2 (and therefore poor insulin function), had 30 per cent smaller brains due to a reduced number of brain cells. They also found that levels of a protein associated with the development of Alzheimer's disease called phospho-Tau were raised in the brains of the diabetic mice.
These results provide strong evidence that insulin and a related hormone called IGF-1 serve a protective function in the brain, according to Dr Brazil's research. They also suggest unsuspected links between diabetes and Alzheimer's disease. "Insulin and the insulin pathway are not only involved in controlling glucose but in the development of the brain itself," he says.
Dr Brazil hopes to do a similar intensive biochemical study (at the Conway Institute) of what happens inside kidney cells when ND takes hold. The work is funded by a programme grant from the Health Research Board and from the Conway, which in turn has received substantial support from the Programme for Research in Third-Level Institutions, organised by the Higher Education Authority.
"We are focusing on a complaint of diabetes rather than on the diabetes itself," says Brazil. "We are trying to work out what goes wrong in the kidney with diabetic nephropathy; why does the filtering capacity of the kidney crash?"
The first clinical sign of the disease is an enlarged kidney, he says. "It takes 15 to 20 years before the whole thing progresses to the point where you are at end stage disease," with dialysis and a kidney transplant often the only answer. "We are trying to intervene to prevent the disease or try to delay it."
The ND research team involves 25 to 30 researchers who are delving into cell chemistry to understand the disease in detail. "We are doing genomic analysis of high glucose treated cells from the kidney," he explains.
The team is particularly interested in the cell's "signal transduction pathways", how proteins and other substances inside the cell interact. An early target is the insulin/IRS-2 pathway, which proved important in Dr Brazil's earlier work.
"It gives you clues as to which pathway can be inhibited to control the disease," he says. "The aim is ultimately to provide clinicians with a better set of targets against the disease."