Sci. Aging Knowl. Environ., 19 March 2003
Vol. 2003, Issue 11, p. nw44
[DOI: 10.1126/sageke.2003.11.nw44]

NOTEWORTHY ARTICLES

Double Duty

Insulin-chomping protein might couple diabetes and Alzheimer's disease

Mary Beckman

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/11/nw44

Key Words: hyperinsulinemia • type II diabetes • amyloid precursor protein • protease

A single protein appears to obliterate used insulin and clean up Alzheimer's-related gunk in mouse brains, according to new results. The work bolsters a link between adult-onset diabetes and the neurodegenerative disorder, and researchers are eager to test whether that connection exists in humans.

The hormone insulin shunts glucose from blood into hungry cells. To push sugar into cells, insulin binds to a cell-surface receptor, and some evidence suggests that the hormone clings until another molecule cuts it loose. Insulin-degrading enzyme (IDE) can butcher insulin and other proteins in the test tube and might cleave the hormone in the body, freeing the receptor for more insulin. As a prelude to adult-onset diabetes, cells start ignoring insulin, and the body partly overcomes this deafness by jacking up the hormone's production. But overproducing insulin can cause permanent trouble, because the body eventually tires of manufacturing excess hormone and cuts back drastically.

Several lines of evidence suggest a connection between diabetes and Alzheimer's disease. IDE's targets include {beta} amyloid, a short protein that clumps together and gums up the brains of Alzheimer's patients (see "Detangling Alzheimer's Disease"). Two epidemiological studies showed that diabetics are almost twice as likely to develop Alzheimer's as are healthy folk, and the region of chromosome 10 on which IDE resides carries mutations found in people with adult-onset diabetes and late-onset Alzheimer's. In addition, up to 80% of late-onset Alzheimer's patients who have no obvious risk factors such as the ApoE4 gene harbor unusually large amounts of insulin. To investigate the putative link and to probe IDE's role in live animals, Farris and colleagues tested whether IDE destroys insulin and {beta} amyloid in rodents.

The team created mice that lacked IDE. The animals seemed healthy: They weighed about the same as normal mice did and could breed and scamper. Measurements of glucose metabolism revealed that the enzyme minces insulin in the rodents. The mice had almost three times the usual amount of insulin in their bloodstreams and didn't take up injected glucose into their cells, two physiological hallmarks of diabetes.

The mice also showed classic features of Alzheimer's disease. Brain tissue from 3-month-old animals--young adults--had approximately 50% more {beta} amyloid than normal. Furthermore, addition of insulin to neurons grown from unaltered mouse embryos prevented destruction of {beta} amyloid, suggesting that insulin can distract IDE from the Alzheimer's protein.

If the results hold true for people, they imply that hampered IDE can foster diabetes and Alzheimer's disease. Furthermore, they suggest that individuals in the early stages of diabetes are at risk for accumulating {beta} amyloid even without mutations in the gene for the enzyme, says neuroscientist Suzanne Craft of the University of Washington, Seattle: "IDE prefers insulin over {beta} amyloid, so just by having high levels of insulin, the enzyme would not degrade {beta} amyloid." Neuroscientist Konrad Talbot of the University of Pennsylvania School of Medicine in Philadelphia says that the result has therapeutic implications for Alzheimer's disease. Perhaps scientists can harness IDE to clear {beta} amyloid from the brain and thus fight neurodegeneration.

--Mary Beckman


March 19, 2003
  1. W. Farris et al., Insulin-degrading enzyme regulates the levels of insulin, amyloid {beta}-protein, and the {beta}-amyloid precursor protein intracellular domain in vivo. Proc. Natl. Acad. Sci. U.S.A., 12 March 2003 [e-pub ahead of print].[Abstract] [Full Text]
Citation: M. Beckman, Double Duty. Sci. SAGE KE 2003, nw44 (19 March 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/11/nw44








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