Impaired Insulin Signaling and Chronic Inflammation in the Alzheimer's Brain
In past years, there has been considerable discussion of Alzheimer's disease as a type 3 diabetes. This is by no means a formal designation, but enough papers have put forward the concept that when a new version of diabetes was in fact discovered not so long ago, it had to be designated type 4. Why call Alzheimer's a form of diabetes? Because dysregulation of insulin metabolism appears to be a feature of the condition. In the paper here, these issues with insulin signaling are linked to the generation of chronic inflammation. This makes a great deal of sense in the broader context of what is known of Alzheimer's disease, as dysregulation of immune cells in the brain, and rising levels of inflammatory signaling, are thought to arise from the presence of amyloid-β and in turn generate tau aggregates and severe pathology in the brain. In effect, inflammation bridges the early, mild stages of the condition and the later severe stages and their very different biochemistries.
Recently, type 2 diabetes mellitus (T2DM) has been identified as a risk factor for Alzheimer's disease (AD). Epidemiological studies of patient data sets have found a clear correlation between T2DM and the risk of developing AD or other neurodegenerative disorders. In one study, 85% of AD patients had diabetes or showed increased fasting glucose levels, compared to 42% in age-matched controls. In longitudinal studies of cohorts of people, it was found that glucose intolerance was a good predictor for the development of dementia later in life.
When analyzing the brain tissue of AD patients, it was observed that insulin signaling was much desensitized, even in AD patients that did not have T2DM. One study found that the levels of insulin, IGF-1, and IGF-II were much reduced in brain tissue. In addition, levels of the insulin receptor, the insulin-receptor associated PI3-kinase, and activated Akt/PKB kinase were much reduced. A second study found increased levels of IGF-1 receptors and the localization of insulin receptors within cells rather than on the cell surface where they could function.
Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common - they induce a chronic inflammation response in the brain. Insulin reduces the chronic inflammation response by inhibiting secondary cell signaling induced by pro-inflammatory cytokines. A desensitization of insulin signaling enhances the inflammation response and the desensitization observed in T2DM, therefore, not only compromises growth factor signaling, and energy utilization in the brain, but also facilitates the chronic inflammation response.
Wasn't the brain one of the few tissues that doesn't require insulin to use glucose ? And yes, googling brings this title: http://diabetes.diabetesjournals.org/content/63/12/3992 (Insulin Regulates Brain Function, but How Does It Get There?)