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.
Keywords: Advanced Glycation Products, Alzheimer’s Disease, Amyloid Beta
Deposition, Calcium Dysregulation, Ceramides, Endoplasmic Reticulum Stress,
Glucose Metabolism, Inflammatory Response, Insulin, Insulin Degrading Enzyme,
Insulin Resistance, Mitochondrial Dysfunction, Neurofibrillary Tangles, Neuronal
Homeostasis, Neurodegeneration, Obesity, Oxidative Stress, Tau
Hyperphosphorylation, The Apolipoprotein E, Toll-Like Receptors, Type 2
Diabetes Mellitus, Type 3 Diabetes, Ubiquitin Proteosome System.
