An emerging body of research suggests that Alzheimer’s disease may be linked to insulin resistance, constituting a third type of diabetes….
This model is based on several observations including an increased risk of developing Alzheimer’s disease for diabetic patients, and reduced insulin levels in the brain tissue of Alzheimer’s disease patients.
Though intriguing, the existing evidence does not reveal if defective insulin signaling is causative of Alzheimer’s or how insulin resistance impacts cognitive function.
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.
Two back-to-back research articles in the Journal of Clinical Investigation – led by Konrad Talbot, Steve Arnold and colleagues at the University of Pennsylvania and by Fernanda De Felice, Sergio Ferreria and colleagues at the University of Rio de Janeiro – address the connection between insulin resistance and Alzheimer’s disease.
Researchers 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 and liraglutide 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.
The University of Pennsylvania team examined insulin signaling in human brain tissue postmortem, and concluded that the activation state of many insulin signaling molecules were highly related to memory and cognitive function. They further suggest that insulin resistance is a common and early feature of Alzheimer’s disease.
The De Felice group further observed impaired insulin signaling in Alzheimer’s brain tissue in rodent and non-human primate model systems as well as from tissue from human patients. They went on to show in a mouse model system of Alzheimer’s disease that treatment with a new anti-diabetic drug normalized insulin signaling and remarkably improved cognitive function. Cumulatively, these two new studies strongly support a connection between insulin resistance and Alzheimer’s disease and provide hope for new therapeutics in Alzheimer’s disease treatment.
Journal of Clinical Investigation. (2012, March 21). “Alzheimer’s Disease And Diabetes Linked By New Evidence.”