Could Alzheimer's Disease Really Be Type 3 Diabetes?
Type 2 diabetes is known to increase the risk for Alzheimer’s disease. Recent research has found that insulin resistance also develops in the brains of patients with Alzheimer’s, which scientists sometimes call “brain diabetes.” This brain insulin signaling deficit results in learning and memory disability and could potentially be known as Type 3 Diabetes.
There is much that still remains unknown about the cause of Alzheimer’s disease (AD), a form of dementia that affects memory, thinking, and behavior. Two brain changes have long been known to form in the brains of patients with dementia – neurofibrillary tangles and beta-amyloid plaques. Tangles are twisted fibers of tau protein that builds up inside the cells. Plaques are accumulations of protein fragments that build up in the spaces between nerve cells. The two abnormal structures combine to block communication between nerve cells and disrupt the processes needed for them to survive.
But now, a third brain change is emerging as a likely suspect contributing to cognitive deficits in patients with Alzheimer’s disease. Brain levels of insulin and insulin receptor (IR) are lower in AD and insulin signaling impairments have been documented in human postmortem analysis and in animal models.
Researchers writing in the Journal of Clinical Investigation suggest that because several pathological features, including the impaired insulin signaling and inflammation, are shared by patients with diabetes and those with AD, the hypothesis is that mechanisms that cause the impairment in insulin in peripheral tissues seen in diabetes may also be present in brain insulin resistance.
The team suggests that stimulating glucagon-like peptide 1 (GLP-1) receptors may represent a promising new pharmaceutical approach to curing AD. GLP-1 agonists such as exenatide (Byetta, Bydureon) significantly reduce blood glucose, insulin and glucagon levels after meals in patients with Type 2 diabetes. This is a different action from insulin injections, which lower blood glucose but raise circulating blood levels of insulin.
GLP-1 also improves insulin production in the pancreas, so it is thought that it may also improve insulin signaling in the hippocampus which helped improve cognition in mice genetically altered to develop AD. Stimulating brain insulin signaling could also prevent synapse deterioration by protecting against amyloid-beta-induced damage.
Inflammation is also an important component of insulin resistance and diabetes. Obesity is another risk factor in this process, as excess fat in the adipose tissue and liver often accompanies chronic inflammation. In the brain, GLP-1 attaches to an appetite receptor in the hypothalamus which often decreases appetite and gradually reduces weight over time.
The authors conclude that “By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenue for the investigation of new therapeutics in AD.”
Bomfin TR, Forny-Germano L, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Aß oligomers. J Clin Invest, March 22, 2012. doi:10.1172/JCI57256
Talbot K et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest, March 22, 2012. doi:10.1172/JCI59903