Alzheimer's: Type 3 Diabetes?

Neurodegeneration research turns to insulin for answers

By | November 1, 2007

In 2005, while testing the effects of impaired insulin signaling on the brain, Suzanne de la Monte at Brown University and her colleagues observed several unexpected phenomena in her experimental mice. Hallmarks of neurodegenerative disease had surfaced: oxidative stress, amyloid fibrils, and cell loss. "It was the craziest thing," de la Monte says. Glucose metabolism and Alzheimer's had been linked previously, says de la Monte, and perhaps her findings explained why.

Looking in the brains of patients diagnosed with Alzheimer's disease, de la Monte found reductions in insulin, insulin-like growth factor, and downstream elements such as tau, insulin receptor substrate, and kinases.1 Type 1 diabetes is a deficiency in insulin production, and type 2 is a resistance to insulin, where there is plenty of insulin but cells don't respond to it. Her group coined the term "type 3 diabetes" to explain their observations. "In Alzheimer's you have both things going on. That's why we called [what we saw] type 3, because it resembles both of them," de la Monte says.

De la Monte's findings made a splash in the media, appearing in the BBC and numerous Alzheimer's news outlets. However, in the scientific community, "I wouldn't say that the term type 3 diabetes has caught on," says Greg Cole at the University of California, Los Angeles.

The term might not be popular because what is happening in the brain is still unclear. Cole says accumulated evidence suggests that insulin and insulin-like growth factor signaling is impaired in patients with Alzheimer's disease. "It looks like in Alzheimer's disease you end up having a defect in these kinds of pathways, which are similar to the pathways for insulin-resistant diabetes," says Cole. But, it's unknown as to which comes first, the disease or the insulin resistance, although de la Monte is confident that the signaling defects precede the disease. As for a decrease in insulin in the brain, "if that deficit is important, we don't know," says Cole.

In July of this year, Morris White at Children's Hospital Boston found that insulin might actually be bad for the brain. He knocked out insulin signaling in mice and found that they live nearly 20% longer.2 Although he didn't conduct a cognitive assay, the animals appeared more resistant to oxidative stress, which should be protective against neurodegeneration. "Attenuated insulin signaling in the brain is probably a good thing," White says.

Excess insulin is also thought to compete with amyloid plaques for degradation, thereby contributing to their nefarious accumulation in the brains of Alzheimer's patients. White says that while these results appear to oppose de la Monte's findings that insulin deficiency is the problem, he agrees that approaching Alzheimer's as a diabetes-like disorder is a good direction to follow.

While scientists continue to work out the insulin-neurodegeneration link, drug companies are zooming ahead to capitalize on it. GlaxoSmithKline has begun Phase III clinical trials on its type 2 diabetes drug, Avandia, for treatment of Alzheimer's. White says the approach makes sense, as it would increase insulin sensitivity and reduce insulin in the brain. Suzanne Craft at the University of Washington is trying the opposite approach, supplying the brain with additional insulin. So far she's found promising results on memory, and clinical trials are in Phase II.

The potential success of both approaches suggests that de la Monte's idea that too little insulin and White's idea of too much insulin might both be operating Alzheimer's disease. "It's not just too much or too little," says Cole, "but proper regulation is what you need."


1. E. Steen et al., "Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease - Is this type 3 diabetes?" J Alzheimer Dis, 7:63-80, 2005. 2. A. Taguchi et al., "Brain IRS2 signaling coordinates lifespan and nutrient homeostasis," Science, 317:369-72, 2007


Avatar of: Sergio Stagnaro MD

Sergio Stagnaro MD

Posts: 59

November 8, 2007

Before Suzanne de la Monte at Brown University and her colleagues, I described a bedside diagnostic method (, Practical Applications)entirely based on impairment of cerebral glucose metabolism. Such as method has been successively illustrated at URL \nAlzheimer's Disease Byophysical Semeiotics supports the pathophysiology of Koudinov's theory.11 January 2002. The data referred in Science article, gathered in mice, corroborate perfectly my observations in man, giving the possibility to recognize Alzheimer's Disease since its first stages, allowing physicians to start promptly the most appropriate therapy.\n
Avatar of: anonymous


Posts: 39

November 25, 2007

Wow. This is the reality of science. Someone comes up with an idea, two groups of equally capable scientists have opposing opinions, and whoever turns out to be right hits the jackpot. Science is a world of natural selection. We keep discarding old ideas and trying new ones, only for those ideas to die too.\n\nMakes you kinda skeptical about any of the "according to qualified scientists" claims. No disrespect to the people studying our world, but great minds DO NOT always think (or believe) alike.
Avatar of: Robert Dodge

Robert Dodge

Posts: 2

November 26, 2007

These are fascinating clues to the nature of the disease, but as Cole's summary suggests, This may be far more complex than "one of these two is right and the other is wrong." Until the mechanism is known, the lure of simple answers to complex problems makes for good copy (and perhaps, hope for a cure), but it is too speculative to assume that these two observations define the universe of causes.\n\nThis is science in progress.
Avatar of: Susan


Posts: 2

November 28, 2007

I just love reading the scientist. This is another article with a potential life changing finding. Too bad the "powers that be" in Canada probably won't read it ...\n\nWhat can we do to ensure that any conclusions to the findings regarding new discoveries about the brain address people who are hypoglycemic? There are many undiagnosed people who suffer momentary lapses due to a decrease of glucose in their brain (for a variety of reasons) who are penalized with inaccurate labels, including mental diseases and alzheimers. \n\nFurther, too many "experts" refuse to state that they don't know what the problem is for sure and instead of clarifying that they are providing an opinion, albeit uninformed, outdated, and close-minded, they imply that what they say is fact. \n\nFinally, the Layman sounds like another frustrated victim of egotism and, excuse any spelling errors and the poor organization of my response, but my blood sugar is low.

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