Consequences of Aberrant Insulin Regulation in the Brain: Can Treating Diabetes be Effective for Alzheimers Disease

Abstract

There is an urgent need for new ways to treat Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Current therapies are modestly effective at treating the symptoms, and do not significantly alter the course of the disease. Over the years, a range of epidemiological and experimental studies have demonstrated interactions between diabetes mellitus and AD. As both diseases are leading causes of morbidity and mortality in the elderly and are frequent co-morbid conditions, it has raised the possibility that treating diabetes might be effective in slowing AD. This is currently being attempted with drugs such as the insulin sensitizer rosiglitazone. These two diseases share many clinical and biochemical features, such as elevated oxidative stress, vascular dysfunction, amyloidogenesis and impaired glucose metabolism suggesting common pathogenic mechanisms. The main thrust of this review will be to explore the evidence from a pathological point of view to determine whether diabetes can cause or exacerbate AD. This was supported by a number of animal models of AD that have been shown to have enhanced pathology when diabetic conditions were induced. The one drawback in linking diabetes and insulin to AD has been the postmortem studies of diabetic brains demonstrating that AD pathology was not increased; in fact decreased pathology has often been reported. In addition, diabetes induces its own distinct features of neuropathology different from AD. There are common pathological features to be considered including vascular abnormalities, a major feature arising from diabetes; there is increasing evidence that vascular abnormalities can contribute to AD. The most important common mechanism between insulin-resistant (type II) diabetes and AD could be impaired insulin signaling; a form of toxic amyloid can damage neuronal insulin receptors and affect insulin signaling and cell survival. It has even been suggested that AD could be considered as “type 3 diabetes” since insulin can be produced in brain. Another common feature of diabetes and AD are increased advanced glycation endproduct-modified proteins are found in diabetes and in the AD brain; the receptor for advanced glycation endproducts plays a prominent role in both diseases. In addition, a major role for insulin degrading enzyme in the degradation of Aβ peptide has been identified. Although clinical trials of certain types of diabetic medications for treatment of AD have been conducted, further understanding the common pathological processes of diabetes and AD are needed to determine whether these diseases share common therapeutic targets.

Neuroprotective and anti-ageing role of leptin

“…Although some authors consider that obesity in middle age is due to a risk of dementia, others questioned the existence of a relationship between the two processes, particularly in humans (Doruk et al 2010, Arab et al 2011. On the other hand, it is well known that both insulin resistance, associated with an increase in plasmatic levels of fatty acids, and high VLDL content contribute to amyloidogenesis (Arab et al 2011).…”

Resveratrol Protects PC12 Cells from High Glucose-Induced Neurotoxicity Via PI3K/Akt/FoxO3a Pathway

“…This cellular damage triggers apoptosis in neurons and supporting glial cells, contributing to the neuropathology associated with diabetes (de la Monte and Tong 2014). Clinical evidence shows that hyperglycemia-induced oxidative stress predisposes to complications in diabetic patients, and its inhibition may block the initiation and progression of neuropathy (Arab et al 2011).…”

The Framework of a Mathematical Model of the Autonomic Nervous System and Physiological Systems: Using the Neuroregulation of Blood Glucose as an Example

“…Moreover insulin is produced in the brain in addition to the pancreas [17]. Accordingly what is the mechanism which simultaneously maintains the levels of blood glucose in the brain and the body?…”