Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Signalling and Therapeutic Implications

Abstract

In the last two decades, numerous in vitro studies demonstrated that insulin receptors and theirs downstream pathways are widely distributed throughout the brain. This evidence has proven that; at variance with previous believes; insulin/insulin-like-growth-factor (IGF) signalling plays a crucial role in the regulation of different central nervous system (CNS) tasks. The most important of these functions include: synaptic formation; neuronal plasticity; learning; memory; neuronal stem cell activation; neurite growth and repair. Therefore; dysfunction at different levels of insulin signalling and metabolism can contribute to the development of a number of brain disorders. Growing evidences demonstrate a close relationship between Type 2 Diabetes Mellitus (T2DM) and neurodegenerative disorders such as Alzheimer’s disease. They, in fact, share many pathophysiological characteristics comprising impaired insulin sensitivity, amyloid β accumulation, tau hyper-phosphorylation, brain vasculopathy, inflammation and oxidative stress. In this article, we will review the clinical and experimental evidences linking insulin resistance, T2DM and neurodegeneration, with the objective to specifically focus on insulin signalling-related mechanisms. We will also evaluate the pharmacological strategies targeting T2DM as potential therapeutic tools in patients with cognitive impairment.

Influence of the Mediterranean and Ketogenic Diets on Cognitive Status and Decline: A Narrative Review

“…Alzheimer's disease (AD), the most common cause of dementia [6], is characterized by the accumulation of amyloid β (Aβ) and hyper-phosphorylation of the Tau protein, with additional reduced acetylcholine levels and cerebral blood flow [2,7]. Furthermore, modifications in the blood-brain barrier (BBB), oxidative stress, mitochondrial impairment, neuroinflammation, and alterations in the insulin signaling have been observed in this condition [8].…”

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

“…Next, we investigated other causative factor such as inflammatory process, mitochondrial dysfunction, or oxidative stress that may have a more critical role in the synaptic and cognitive deficits in T2DM (Carvalho et al, ; Chornenkyy, Wang, Wei, & Nelson, ; Ling et al, ; Pintana et al, ; Tumminia, Vinciguerra, Parisi, & Frittitta, ; Verdile et al, ). In addition, others authors have shown that db/db mice have reductions in brain weight and spine density, which were worsened in APP/PS1xdb/db mice, indicating a role for Aβ in these deficits (Infante‐Garcia, Ramos‐Rodriguez, Galindo‐Gonzalez, & Garcia‐Alloza, ).…”

The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers

“…This, in turn, affects other signal transduction pathways, including threonine-serine protein kinase, glycogen synthase kinase 3 beta (GSK3β) and the FoxO transcription factor family. For many of these paths, a key role in the proper functioning of the brain is assigned [55]. T2DM is a disease with a dynamically changing course, progressing from dominant insulin resistance, through compensatory hyperinsulinemia, to the exhaustion of the secretory capacity of pancreatic β cells.…”

“…The intraneuronal inclusion of the microtubule-associated protein tau serves as another established biomarker for AD. Tau protein, known to increase gradually with age from <300 pg/mL (21-50 years) to almost <500 (>71 years), demonstrates a significant exponential increase in AD sufferers from >450 to >600 pg/mL (in age rage [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70], hence proving to be a good prognostic biomarker [119]. AD exhibits the condition of tau protein being phosphorylated in almost 39 possible sites, with position 181 working as a definite biomarker in AD.…”