Diabetes mellitus and Alzheimer’s disease: GSK-3β as a potential link

Zhang, Ying; Huang, Nanqu; Yan, Fei; Jin, Hai; Zhou, Shaoyu; Shi, Jingshan; Jin, Feng

doi:10.1016/j.bbr.2017.11.015

Cited by 232 publications

(176 citation statements)

References 122 publications

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“…GSK3 also plays a role in the pathogenesis of common diseases, e.g., neurological/neurodegenerative diseases [13,15]; diabetes mellitus [16]; inflammatory diseases [17], such as rheumatoid arthritis [18]; and different types of cancer [19]. Moreover, GSK3 is also of priming phosphorylation has to be mediated by another kinase, GSK3 is able to perform multiple successive phosphorylation steps at substrates containing a series of adjacent consensus sequences, thus generating its own priming phosphorylation for further phosphorylation events [38].…”

Section: Introductionmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

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GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

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Section: Introductionmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

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“…10 In addition to functioning as a primary energy source, mitochondria produce fatty acids, function as a storage depot for calcium ions, generate heat, and are also known modulators of cell death and survival through the regulation of apoptosis. [14][15][16] Regulation of GSK-3β is phosphorylation dependent. To protect against disease, mitochondria have developed multiple quality control mechanisms, including fission/fusion and mitophagy.…”

Section: Introductionmentioning

confidence: 99%

Insulin receptor preserves mitochondrial function by binding VDAC1 in insulin insensitive mucosal epithelial cells

Titone

Robertson

2019

The FASEB Journal

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Unlike many epithelial tissues, the corneal epithelium is insulin insensitive, meaning it does not require insulin for glucose uptake. In this study, we show that insulin differentially regulates mitochondrial respiration in two human mucosal epithelial cell types: insulin‐insensitive corneal epithelial cells and insulin‐sensitive bronchial epithelial cells. In both cell types, insulin blocks glycogen synthase kinase beta (GSK3β) activity. In the corneal epithelium however, insulin selectively regulates PTEN‐induced kinase 1 (PINK‐1)‐mediated mitophagy and mitochondrial accumulation of insulin receptor (INSR). While insulin blocked basal levels of PINK‐1‐mediated mitophagy in bronchial epithelial cells, mitochondrial trafficking of INSR was not detectable. We further show that in corneal epithelia, INSR interacts with the voltage‐dependent anion channel‐1 (VDAC1) in mitochondria and that INSR knockdown triggers robust mitochondrial fragmentation, alterations in mitochondrial polarization, and blocks the induction of PINK‐1‐mediated mitophagy. Collectively, these data demonstrate that INSR interacts with VDAC1 to mediate mitochondrial stability. We also demonstrate unique interactions between VDAC1 and other receptor tyrosine kinases, indicating a novel role for this family of receptors in mitochondria.

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“…In H4 cells, transfected with the mutated T330A GSK-3β, Pin1 was not able to bind and inhibit GSK-3β activity, thereby increasing the level of toxic amyloidogenic APP processing [73]. It has been speculated that the initial steps of tau phosphorylation have a neuronal protective role against the toxicity exerted by Aβ deposits [74,75], but they become detrimental when the excessive phosphorylation of tau causes the accumulation of NFTs [75]. Thus, the fine regulation of this post-translational modification is central in the pathogenesis of AD.…”

Section: Role Of Pin1 In Neurodegenerative Disordersmentioning

confidence: 99%

“…They speculated a new type of diabetes that they named “type 3 diabetes” [16,17]. T3D would be characteristic of AD patients, affecting glucose metabolism exclusively in the brain or more broadly [75]. The reduced expression of insulin and IGF-1 receptors might explain the insulin resistance registered in the AD brain, thereby affecting negatively the insulin transduction pathway.…”

Section: Pin1 Links Brain Impaired Glucose Metabolism and Neuronalmentioning

confidence: 99%

See 1 more Smart Citation

Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?

Bianchi

Manco

2018

IJMS

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Prolyl isomerases (Peptidylprolyl isomerase, PPIases) are enzymes that catalyze the isomerization between the cis/trans Pro conformations. Three subclasses belong to the class: FKBP (FK506 binding protein family), Cyclophilin and Parvulin family (Pin1 and Par14). Among Prolyl isomerases, Pin1 presents as distinctive feature, the ability of binding to the motif pSer/pThr-Pro that is phosphorylated by kinases. Modulation of Pin1 is implicated in cellular processes such as mitosis, differentiation and metabolism: The enzyme is dysregulated in many diverse pathological conditions, i.e., cancer progression, neurodegenerative (i.e., Alzheimer’s diseases, AD) and metabolic disorders (i.e., type 2 diabetes, T2D). Indeed, Pin1 KO mice develop a complex phenotype of premature aging, cognitive impairment in elderly mice and neuronal degeneration resembling that of the AD in humans. In addition, since the molecule modulates glucose homeostasis in the brain and peripherally, Pin1 KO mice are resistant to diet-induced obesity, insulin resistance, peripheral glucose intolerance and diabetic vascular dysfunction. In this review, we revise first critically the role of Pin1 in neuronal development and differentiation and then focus on the in vivo studies that demonstrate its pivotal role in neurodegenerative processes and glucose homeostasis. We discuss evidence that enables us to speculate about the role of Pin1 as molecular link in the pathogenesis of type 3 diabetes i.e., the clinical association of dementia/AD and T2D.

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Diabetes mellitus and Alzheimer’s disease: GSK-3β as a potential link

Cited by 232 publications

References 122 publications

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Insulin receptor preserves mitochondrial function by binding VDAC1 in insulin insensitive mucosal epithelial cells

Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?

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