Novel insights into non-alcoholic fatty liver disease and dementia: insulin resistance, hyperammonemia, gut dysbiosis, vascular impairment, and inflammation.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by multiple pathologies. The progression of dementia with NAFLD may be affected by various risk factors, including brain insulin resistance, cerebrovascular dysfunction, gut dysbiosis, and neuroinflammation. Many recent studies have focused on the increasing prevalence of dementia in patients with NAFLD. Dementia is characterized by cognitive and memory deficits and has diverse subtypes, including vascular dementia, Alzheimer's dementia, and diabetes mellitus-induced dementia. Considering the common pathological features of NAFLD and dementia, further studies on the association between them are needed to find appropriate therapeutic solutions for diseases. This review summarizes the common pathological characteristics and mechanisms of NAFLD and dementia. Additionally, it describes recent evidence on association between NAFLD and dementia progression and provides novel perspectives with regard to the treatment of patients with dementia secondary to NAFLD.

Role of ketone bodies in diabetes-induced dementia: sirtuins, insulin resistance, synaptic plasticity, mitochondrial dysfunction, and neurotransmitter.

Patients with type 2 diabetes can have several neuropathologies, such as memory deficits. Recent studies have focused on the association between metabolic imbalance and neuropathological problems, and the associated molecular pathology. Diabetes triggers neuroinflammation, impaired synaptic plasticity, mitochondrial dysfunction, and insulin resistance in the brain. Glucose is a main energy substrate for neurons, but under certain conditions, such as fasting and starvation, ketone bodies can be used as an energy fuel for these cells. Recent evidence has shed new light on the role of ketone bodies in regulating several anti-inflammation cellular pathways and improving glucose metabolism, insulin action, and synaptic plasticity, thereby being neuroprotective. However, very high amount of ketone bodies can be toxic for the brain, such as in ketoacidosis, a dangerous complication that may occur in type 1 diabetes mellitus or alcoholism. Recent findings regarding the relationship between ketone bodies and neuropathogenesis in dementia are reviewed in this article. They suggest that the adequately low amount of ketone bodies can be a potential energy source for the treatment of diabetes-induced dementia neuropathology, considering the multifaceted effects of the ketone bodies in the central nervous system. This review can provide useful information for establishing the therapeutic guidelines of a ketogenic diet for diabetes-induced dementia.

The importance of BDNF and RAGE in diabetes-induced dementia.

Diabetes-induced dementia is an emerging neurodisorder all over the world. The prevalence rates of dementia and diabetes have been gradually increasing worldwide. Diabetes has been known to lead to oxidative stress, inflammation aggravation, and hyperglycemia conditions in the brain. Various diabetic implications cause the lower secretion of brain-derived neurotrophic factor (BDNF) and the increase of receptor for advanced glycation end products (RAGE), ultimately leading to both cerebrovascular dysfunction and cognitive decline. Here, we summarized the significant evidences highlighting the specific mechanisms between BDNF and RAGE and cerebrovascular dysfunction and memory function and how these relate to diabetes-induced dementia. Especially, we review that the association between BDFN and RAGE in neuroinflammation, the reduction of long-term potentiation, and the vascular implications in brain.

The Glymphatic System in Diabetes-Induced Dementia.

The glymphatic system has emerged as an important player in central nervous system (CNS) diseases, by regulating the vasculature impairment, effectively controlling the clearance of toxic peptides, modulating activity of astrocytes, and being involved in the circulation of neurotransmitters in the brain. Recently, several studies have indicated decreased activity of the glymphatic pathway under diabetes conditions such as in insulin resistance and hyperglycemia. Furthermore, diabetes leads to the disruption of the blood-brain barrier and decrease of apolipoprotein E (APOE) expression and the secretion of norepinephrine in the brain, involving the impairment of the glymphatic pathway and ultimately resulting in cognitive decline. Considering the increased prevalence of diabetes-induced dementia worldwide, the relationship between the glymphatic pathway and diabetes-induced dementia should be investigated and the mechanisms underlying their relationship should be discussed to promote the development of an effective therapeutic approach in the near future. Here, we have reviewed recent evidence for the relationship between glymphatic pathway dysfunction and diabetes. We highlight that the enhancement of the glymphatic system function during sleep may be beneficial to the attenuation of neuropathology in diabetes-induced dementia. Moreover, we suggest that improving glymphatic system activity may be a potential therapeutic strategy for the prevention of diabetes-induced dementia.

Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two age-related amyloid diseases that affect millions of people worldwide. Broadly supported by epidemiological data, the higher incidence of AD among type 2 diabetic patients led to the recognition of T2D as a tangible risk factor for the development of AD. Indeed, there is now growing evidence on brain structural and functional abnormalities arising from brain insulin resistance and deficiency, ultimately highlighting the need for new approaches capable of preventing the development of AD in type 2 diabetic patients. This review provides an update on overlapping pathophysiological mechanisms and pathways in T2D and AD, such as amyloidogenic events, oxidative stress, endothelial dysfunction, aberrant enzymatic activity, and even shared genetic background. These events will be presented as puzzle pieces put together, thus establishing potential therapeutic targets for drug discovery and development against T2D and diabetes-induced cognitive decline-a heavyweight contributor to the increasing incidence of dementia in developed countries. Hoping to pave the way in this direction, we will present some of the most promising and well-studied drug leads with potential against both pathologies, including their respective bioactivity reports, mechanisms of action, and structure-activity relationships.

The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain.

Alzheimer's disease (AD), characterized by the aggregation of amyloid-ß (Aß) protein and neuroinflammation, is the most common neurodegenerative disease globally. Previous studies have reported that some AD patients show impaired glucose utilization in brain, leading to cognitive decline. Recently, diabetes-induced dementia has been called "type 3 diabetes", based on features in common with those of type 2 diabetes and the progression of AD. Impaired glucose uptake and insulin resistance in the brain are important issues in type 3 diabetes, because these problems ultimately aggravate memory dysfunction in the brain. Glucagon-like peptide 1 (GLP-1) has been known to act as a critical controller of the glucose metabolism. Several studies have demonstrated that GLP-1 alleviates learning and memory dysfunction by enhancing the regulation of glucose in the AD brain. However, the specific actions of GLP-1 in the AD brain are not fully understood. Here, we review evidences related to the role of GLP-1 in type 3 diabetes.