Frontiers in Clinical Drug Research – Diabetes and Obesity

Volume 4

by

Atta-ur-Rahman

DOI: 10.2174/97816810844591170401
eISBN: 978-1-68108-445-9, 2019
ISBN: 978-1-68108-446-6
ISSN: 2467-9607 (Print)
ISSN: 2352-3220 (Online)





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Through the Perspective of Histology - The Alzheimer’s Disease Promotion by Obesity and Glucose Metabolism: Type 3 Diabetes

- Pp. 135-198 (64)

Cigdem Elmas and Cemile Merve Seymen

Abstract

Since the 1990s The World Health Organisation (WHO) has stated that “… obesity should now be regarded as one of the greatest neglected public health problems of our time…” and defined the global epidemic of being overweight and obese as “globesity”. A positive energy balance, which consists of an imbalance between energy intake and calorie expenditure is the main cause of obesity, however, genetic, environmental, socioeconomical, behavioral and psychological factors may also be the inducing factors when it comes to obesity. The excess of adiposity has an enhancing effect on the development of hypertension, cardiovascular diseases and type 2 diabetes mellitus (T2DM) as a result of the resistance to insulin-mediated glucose disposal. T2DM which represents a common disease associated with obesity and often aging is characterized by high blood glucose levels, impaired insulin production and peripheral insulin resistance. Homeostatic degradation of glucose affects the cerebral functions directly or indirectly because glucose is a significant metabolic substrate for all cells and also for the cells of the brain. Insulin has a key effect on the regulation of energy metabolism of neurons and neuronal recovery, which acts as a growth factor on all cells including neurons in the central nervous system. Therefore, simply put, impairment in neuronal homeostasis which occurs as a result of insulin deficiency. These are considered to be a risk factor for Alzheimer’s disease (AD) development. Indeed, many studies have shown that glucose intolerance and impairment of insulin secretion are associated with a higher risk to develop dementia or AD. It is worth remembering that AD is associated with brain insulin resistance and deficiency, whereas T2DM is associated with peripheral insulin resistance. In short, it can be said that T2DM causes AD-type neurodegeneration in the brain. T2DM and AD share several molecular processes that underlie the degenerative developments. Dysregulated glucose metabolism, abnormalities in insulin signaling, the formation of advanced glycation end products, oxidative stress, the activation of inflammatory pathways and abnormal protein processing are the common characteristics of T2DM and AD. The misfolding of proteins plays an important role in both diseases, so as the aggregation of amyloid peptides. AD is characterized by the deposition of amyloid within neurons and amyloid plaques. Also in AD, the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects induced by a dysfunction of the proteasome. According to one study which was conducted on T2DM rats, T2DM-dependent decreases in p62 (a known cargo molecule that transports polyubiquitinated tau to proteosomal and autophagic degradation systems) transcription which is a primary mechanism underlying increased AD-like pathology. In some studies, brain amyloid deposition occurs as a result of increased blood-brain barrier permeability in case of diabetes conditions. In the recent years, according to some members of the diabetes community, AD is seen as a neuroendocrine disorder and the term “Type 3 Diabetes” defines the insulin deficiency and resistance in the brain of those with AD. In the context of these information, in this chapter, we propose a study about “Type 3 Diabetes” with the underlying mechanisms through the perspective of histology.

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