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Interviewees: Francesca Fang-Liao,University of Tennessee School of Medicine and Huaxi Xu, Burnham Institute for Medical Research and Gregory Brewer, Southern Illinois University School of Medicine
Besides well-known complications like nerve damage, people with type 2 diabetes also have twice the normal risk of Alzheimer’s disease. In fact, some researchers even describe Alzheimer’s as a "type 3" diabetes.
So Alzheimer’s researchers at San Diego’s Burnham Institute for Medical Research tested the effects of diabetes treatments on brain cells. They found that metformin, a drug commonly-prescribed to diabetics and prediabetics (those at risk of becoming diabetic), can more than double the production of amyloid-beta, or a-beta, the protein that forms toxic brain plaques in Alzheimer’s.
Francesca Fang-Liao, Huaxi Xu and their team saw this increase in a-beta after treating brain cells in the lab with metformin. However, the effect was reversed when they added insulin. As they wrote in the Proceedings of the National Academy of Sciences, they also confirmed both findings in the brains of mice given metformin, or metformin plus insulin.
"Based on the chemical structure of metformin, it doesn’t look to be able to cross the blood brain barrier," says Liao, who is now at the University of Tennessee School of Medicine. "However… when we gave metformin in the drinking water [of mice] we found that after one or two days it reached to the brain, accumulating there in significant concentrations.
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"We found that (for the metformin-only mice) the a-beta level had been greatly increased in the brain, particularly in both the cortical area and the hippocampal area. Those are the regions that are mostly affected in the Alzheimer’s disease patient," she explains.
"We believe that this work has probably significant implications in the current medication prescribed to the diabetic patient," says Liao.
Adds Xu, "If you are a patient with diabetes, you already have a higher chances of getting Alzheimer’s disease than normal people. If you take metformin alone, you further increase the chance of getting Alzheimer’s disease."
But other Alzheimer’s experts are more cautious. Southern Illinois University School of Medicine’s Gregory Brewer says the study is "intriguing and raises a red flag of caution about metformin. But on the other hand, the missing link in the paper is the fact that their studies did not show any problems or measure any problems with memory."
Brewer, who holds an endowed Chair in Alzheimer’s disease research, points out that a-beta is produced in very tiny amounts in our cells throughout our lifetime, and that some researchers think small amounts of a-beta may actually be required for learning and memory.
"What we don’t know is whether those levels were toxic to the brain cells that they were studying," Brewer says. He says that if further research does reveal memory problems in mice that get metformin alone, it’s good news that combination therapy appears to be a solution.
But in the meantime, "the complications from diabetes are more severe than from Alzheimer’s disease… if you don’t treat the diabetes, you’ll die much sooner." Brewer adds that a healthy diet and exercise are known to be beneficial in both diabetes and Alzheimer’s disease.
Liao and Xu say they are now working on behavioral and memory testing in the mice, but point out that other research is already hinting that insulin may reduce diabetics’ risk of Alzheimer’s.
They point to a human study published in December 2008 in which researchers led by Michal Beeri at Mount Sinai School of Medicine compared brain autopsy findings of diabetic patients against the patients’ treatment records.
"They found that the patients’ brain from the single therapy has shown much more dramatic Alzheimer’s disease pathology than the patient that had taken combination drugs," explains Liao. "So that’s kind of supporting our observation. However, they haven’t collected enough patients which have been taking metformin specifically… as a single agent."
Liao says collecting and comparing that information in large numbers of patients would take major effort and funding, and hopes one of the outcomes of their work will be to call attention to the need for such a study.
Liao says that thanks to previous research by Xu and others, more doctors are already prescribing insulin along with metformin for treating diabetes.
"Indeed, in the clinical setting, insulin has been brought into the treatment more and more frequently nowadays, even in the prediabetic setting, in addition to metformin," she says. "I would say that would be a good trend."
The researchers agree with Brewer that a-beta itself remains a subject of controversy among Alzheimer’s researchers.
"Whether the human body or human cell needs a certain level of a-beta protein for normal function is still under great debate in the Alzheimer’s field," says Xu. But, he says, researchers in the field do agree that "over-production of this a-beta protein, by any abnormal process associated with genetic reasons or environmental factors, is bad for the human being."
This research was published in the Proceedings of the National Academy of Sciences early online edition the week of February 23, 2009, and was funded by the National Institutes of Health and the Alzheimer’s Association.
Elsewhere on the Web:
"Alzheimer’s Gene Slows Brain’s Ability to Export Toxic Protein" from the University of Rochester