“Exercise is the most potent insulin-sensitizing agent we have,” said Dr. Suzanne Craft, a geriatrician and Alzheimer’s researcher at the Veterans Administration Puget Sound Health Care System, Seattle, Washington.
“A single bout of aerobic exercise improves insulin sensitivity for 24 hours. It’s much more potent than any medication. Caloric restriction also lowers hyperinsulinemia and improves insulin sensitivity.”
A large body of work now suggests that insulin resistance increases the risk of Alzheimer’s by multiple mechanisms, Dr. Craft said. Far from being active only in the periphery, insulin readily crosses the blood-brain barrier and binds to receptors located throughout the brain – especially in areas of strategic importance in cognition: the hippocampus, entorhinal cortex, and frontal cortex. Once in the brain, insulin interacts with amyloid beta in several ways, increasing its intracellular clearance through insulin degrading enzyme and apparently even protecting neurons from the protein’s toxic effects.
“This has been known for some time, but recent research has shown that amyloid beta may have its own independent effects on insulin signalling,” Dr. Craft said. A series of experiments by William L. Klein, Ph.D., concluded that soluble oligomers of amyloid beta can remove insulin receptors from the dendritic plasma membranes of hippocampal neurons. However, Dr. Craft said, “If insulin was administered before the oligomeric Abeta, the dendritic spines were protected.”
The study, published in February, concluded that insulin receptor signalling downregulated the oligomeric binding sites. The addition of rosiglitazone potentiated this effect, suggesting that insulin-sensitizing agents may have some role in cognitive protection (Proc. Natl. Acad. Sci. U.S.A. 2009;106:1971-6).
“Insulin appears to mitigate many of the negative effects of amyloid and regulates its clearance, while beta amyloid appears to reduce insulin signalling. So high levels of insulin in the brain can induce a brain insulin-resistance by removing the insulin receptors from the nerve cell membranes,” Dr. Craft said.
She recently investigated insulin’s effect on memory in a group of 33 patients with Alzheimer’s or mild cognitive impairment and 59 elderly controls. The patients received placebo or five escalating doses of intranasal insulin, which travels directly into the central nervous system along the olfactory and trigeminal vasculature. Cognition was tested 15 minutes after each treatment. “We saw a 50% improvement in memory compared to baseline with the highest dose,” Dr. Craft said (J. Alz. Dis. 2008;13:323-31).
Insulin also affects vascular function in the brain. “It’s very well known that insulin resistance is accompanied by peripheral vascular dysfunction, but the understanding that this may also manifest in the brain is very new and potentially important.”
In insulin resistance, there is a downregulation of the phosphoinositide-3 (PI3) kinase pathway, which mediates vascular relaxation. But the mitogen-activated protein (MAP) kinase pathway, which mediates vasoconstriction, is driven by high levels of insulin and thus, does not downregulate with insulin resistance. “You get a reduction in vasodilation and hyperactivation of vasoconstriction,” Dr. Craft said. “This imbalance is thought to underlie many of the vascular dysfunctions associated with insulin resistance.”
She saw this in a recent study of 196 brains (71 with dementia). The brains were divided into four groups: normal; diabetic without dementia; diabetic with dementia; and dementia without diabetes.
“We saw a surprising pattern when we looked at plaques and tangles: the brains of the patients with dementia but no diabetes had a high load, as anticipated, but the brains of diabetic patients with dementia had a plaque load that was similar to the normal controls.”
The patients with both dementia and diabetes did, however, show high levels of microvascular lesions, which were absent in the other groups. “The volume of the lesions is small, so they are almost certainly not directly responsible for the cognitive impairment, but this finding may point to some broader based vascular dysfunction,” Dr. Craft said.