The beta secretase BACE1 regulates the expression of insulin receptor in the liver

Meakin, Paul J.; Mezzapesa, Anna; Benabou, Eva; Haas, Mary E.; Bonardo, Bernadette; Grino, Michel; Brunel, Jean‐Michel; Desbois-Mouthon, Christèle; Biddinger, Sudha B.; Govers, Roland; Ashford, M. L. J.; Peiretti, Franck

doi:10.1038/s41467-018-03755-2

Cited by 54 publications

(91 citation statements)

References 66 publications

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“…VAD is known to play a critical pathophysiological role in clinical metabolic syndrome and type 2 diabetes. Interestingly, a recent study reported that the amount of biologically insulin receptor active is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner 22 . They demonstrated that BACE1 (an aspartyl protease, not serine protease) regulated the cleavage of insulin receptor and insulin signaling mainly in db/db mouse livers 22 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance

Kuo

Chen

Lin

et al. 2020

Sci Rep

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Recent evidence suggests that enhanced protease-mediated inflammation may promote insulin resistance and result in diabetes. this study tested the hypothesis that serine protease plays a pivotal role in type 2 diabetes, and inhibition of serine protease activity prevents hyperglycemia in diabetic animals by modulating insulin signaling pathway. We conducted a single-center, cross-sectional study with 30 healthy controls and 57 patients with type 2 diabetes to compare plasma protease activities and inflammation marker between groups. Correlations of plasma total and serine protease activities with variables were calculated. in an in-vivo study, LDLR −/− mice were divided into normal chow diet, high-fat diet (HFD), and HFD with selective serine protease inhibition groups to examine the differences of obesity, blood glucose level, insulin resistance and serine protease activity among groups. Compared with controls, diabetic patients had significantly increased plasma total protease, serine protease activities, and also elevated inflammatory cytokines. Plasma serine protease activity was positively correlated with body mass index, hemoglobin A1c, homeostasis model assessment-insulin resistance index (HOMA-IR), tumor necrosis factor-α, and negatively with adiponectin concentration. In the animal study, administration of HFD progressively increased body weight, fasting glucose level, HOMA-IR, and upregulated serine protease activity. Furthermore, in-vivo serine protease inhibition significantly suppressed systemic inflammation, reduced fasting glucose level, and improved insulin resistance, and these effects probably mediated by modulating insulin receptor and cytokine expression in visceral adipose tissue. Our findings support the serine protease may play an important role in type 2 diabetes and suggest a rationale for a therapeutic strategy targeting serine protease for clinical prevention of type 2 diabetes. Metabolic syndrome is a global public health issue of increasing magnitude. Obesity, insulin resistance, proinflammatory and prothrombotic states, atherogenic dyslipidemia, and higher blood pressure are risk factors for metabolic syndrome 1. Among these factors, obesity-induced insulin resistance is a major contributor to the

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Section: Discussionmentioning

confidence: 99%

Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance

Kuo

Chen

Lin

et al. 2020

Sci Rep

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Section: Inhibition Of α-Glucosidase Ptp1b and β-Secretase And Antiomentioning

confidence: 99%

“…During diabetes, β-secretase-dependent cleavage of IR is increased and the amount of IR in the liver is reduced [11]. It was observed that infusion of a β-secretase inhibitor leads to partial restoration of the liver IR [11,12]. Aminostyrylbenzofurans, for example, have previously been found to display better inhibitory activities (IC 50 = 0.07-0.53 µM) than curcumin with an IC 5o value of 0.80 µM [12].…”

Section: Inhibition Of α-Glucosidase Ptp1b and β-Secretase And Antiomentioning

confidence: 99%

“…α-Glucosidase and PTP1B are the key targets to treat diabetes and obesity [9] and compounds with dual inhibitory activity against these enzymes exhibit synergistic effects to prevent hyperglycaemia, in turn, effectively improve insulin sensitization [10]. In vivo studies have demonstrated that β-secretase (BACE-1) regulates the amount of IR and insulin signalling in the liver making inhibitors of this enzyme, to enhance insulin signalling during diabetes [11,12]. Likewise, oxidative stress is implicated in the early stages and progression of T2D due to disruption of the pro-oxidant/antioxidant balance leading to the development of insulin resistance [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, In Vitro Evaluation and Molecular Docking of the 5-Acetyl-2-aryl-6-hydroxybenzo[b]furans against Multiple Targets Linked to Type 2 Diabetes

et al. 2020

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The 5-acetyl-2-aryl-6-hydroxybenzo[b]furans 2a-h have been evaluated through in vitro enzymatic assay against targets which are linked to type 2 diabetes (T2D), namely, α-glucosidase, protein tyrosine phosphatase 1B (PTP1B) and β-secretase. These compounds have also been evaluated for antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging method. The most active compounds against α-glucosidase and/or PTP1B, namely, 4-fluorophenyl 2c, 4-methoxyphenyl 2g and 3,5-dimethoxyphenyl substituted 2h derivatives were also evaluated for potential anti-inflammatory properties against cyclooxygenase-2 activity. The Lineweaver-Burk and Dixon plots were used to determine the type of inhibition on compounds 2c and 2h against α-glucosidase and PTP1B receptors. The interactions were investigated in modelled complexes against α-glucosidase and PTP1B via molecular docking.

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“…It is not only the altered protein levels and altered volume of regions in brain but also the expression and activity of enzymes which regulate the pathology of diabetes associated AD. The β secretase enzyme which is involved in cleavage of amyloid precursor protein (APP), and in the formation of Aβ plaque; is also involved in cleavage of insulin receptor which strengthens the link between Alzheimer's and diabetes (Meakin et al, ). Also, soluble APP β (sAPPβ) which is a product of enzyme β secretase is a major determinant in case of insulin resistance (Botteri et al, ).…”

Section: Tie‐ups Between Diabetes Mellitus and Alzheimer'smentioning

confidence: 99%

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

Jash

Gondaliya

Kirave

et al. 2019

Drug Development Research

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Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age‐related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie‐ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro‐RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same.

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The beta secretase BACE1 regulates the expression of insulin receptor in the liver

Cited by 54 publications

References 66 publications

Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance

Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance

Synthesis, In Vitro Evaluation and Molecular Docking of the 5-Acetyl-2-aryl-6-hydroxybenzo[b]furans against Multiple Targets Linked to Type 2 Diabetes

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

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