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See Inside June 2008

Your Brain on Diabetes

More signs that insulin ills set off neurodegenerative conditions

Anyone who is diabetic—or knows a diabetic—recognizes the importance of insulin. The hormone helps cells store sugar and fat for energy; when the body cannot produce enough of it (type 1 diabetes) or responds inadequately to it (type 2 diabetes), a range of circulatory and heart problems develop. But that is not all: recent research suggests that insulin is crucial for the brain, too—insulin abnormalities have been implicated in neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s. Among the latest findings is the discovery that a gene linked to insulin processing is located in a chromosomal area linked to Parkinson’s.

Historically, scientists believed that insulin was produced only by the pancreas and had no business in the central nervous system. Then, in the mid-1980s, several research groups spotted the hormone and its receptor in the brain. It appeared that the hormone not only crossed the blood-brain barrier but that it was also produced, at low levels, by the brain itself.

Soon afterward, scientists discovered that insulin plays an important role in learning and memory. People who inject or snort insulin immediately get better at recalling stories and performing other memory tasks. Learning also raises insulin levels: rats mastering spatial memory tasks have higher brain insulin levels than sedentary rats do.

These observations led neuropathologist Suzanne de la Monte and her colleagues at Brown University to ask whether brain insulin might have a part in Alz­heimer’s, which is characterized by severe memory loss. They compared postmortem insulin and insulin receptor levels in healthy brains and brains of Alzheimer’s patients. Average insulin levels in the neural parts associated with learning and memory were up to four times higher in the healthy brains, which also had up to 10 times as many insulin receptors.

“That made it clear that one could get exactly the same problems as in regular diabetes except confined to the brain,” says de la Monte, who refers to Alzheimer’s as “type 3 diabetes.” Because brain insulin is linked to insulin in the rest of the body via the blood-brain barrier, diabetics are more likely to develop Alzheimer’s, too—nearly twice as likely, according to a 2002 study. They also suffer more memory and learning problems than the general population.

De la Monte and others, including neuroendocrinologist Ignacio Torres Alemán of the Cajal Institute in Madrid, have also found links between Alzheimer’s and low brain levels of insulinlike growth factor 1 (IGF-1) and its receptor—proteins similar in structure to insulin and its receptor (insulin occasionally binds to the IGF-1 receptor, and vice versa). “We have suggested that Alzheimer’s disease originates because of an exacerbated loss of IGF-1 support to brain cells,” Torres Alemán says.

A handful of recent studies have also linked insulin and IGF-1 to Parkinson’s and Huntington’s. The prevalence of diabetes in patients with Huntington’s is seven times higher than average, and at least half of Parkinson’s patients have glucose metabolism problems. Robert Smith, an endocrinologist at Brown, recently discovered a protein called GIGYF2 that interacts with insulin and IGF-1 receptors. To better understand GIGYF2’s function, Smith mapped the location of its gene in the human genome. Reporting in the April 11 American Journal of Human Genetics, he says, “we found that it was smack dab in the PARK11 site,” a region of chromosome 2 that is linked to Parkinson’s—although he is not certain what the gene’s role in Parkinson’s may be.

Indeed, one of the biggest remaining questions is how, exactly, defects in insulin and IGF-1 signaling might hurt the brain. “This is a crucial topic—something we’re spending a great deal of effort unraveling,” de la Monte says. Some scientists believe that insulin is involved in the production of large protein plaques observed in the brains of patients with Alz­heimer’s and Parkinson’s. When Smith added above normal levels of GIGYF2 to neurons in the lab, large GIGYF2 aggregates formed and killed the cells. Other studies have determined that insulin modulates the production and degradation of amyloid beta, the protein that forms sticky plaques seen in Alzheimer’s brains.

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