Cognitive disorder and dementia in type 2 diabetes mellitus

Abstract

Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer’s disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.

MRI-based machine learning model: A potential modality for predicting cognitive dysfunction in patients with type 2 diabetes mellitus

“…A meta-analysis confirmed that the incidence of MCI in patients with T2DM was approximately 45.0% (95% CI = 36.0, 54.0) ( You et al, 2021 ). Multiple pieces of evidence have indicated that T2DM is related to vascular dementia (VD) and Alzheimer’s disease (AD) ( Chau et al, 2020 ; Lyu et al, 2020 ; Ortiz et al, 2022 ). Recent studies have revealed that older patients with T2DM have a higher risk of MCI or dementia, compared to young patients with a similar condition ( Sanke et al, 2014 ; Gao et al, 2016 ; Machii et al, 2020 ; Suain Bon et al, 2021 ).…”

High Glycemia and Soluble Epoxide Hydrolase in Females: Differential Multiomics in Murine Brain Microvasculature

“…The HGD diet is rich in sucrose and was chosen since sucrose has a high glycemic index, and compared to LGD, the quantity of sucrose is double. A diet based on sucrose enrichment has been well studied in the context of neurodegenerative brain diseases such as Alzheimer’s disease [ 91 ], of interest to our work, and sucrose can be responsible for cognitive disorders and dementia [ 92 ].…”

Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome

“…In fact, the significance of the link between T2D and AD is now defined by the term “type 3 diabetes”, which describes a subset of diabetic patients who develop AD dementia [ 117 – 119 ]. In T2D, insulin resistance and altered IGF-1/IGF-1R signaling are associated with cognitive decline, Aβ production, tau hyperphosphorylation, proinflammatory marker’s expression, oxidative stress, and dyslipidemia [ 120 , 121 ]. Rui-Hua et al found that decreased serum IGF-1 levels were associated with T2D-associated cognitive decline in clinical trials [ 122 ].…”