Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 15287 - 15287

Published: Dec. 4, 2022

The global prevalence of diabetes mellitus and Alzheimer's disease is increasing alarmingly with the aging population. Numerous epidemiological data suggest that there a strong association between type 2 an increased risk dementia. These diseases are both degenerative progressive share common factors. amyloid cascade plays key role in pathophysiology disease. accumulation beta peptides gradually leads to hyperphosphorylation tau proteins, which then form neurofibrillary tangles, resulting neurodegeneration cerebral atrophy. In disease, apart from these processes, alteration glucose metabolism insulin signaling brain seems induce early neuronal loss impairment synaptic plasticity, years before clinical manifestation large amount evidence on existence resistance during has led description this as "type 3 diabetes". Available animal models have been valuable understanding relationships but date, mechanistical links poorly understood. non-exhaustive review, we describe main molecular mechanisms may link two diseases, emphasis impaired IGF-1 signaling. We also focus GSK3β DYRK1A, markers closely associated pancreatic β-cell dysfunction diabetes, thus represent therapeutic targets for diseases.

Language: Английский

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Understanding glucose metabolism and insulin action at the blood–brain barrier: Implications for brain health and neurodegenerative diseases

Acta Physiologica, Journal Year: 2025, Volume and Issue: 241(2)

Published: Jan. 16, 2025

The blood-brain barrier (BBB) is a highly selective, semipermeable critical for maintaining brain homeostasis. BBB regulates the transport of essential nutrients, hormones, and signaling molecules between bloodstream central nervous system (CNS), while simultaneously protecting from potentially harmful substances pathogens. This selective permeability ensures that nourished shielded toxins. An exception to this are regions, such as hypothalamus circumventricular organs, which irrigated by fenestrated capillaries, allowing rapid direct response various blood components. We overview metabolic functions BBB, with an emphasis on impact altered glucose metabolism insulin in pathogenesis neurodegenerative diseases. Notably, endothelial cells constituting exhibit distinct characteristics, primarily generating ATP through aerobic glycolysis. occurs despite their exposure abundant oxygen bloodstream, typically supports oxidative phosphorylation. effects astrocytes, form glial limitans component show marked sexual dimorphism. nutrient sensing hypothalamus, along signaling, systemic metabolism. Insulin modifies regulating expression tight junction proteins, angiogenesis, vascular remodeling, well modulating flow brain. disruptions particularly evident diseases, Alzheimer's disease Parkinson's disease, where breakdown accelerates cognitive decline. review highlights role normal functionality investigates how these pathways contribute onset progression

Language: Английский

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Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3278 - 3278

Published: Feb. 7, 2023

A decrease in the activity of insulin signaling system brain, due to both central resistance and deficiency, leads neurodegeneration impaired regulation appetite, metabolism, endocrine functions. This is neuroprotective properties brain its leading role maintaining glucose homeostasis as well network responsible for functioning nervous, endocrine, other systems. One approaches restore use intranasally administered (INI). Currently, INI being considered a promising drug treat Alzheimer’s disease mild cognitive impairment. The clinical application developed treatment neurodegenerative diseases improve abilities stress, overwork, depression. At same time, much attention has recently been paid prospects using cerebral ischemia, traumatic injuries, postoperative delirium (after anesthesia), diabetes mellitus complications, including dysfunctions gonadal thyroid axes. review devoted current trends these diseases, which, although differing etiology pathogenesis, are characterized by brain.

Language: Английский

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Amygdala activity and amygdala-hippocampus connectivity: Metabolic diseases, dementia, and neuropsychiatric issues

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 162, P. 114647 - 114647

Published: April 1, 2023

With rapid aging of the population worldwide, number people with dementia is dramatically increasing. Some studies have emphasized that metabolic syndrome, which includes obesity and diabetes, leads to increased risks cognitive decline. Factors such as insulin resistance, hyperglycemia, high blood pressure, dyslipidemia, central in syndrome are associated synaptic failure, neuroinflammation, imbalanced neurotransmitter levels, leading progression dementia. Due positive correlation between diabetes dementia, some called it "type 3 diabetes". Recently, patients decline due imbalances has considerably increased. In addition, recent reported neuropsychiatric issues anxiety, depressive behavior, impaired attention common factors disease those nervous system (CNS), amygdala a region regulates emotional memory, mood disorders, attention, function. The connectivity other brain regions, hippocampus, activity contribute diverse neuropathological issues. Thus, this review summarizes significant consequences critical roles both syndromes Further on function imbalance-related needed treat problems type

Language: Английский

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Complete remission of depression and anxiety using a ketogenic diet: case series

Frontiers in Nutrition, Journal Year: 2024, Volume and Issue: 11

Published: May 14, 2024

Background There is little data that describe the use of ketogenic metabolic therapy to achieve full remission major depression and generalized anxiety disorder in clinical practice. We present a retrospective case series three adults with complex comorbidity, treated personalized therapy, who achieved complete improvements flourishing, self-compassion, health. Methods Three adults, ages 32–36, depression, anxiety, other disorders, comorbid psychiatric conditions were for 12–16 weeks whole food animal-based (1.5:1 ratio) specialized psychiatry Interventions included twice-weekly visits an experienced registered dietitian; daily photo journaling capillary blood BHB/glucose/GKI monitoring; virtual groups; family/friends support; nature walks talks several times per week, community building. Successful adoption diet was defined as achievement maintenance BHB ≥ 0.8 mmol/L GKI < 6. Remission assessed by GAD-7 PHQ-9, quality life subjectively validated scales flourishing self-compassion. Metabolic health laboratories/biometric measures. Results Two patients (PHQ-9 ≤ 4) (GAD-7 within 7 therapeutic nutritional ketosis; one required 12 weeks. Anxiety responded remitted more quickly than depression. Flourishing self-compassion increased steadily. Patients lost 10.9 14.8% their initial body weight improved metabolically; optimal Conclusion Complete occurred 7–12 ketosis during treatment (ratio 1.5:1) engaged program.

Language: Английский

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Metabolomics in Parkinson’s Disease and Correlation with Disease State

Metabolites, Journal Year: 2025, Volume and Issue: 15(3), P. 208 - 208

Published: March 18, 2025

Changes in the level of metabolites, small molecules that are intermediates produced by metabolism or catabolism, associated with developing diseases. Metabolite signatures body fluids such as plasma, cerebrospinal fluid, urine, and saliva Parkinson’s disease. Here, we discuss alteration metabolites TCA cycle, pentose phosphate pathway, kynurenic network, redox system. We also summarize efforts many research groups to differentiate between metabolite profiles characterize PD motor progression dyskinesia, gait balance, non-motor symptoms depression cognitive decline. Understanding how changes lead may allow for identification individuals at earliest stage disease development new therapeutic strategies.

Language: Английский

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Insulin resistance as the molecular link between diabetes and Alzheimer's disease

World Journal of Diabetes, Journal Year: 2024, Volume and Issue: 15(7), P. 1430 - 1447

Published: July 8, 2024

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies indicated possible link between DM an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays vital protecting brain functions. Insulin resistance (IR), especially prevalent type 2 diabetes, is believed to play significant AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various functions, making individuals more susceptible defining features, such as the buildup beta-amyloid plaques tau protein tangles. Emerging research suggests addressing insulin-related issues might help reduce or even reverse changes linked This review aims explore rela-tionship AD, with focus on IR. It explores molecular mechanisms by which IR lead assesses current treatments target Understanding IR's connection AD offers new possibilities highlights importance continued this interdisciplinary field.

Language: Английский

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Revolutionizing Neurological Disorder Treatment: Integrating Innovations in Pharmaceutical Interventions and Advanced Therapeutic Technologies

Current Pharmaceutical Design, Journal Year: 2024, Volume and Issue: 30(19), P. 1459 - 1471

Published: April 15, 2024

Neurological disorders impose a significant burden on individuals, leading to disabilities and reduced quality of life. However, recent years have witnessed remarkable advancements in pharmaceutical interventions aimed at treating these disorders. This review article aims provide an overview the latest innovations breakthroughs neurological disorder treatment, with specific focus key therapeutic areas such as Alzheimer's disease, Parkinson's multiple sclerosis, epilepsy, stroke. explores emerging trends drug development, including identification novel targets, development innovative delivery systems, application personalized medicine approaches. Furthermore, it highlights integration advanced technologies gene therapy, optogenetics, neurostimulation techniques. These hold promise for precise modulation neural circuits, restoration neuronal function, even disease modification. While offer hopeful prospects more effective tailored treatments, challenges need improved diagnostic tools, new targets intervention, optimization methods will remain. By addressing continuing invest research collaboration, we can revolutionize treatment significantly enhance lives those affected by conditions.

Language: Английский

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A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 6, 2024

The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity T2DM AD. Ceramides structural components cell membrane lipids act as signal molecules regulating homeostasis. Their synthesis degradation play crucial roles in maintaining metabolic balance vivo , serving important mediators development neurodegenerative disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, impacts glucose lipid homeostasis metabolism-related tissues like liver, skeletal muscle, adipose tissue, driving occurrence progression T2DM. connection changes levels brain, amyloid β accumulation, tau hyper-phosphorylation evident. Additionally, regulates survival apoptosis through related signaling pathways, actively participating Regulatory enzymes, their metabolites, pathways impact core pathological molecular mechanisms shared by AD, such insulin resistance response. Consequently, may become potential therapeutic target intervention paper comprehensively summarizes discusses role its metabolites pathogenesis well latest progress treatment with

Language: Английский

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Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 16, 2024

Abstract Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that is primary substrate for sustaining neuronal in multiple brain regions, its role regulating sleep/wake architecture not fully understood. Here we investigated involvement astrocytic supply maintaining consolidated wakefulness downregulating, a cell-specific manner, expression monocarboxylate transporters (MCTs) lateral hypothalamus transgenic mice. Our results demonstrate reduced MCT4 astrocytes disrupts to wake-promoting orexin neurons, impairing stability. Additionally, show MCT2-mediated uptake necessary tonic firing neurons and stabilizing wakefulness. findings provide both vivo vitro evidence supporting astrocyte-to-orexinergic neuron proper

Language: Английский

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