Much as been flying through the diabetes web sites about the relationship to diabetes and Alzheimer's Disease (AD) in view of the finding of insulin receptors in the brain. Today I would like to discuss recent information from The Journal of Pediatrics, The New England Journal of Medicine, and Neurology. As you may remember, I recently posted information that suggested that kids who experience both frequent hyperglycemia and hypoglycemia may have some task related memory problems (that may not be clinically significant).
In a paper by Ghetti and Glaser et.al, published in the Journal of Pediatrics (Volume 156, Issue 1, pages 109-114, January, 2010), it was demonstrated that diabetic ketoacidosis disrupts memory function typical of injuries that cause low oxygen (hypoxia) and increase acid levels (ischemia). This was observed even without symptoms suggestive of brain injury. In the study, two groups of children (33) with DKA and (29) without DKA were asked to recall events with specific details (two tasks: event-color associations and event-spatial associations). The results demonstrated that those children with a history of DKA had significantly lower rates of accurate memory on both tasks then did children without a DKA history (p< .01). Thus, the authors concluded that prevention of DKA with both a known history of diabetes as well as rapid diagnosis of new-onset diabetes would hopefully prevent memory disruption.
In a review article published by Drs Querfurth and LaFerla, "Mechanisms of Disease: Alzheimer's Disease" in The New England Journal of Medicine (Volume 362, No. 4, pages 329-344, January 28, 2010), the authors discussed insulin (as well as many other factors) as it relates to Alzheimer's disease and oxidative metabolism. One cannot simplify Alzheimer disease pathophysiology as there are a number of mechanisms that contribute to AD. These include protein abnormalities, such as B-amyloid, and TAU (neurofibrillary tangles), depletion of neurotrophin and neurotransmitters, and mitochondrial dysfunction. The key fact to remember is that Alzheimer's disease is a disorder of synaptic failure (the area between neurons in which there is electrochemical communication). Thus, anything that deregulates synaptic function may contribute to the development of AD. The mitochondria are the energy producing cells of the body. The dysfunctional mitochondria release oxidizing free radicals that result in considerable oxidative stress. (Keep in mind that diabetes occurs when there is an inability to get glucose into the cells, which is the source of energy for those mitochondrial powerhouses. Insulin is the hormone that allows glucose to enter the cells and start oxidative metabolism.) Vascular effects, inflammation, calcium metabolism, axonal transport deficits, and cholesterol metabolism also play a role in the development of Alzheimer's disease.
According to the authors, the insulin-signaling pathway is another metabolic disturbance of emerging importance in AD. "Subgroups of patients with advanced AD have high fasting insulin levels and low rates of glucose disposal (peripheral resistance)." Glucose intolerance and type 2 diabetes are considered to be risk factors for dementia. In addition, "levels of insulin receptors, glucose-transport proteins, and other insulin-pathway components in the brain are reduced in some studies of AD." It also appears that aging and life span are influenced by insulin. In other words, resistance to insulin signaling prevents neurons from obtaining energy and is subject to oxidative stress or other metabolic insults. This may result in the loss of synaptic communication between neurons. In addition, higher serum blood sugar levels that normally occur in older individuals may directly damage brain structures related to memory as well as wreck havoc with enzyme pathways and reduce levels of "insulin degrading" enzyme in the brain of people with Alzheimer's disease. Indeed, treatment with thiazolidine drugs apparently activated an insulin gene and prevented AD-associated changes and cognitive decline in mice.
