Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer’s disease

Background The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown. Methods We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms. Results We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'. Conclusions Collectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.

Phospholipase C-related catalytically inactive protein acts as a positive regulator for insulin signalling in adipocytes

Insulin signalling is tightly controlled by various factors, but the exact molecular mechanism remains incompletely understood. We previously reported that phospholipase C-related but catalytically inactive protein (PRIP) interacts with Akt, the central molecule in insulin signalling. Here, we investigated whether PRIP is involved in the regulation of insulin signalling in adipocytes. We found that insulin signalling including insulin-stimulated phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Akt, and glucose uptake, were impaired in adipocytes from PRIP-knockout (KO) mice compared with those from wild-type (WT) mice. The amount of IR expressed on the cell-surface was decreased in PRIP-KO adipocytes. Immunoprecipitation assay showed that PRIP interacted with IR. The reduced cell-surface IR in PRIP-KO adipocytes was comparable with that in WT cells when Rab5 expression was silenced using specific siRNA. In contrast, the dephosphorylation of IRS-1 at serine residues, some of which were reported to be involved in the internalisation of IR, was impaired in cells from PRIP-KO mice. These results suggest that PRIP facilitates insulin signalling by modulating the internalisation of IR in adipocytes.

Hypoglycemic and Hepatoprotective Effects of Dried and Rice-Fried Psidium guajava Leaves in Diabetic Rats

Psidium guajava leaves (PGL) have been long used as an adjuvant therapy for diabetics. The present study evaluated the in vivo hypoglycemic and hepatoprotective effects of dried and the rice-fried PGL decoctions (PGLD and RPGLD). Our results indicated that both PGLD and RPGLD could significantly decrease the contents of fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) in diabetic rats. Compared with the HFD/STZ (high-fat diet with streptozotocin) group, the PGLD and RPGLD-treated diabetic rats showed different degrees of recovery against the liver pathological changes. The upregulated expressions of glucokinase (GK), glucose transporter 2 (GLUT2), insulin growth factor-1 (IGF-1), insulin receptor substrate-1 (IRS-1), and insulin receptor substrate-2 (IRS-2) in PGLD and RPGLD-treated groups were observed. In general, RPGLD exhibited a much better antidiabetic effect than PGLD, which was further verified by the comprehensive evaluation with the TOPSIS method. Besides, HPLC (high-performance liquid chromatography) and UPLC-MS/MS (ultra-performance liquid chromatography-tandem mass spectrometry) analyses revealed that the contents of the primary constituents (ellagic acid, hyperoside, isoquercitroside, reynoutrin, guaijaverin, auicularin, and quercetin) in RPGLD increased obviously compared with PGLD. These results shed new light on the antidiabetic potential and mechanism of PGL, as well as the “higher efficacy” of the rice-fried processing method in traditional Chinese medicine.

Effects of COVID-19, diabetes mellitus, and cardiovascular diseases on insulin receptor substrate-1 amount in the blood plasma of patients

Insulin receptor substrate (IRS) is a key adapter protein mediating effects of insulin and insulin-like growth factors (IGF) in cells. IRS-1 is a member of the insulin receptor substrate family, which is associated with tumor initiation and progression. The aim of the study is to determine the level of IRS-1 in the blood of patients (n = 81) with diabetes mellitus and COVID-19. IRS-1 was determined with enzyme-linked immunosorbent assay (ELISA) (Elabscience, USA). The measurements were performed at an optical wavelength of 450 nm. The level of IRS-1 in the blood plasma of patients with COVID-19 was much (from 3.5 to more than 6 times) higher than that in the blood of healthy people. The IRS-1 amounts in COVID-19 patients with diabetes and diabetes + CVD were significantly higher than in patients with COVID-19 without concomitant diseases. The level of IRS-1 in blood plasma may be one of the promising markers of COVID-19.

PCOS Modulatory Activity of Tinospora cordifolia leaves – An Insilico Approach

The polycystic ovarian syndrome affects women of all age groupsis mainly due to hyperinsulinemia and hyperandrogenism.The insulin action in the ovaries is mediated by binding to its receptor namely IRS (Insulin receptor substrate).The present investigation is undertaken to select a suitable antagonistic ligand from the bioactive phyto components of Tinosporacordifolialeaves to inhibit IRS1 and IRS 2 receptors to prevent the binding of insulin and subsequent hyperandrogenism.The phyto ligands used for the study were obtained from the previous literature and the IRS1 and IRS 2 receptor protein structure were retrieved from PDB (protein Data bank). Using the Corina 3D converter the ligand 3D structures were obtained. Molecular docking analysis was performed through Patch dock server to select a suitable ligand based on docking score for the IRS1 and IRS 2 receptor protein.Three ligands namely Berberine, Rumphioside I and Syringin showed better docking score among the ligand selectedand their inhibitory activity were analysed by intermolecular interactions using “LIGPLOT” analysis. It can be concluded that these three ligands can be used for the successful treatment of PCOS after proper preclinical and clinical studies.

Adipokines in Insulin Resistance: Current Updates

Obesity is a chronic metabolic disease that affects both the pediatric and adult populations. Adipose tissue acts as an endocrine organ which secretes various adipokines involved in fat mass regulation and energy balance via modulating the metabolic signalling pathways. Altered secretion of adipokines promotes multiple complications, including insulin resistance. The primary mechanism of action that underlines the involvement of adipokines in the development of insulin resistance includes phosphorylation/de-phosphorylation of insulin receptor substrate-1 (IRS-1) facilitate by other signalling molecules like a suppressor of cytokine signalling 1 (SOCS-1). Adipokines mediated insulin resistance further contribute to the development of atherosclerosis, dyslipidemia, fatty liver disease, cancer etc. Thus, this review provides recent updates on the role of resistin, lipocalin-2, RBP-4, chemerin, TNF-alpha and IL-6 adipokines in the progression of insulin resistance.