Regulator Of Insulin Signaling Pathway Research Articles

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

<p>Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. </p><p> Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. </p><p> This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.</p>

Potential Effect of Chloroquine in Modulating Hyperglycemia and PTEN Receptor Linked Dyslipidemia on Alloxan-induced Diabetic Mice

Background: Diabetes mellitus is a life-threatening disease associated with worsening of glycemic control, progressive metabolic dysfunctions and disruption of the Phosphatase and Tensin Homolog (PTEN) receptor. Purpose: To evaluate the effect of chloroquine on blood glucose level and lipid profile of alloxan-induced diabetic mice and to observe its interaction with PTEN, a negative regulator of insulin signaling pathway. Methodology: Thirty mice were used for the experiment. A group (n = 5) was kept as healthy control while the others were pre-treated with 140 mg/kg of alloxan monohydrate in distilled water. The alloxan-induced diabetic mice were randomly divided into four groups: diabetic model control group, 60 mg/kg chloroquine, 120 mg/kg chloroquine, and 10 mg/kg glibenclamide treatment groups respectively. Treatment was done once daily for seven days and the blood glucose level was investigated acutely and then daily throughout the experimental period. A molecular docking study was also conducted to evaluate the interaction of chloroquine with PTEN using PYRX software, while an automated COBAS C 311 machine was used to analyze the lipid profile after the treatment period. Results: Oral administration of chloroquine gradually and significantly lowered the raised blood glucose level in a time- and dose-dependent manner. A repeated study with 120 mg/kg of chloroquine revealed a decline in blood sugar from 221.5 ± 3.6 on day 1 to 85.5 ± 2.4 on day 7 in comparison to glibenclamide, whose sugar level was reduced to 75.5 ± 3.7 at the end of day 7. The docking study revealed a non-competitive inhibition with an inhibition score of -6.1 in comparison to metformin, which had a score of -4.4, and glibenclamide, which had a score of -9.0. This interaction resulted in a conformational change of the receptor, hence, enhancing glucose uptake and reducing the raised hyperglycemia. Treatment with chloroquine was also observed to reduce the total cholesterol and triglyceride levels from 162 in the model group to 144 and 141 to 116 mmol/L, respectively. The levels of low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein (VLDL) following treatment with chloroquine were not statistically different from the non-diabetic healthy mice. These values were very similar to those obtained with glibenclamide-treated diabetic mice. Conclusion: From the results, chloroquine possesses potent antidiabetic properties and can improve dyslipidemia imposed by hyperglycemia probably owing to its inhibition of PTEN, a negative regulator of insulin resistance.

Development, biological evaluation, and molecular modelling of some benzene-sulfonamide derivatives as protein tyrosine phosphatase-1B inhibitors for managing diabetes mellitus and associated metabolic disorders.

Exploring new inhibitors with good bioavailability and high selectivity for managing type 2 diabetes mellitus (T2DM) and its associated complications is a major challenge for research, academia, and the pharmaceutical industry. Protein tyrosine phosphatase-1B (PTP1B) arose as an important negative regulator in insulin signaling pathways associated with metabolic disorders, including T2DM and obesity. Novel neutral compounds with a benzene-sulfonamide scaffold were designed and synthesized based on structural- and ligand-based drug design strategies for fragment growth. Promising hits against PTP1B were identified through in vitro enzymology inhibition assay. Mechanistic aspects of the compound's different inhibition activities were rigorously investigated through molecular docking coupled with explicit dynamics simulations. Four identified hits, 3c, 8, 10a, and 11, with sub-micromolar PTP-1B IC50 and significant predicted pharmacokinetic and pharmacodynamic parameters, were further biologically evaluated for their anti-diabetic, anti-obesity, anti-inflammatory, and anti-oxidant effects in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2DM rat model. All these hit compounds exhibited a significant anti-diabetic and anti-obesity effect and a significant efficacy in reducing oxidative stress and increasing anti-oxidant enzymes while reducing inflammatory markers. Improving compound potency was further highlighted by improving the pharmacokinetic profile of the most active compound, 10a, through nano formulation. Compound 10a nano formulation showed the most promising anti-diabetic and anti-obesity effects and a remarkable histopathological improvement in all organs studied.

Three-state dynamics of zinc(II) complexes yielding significant antidiabetic targets

Protein Tyrosine Phosphatase 1B (PTP1B), being negative regulator of insulin signaling pathways is considered as potential medicinal target. Selective and targeted inhibitors for PTP1B can impact the therapeutic options available to cure chronic illness such as diabetes. Significant research evidence including computational studies on the role of Zn2+ in binding and inhibiting the catalytic pocket have been reported along with experimental exploration of zinc(II) complexes as potent inhibitors of the enzyme. The current study has employed advanced computational methods to explore the binding and conformational orientation of zinc(II) complexes in the active site of apoenzyme, phosphoenzyme, and TSA 2 of PTP1B. Metal ion modeling was performed for zinc metal center (Zn-OOOO) utilizing a Python based Metal Center Parameter Builder (MCPB.py). The findings of the study suggest that zinc(II) complex binds to structurally and functionally important residues in open and closed conformation as well as in the phosphorylated state of the enzyme. It was observed that when the catalytic cysteine is phosphorylated in a closed conformation, the zinc(II) complex forms significant interactions with PHE182, VAL184, GLY183, and PRO180 while pushing away Q-loop GLN262 which is crucial for the hydrolysis of phosphoenzyme. Subsequently, the reported inhibitor has also demonstrated its potential to function as allosteric modulator of the enzyme occupying catalytic WPD loop residues. The study uncovers putative binding sites of zinc-containing drugs and gives insight into the size and design of such compounds which keeps them accessible and anchored in the vicinity of active site residues. Reported inhibitor offers enhanced selectivity and inhibition in all three states of the enzyme in contrast to zinc ions which can only impede enzyme in the phosphorylated state. In addition to this, investigation of ASP265→GLU265 mutation reveals the role of GLU265 in affecting the flexibility of WPD loop residues highlighting it as loss-of-function mutation. Our results hints towards a metallodrug approach that builds on the research evidence of inhibition effects of Zn2+ in the binding pocket of PTP1B. The findings presented are noteworthy, not just due to their significant relevance for clinical application, but also for the design and synthesis of novel zinc(II) complexes.

Integration of microRNA and mRNA analyses depicts the potential roles of Momordica charantia saponin administration in insulin resistance of juvenile common carp (Cyprinus carpio) fed with a high-starch diet.

Background: The regulation of target gene mRNA mediated by microRNA may play an important role in glucose metabolism in fish. Previous research findings of our research group revealed that Momordica charantia saponin (MS) administration in a high-starch diet could improve insulin resistance of common carp through renovating insulin signaling pathways, whose fundamental mechanisms have remained unknown by far. To reveal this potential mechanism, we aimed to investigate the difference in miRNA and mRNA expression profiles between common carp fed with high-starch diets containing MS (HS_MS1 and HS_MS2) and common carp fed with high-starch (HS) diets. Results: Through miRNA deep-sequencing, 10 significantly differentially expressed miRNAs in HC and HS_MS1, including one upregulated and nine downregulated miRNAs, were identified, whereas 10 significantly differentially expressed miRNAs in HC and HS_MS2, including four upregulated and six downregulated miRNAs, were identified. These miRNAs may not only be involved in the regulation of insulin signaling pathways and insulin resistance in common carp but also be the markers for liver insulin resistance in MS therapy for the remission of insulin resistance. This study identified 10 potential known miRNAs, namely, ccr-miR-10b, ccr-miR-122, ccr-miR-143, ccr-miR-146a, ccr-miR-155, ccr-miR-16c, ccr-miR-200a, ccr-miR-29a, ccr-miR-34, and ccr-miR-375, as candidates participating in modulating the liver insulin resistance. According to the biopathway enrichment analysis of the 252 target genes using the KEGG classical biopathway database, the relative expression levels of gsk3bb, pik3r1, and pik3r3b were analyzed using RNA-seq. Compared to the HC group, a significant decrease in the relative expression levels of pik3r1 and pik3r3b was observed in HS_MS1 and HS_MS2 groups (p < 0.05). This study raised a presumption of the presence of ccr-miR-29a targeting pik3r1 or ccr-miR-143 targeting pik3r3 playing likely roles in Momordica charantia saponins remitting the liver insulin resistance. Conclusion: The findings will further deepen the understanding of the carbohydrate metabolism of common carp and provide an important scientific basis for the application of Momordica saponins as functional nutrients to alleviate insulin resistance of fish in fish culture.

PTP1B Inhibitor Claramine Rescues Diabetes-Induced Spatial Learning and Memory Impairment in Mice.

Accumulating clinical and epidemiological studies indicate that learning and memory impairment is more prevalent among people with diabetes mellitus (DM). PTP1B is a member of protein tyrosine phosphatase family and participates in a variety of pathophysiological effects including inflammatory, insulin signaling pathway, and learning and memory. This study was aimed to investigate the effects of CA, a specific inhibitor of PTP1B, on spatial learning and memory impairment in diabetic mice caused by high-fat diet and injection of streptozotocin. We found that the protein expressions of PTP1B increased in hippocampal CA1, CA3, and PFC regions of diabetic mice. Network pharmacology results showed that PTP1B might be one of the key targets between diabetes and cognitive dysfunction, and CA might alleviate DM-induced cognitive dysfunction. Animal experiments showed that CA ameliorated DM-induced spatial learning and memory impairment, and improved glucose and lipid metabolic disorders. Moreover, administration of CA alleviated hippocampal structure damage and enhanced the expressions of synaptic proteins, including PSD-95, SYN-1, and SYP in diabetic mice. Furthermore, CA treatment not only significantly down-regulated the expressions of PTP1B and NLRP3 inflammatory related proteins (NLRP3, ASC, Caspase-1, COX-2, IL-1β, and TNF-α), but also significantly up-regulated the expressions of insulin signaling pathway-related proteins (p-IRS1, p-PI3K, p-AKT, and p-GSK-3β) in diabetic mice. Taken together, these results suggested that PTP1B might be a targeted strategy to rescue learning and memory deficits in DM, possibly through inhibition of NLRP3 inflammasome and regulation of insulin signaling pathway.

Differential Expression of Suppressor of Cytokine Signaling and Interferon Gamma in Lean and Obese Patients with Type 2 Diabetes Mellitus.

The model of obesity-induced insulin resistance has long been used to explain the development of type 2 diabetes mellitus (T2DM) in obese individuals (body mass index (BMI) > 25 kg/m2), but this model failed to explain the development of the disease in lean individuals (BMI < 18.5 kg/m2). Defects in the insulin signaling pathway have been postulated to play a role in these patients, particularly in suppressors of cytokine signaling (SOCS) proteins, which are involved in the downregulation of insulin transduction. The expression of SOCS is also known to be induced by cytokines such as interferon gamma (IFN-γ). It is still not clear whether these pathways operate differently in lean versus obese patients with T2DM. Therefore, this pilot study was designed to study the expression of SOCS1, SOCS3, and IFN-γ in lean and obese patients with T2DM. The levels of IFN-γ in serum and the messenger RNA (mRNA) expression of SOCS (SOCS1 and SOCS3) and IFN-γ genes in whole blood in lean and obese patients with T2DM. Sixty newly diagnosed T2DM patients (not on any pharmacotherapy) were enrolled and divided into 2 groups of lean (BMI < 18.5 kg/m2) and obese (BMI > 25 kg/m2) patients (n = 30 per group). Serum IFN-γ was measured by enzyme-linked immunosorbent assay (ELISA), and mRNA expression of IFN-γ, SOCS1, and SOCS3 was measured by real-time polymerase chain reaction (PCR) using the ∆∆ Ct method. Serum IFN-γ levels were 10.83 ± 5.81 pg/mL in the lean group and 9.35 ± 5.14 pg/mL in the obese group (P = 0.02). Fasting serum insulin levels were 16.07 ± 8.39 µIU/mL in the lean group and 27.11 ± 4 .91 µIU/mL in the obese group (P = 0.001). There was a 3.16-fold increase in mRNA expression of IFN-γ and a 1.3-fold increase in mRNA expression of SOCS1 in the lean group compared to the obese group. mRNA expression of SOCS3 was similar in both groups. The level of IFN-γ increased at both transcriptional and translational levels, and mRNA expression of SOCS1 was higher in the lean group than in the obese group. The SOCS protein is a known negative regulator in insulin signaling pathways. Thus, our findings and available scientific literature suggest that IFN-γ might impair the insulin signaling pathway to a greater extent in lean patients than in obese patients via induction of SOCS1. This signaling pathway could be a major contributing factor to hyperglycemia in lean patients with T2DM compared with obese counterparts. This suggests that different therapeutic approaches to these groups might be of greater benefit in the treatment of T2DM.

An Overview of Phytotherapy Used in the Management of Type II Diabetes.

Diabetes mellitus is related to unconstrained high blood sugar and linked with long-term impairment, dysfunction and failure of several organs. Since 1980, the global frequency of diabetes has almost doubled in the adult population. In very rare cases due to poor prevention and management programs, diabetes causes worsening of health and reduced lifespan of the world population, thus impacting on the world's economy. Supplements, however, help in the improvement of nutritional deficiencies. Phytotherapeutics has the advantage of being economical and easy to access with marginal side effects. So, it is a preferred candidate for the management of diabetes. Currently, a multitude of pharmaceuticals are used which are obtained from natural sources having medicinal properties. The mechanistic approaches are based on the regulation of insulin signaling pathways, translocation of GLUT-4 receptors and/or activation of PPAR γ. These natural compounds include numerous flavonoids which help in preventing glucose absorption by preventing the absorption of α-amylase and α-glucosidase. But to validate the efficacy and safety profile of these compounds, detailed validatory clinical studies are required. This review majorly focuses on the mechanistic approaches of various naturally derived compounds relevant for the condition of Diabetes Mellitus.

Design, synthesis, kinetic, molecular dynamics, and hypoglycemic effect characterization of new and potential selective benzimidazole derivatives as Protein Tyrosine Phosphatase 1B inhibitors

Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling pathway and has been validated as a therapeutic target for type 2 diabetes. A wide variety of scaffolds have been included in the structure of PTP1B inhibitors, one of them is the benzimidazole nucleus. Here, we report the design and synthesis of a new series of di- and tri- substituted benzimidazole derivatives including their kinetic and structural characterization as PTP1B inhibitors and hypoglycemic activity. Results show that compounds 43, 44, 45, and 46 are complete mixed type inhibitors with a Ki of 12.6 μM for the most potent (46). SAR type analysis indicates that a chloro substituent at position 6(5), a β-naphthyloxy at position 5(6), and a p-benzoic acid attached to the linker 2-thioacetamido at position 2 of the benzimidazole nucleus, was the best combination for PTP1B inhibition and hypoglycemic activity. In addition, molecular dynamics studies suggest that these compounds could be potential selective inhibitors from other PTPs such as its closest homologous TCPTP, SHP-1, SHP-2 and CDC25B. Therefore, the compounds reported here are good hits that provide structural, kinetic, and biological information that can be used to develop novel and selective PTP1B inhibitors based on benzimidazole scaffold.

63Identification of insulin signaling pathway-related circulating circRNAs as biomarkers of type 2 diabetes

Abstract Background The underlying molecular mechanism of type 2 diabetes (T2D) is that abnormalities occur in the insulin signaling pathway. Circular RNAs (circRNAs) are involved in the development of diseases by regulating gene expression and become promising novel biomarkers for diseases. This study systematically screened and validated the insulin signaling pathway-related circulating circRNAs in T2D. Methods circRNA expression profiles were screened by microarray between five T2D patients and five healthy controls. The candidate circRNAs were then selected from those differently expressed circRNAs whose potential target miRNAs are involved in regulating key genes in the isulin signaling pathway. The expression of candidate circRNAs were validated in a second sample with 20 T2D cases and 20 controls by real-time quantitative PCR. Eventually, the association between circRNAs and T2D and their clinical significance were further confirmed in a large independent sample, including 103 T2D cases, 93 controls and 80 individuals with impaired fasting glucose (IFG) as prediabetes cases. Results Four circRNAs including hsa_circ_0063425, hsa_circ_0056891, hsa_circ_0078166 and hsa_circ_0071336 were validated by RT-qPCR. Low expressed circ_0063425, hsa_circ_0056891 and hsa_circ_0071336 were independent predictor of T2D, IFG and insulin resistance. The three-circRNA panel had a high accuracy for diagnosing T2D and IFG, especially when BMI was integrated. Bioinformatics Gene Ontology and pathway analysis confirmed that these circRNAs involve in the regulation of insulin signaling pathway. Conclusion circ_0063425, hsa_circ_0056891 and hsa_circ_0071336 are valuable circulating biomarkers for T2D, and may involve in regulating insulin signaling pathway. Key messages Insulin signaling pathway-related circulating circRNAs were identification as biomarkers of T2D.

Role of protein tyrosine phosphatase 1B inhibitor in central insulin resistance and associated cognitive deficits

BackgroundProtein tyrosine phosphatase 1B (PTP1B) inhibitors are potential candidates for the treatment of peripheral insulin resistance and diabetes mellitus. Similar to peripheral action within the brain also, PTP1B activation impairs insulin signaling pathways. Activation of PTP1B in brain also accentuates neuroinflammation, oxidative stress and decreases neurotrophic factors in various brain dysfunctions including cognitive decline. ObjectivesThe main objective of our study was to elucidate the role of alendronate, a potent PTP1B inhibitor (blood brain barrier crossing bisphosphonate) in central insulin resistance and associated memory deficits. MethodologyTo induce central insulin resistance, streptozotocin (3 mg/kg) intracerebroventricular (ICV) was administered in two alternate days (1st and 3rd). After 21 days, memory was assessed via using the passive avoidance and Morris water maze paradigm. At the end of behavioral studies, animals were sacrificed to assess a variety of biochemical and molecular parameters in the hippocampus and cerebral cortex region of the brain. Treatment drug alendronate (3 mg/kg/day, p.o) and standard drug donepezil (3 mg/kg/i.p.) were administered from the 3rd day of STZ administration till the end of the study. Inhibition of PTP1B activates phosphoinsotide-3 kinase (PI3 K) (down-stream regulator of insulin signaling pathway).Thus, to illuminate the mechanism of action of alendronate, PI3 K inhibitor, wortmannin was administered in presence of alendronate in one group. ResultsAdministration of alendronate to ICV streprozotocin treated rats resulted in modulation of the insulin signaling pathway and associated behavioral, biochemical and molecular changes in central insulin resistance. However, the protective effect of alendronate was entirely vanished when it was administered in the presence of wortmannin. ConclusionAlendronate can be an important treatment strategy in central insulin signaling pathway dysfunction and associated cognitive deficits. Protective effect of alendronate is via modulation of PI3-K/Akt signaling pathway.

MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle

In type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 -/- mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.

New insight into the role of isorhamnetin as a regulator of insulin signaling pathway in type 2 diabetes mellitus rat model: Molecular and computational approach

We intended to examine the molecular mechanism of action of isorhamnetin (IHN) to regulate the pathway of insulin signaling. Molecular analysis, immunofluorescence, and histopathological examination were used to assess the anti-hyperglycemic and insulin resistance lowering effects of IHN in streptozotocin /high fat diet-induced type 2 diabetes using Wistar rats. At the microscopic level, treatment with IHN resulted in the restoration of myofibrils uniform arrangement and adipose tissue normal architecture. At the molecular level, treatment with IHN at three different doses showed a significant decrease in m-TOR, IGF1-R & LncRNA-RP11-773H22.4. expression and it up-regulated the expression of AKT2 mRNA, miR-1, and miR-3163 in both skeletal muscle and adipose tissue. At the protein level, IHN treated group showed a discrete spread with a moderate faint expression of m-TOR in skeletal muscles as well as adipose tissues. We concluded that IHN could be used in the in ameliorating insulin resistance associated with type 2 diabetes mellitus.

The Role of JNk Signaling Pathway in Obesity-Driven Insulin Resistance.

Obesity is not only closely related to insulin resistance but is one of the main factors leading to the formation of Type 2 Diabetes (T2D) too. The c-Jun N-terminal kinase (JNK) family is a member of the mitogen-activated protein kinase (MAPK) superfamily. JNK is also one of the most investigated signal transducers in obesity and insulin resistance. JNK-centric JNK signaling pathway can be activated by growth factors, cytokines, stress responses, and other factors. Many researches have identified that the activated phosphorylation JNK negatively regulates insulin signaling pathway in insulin resistance which can be simultaneously regulated by multiple signaling pathways related to the JNK signaling pathway. In this review, we provide an overview of the composition of the JNK signaling pathway, its regulation of insulin signaling pathway, and the relationship between the JNK signaling pathway and other pathways in insulin resistance.

Identification of protein tyrosine phosphatase 1B (PTP1B) inhibitors through De Novo Evoluton, synthesis, biological evaluation and molecular dynamics simulation

Protein tyrosine phosphatase 1B (PTP1B) is a widely expressed 50 kDa enzyme and the first intracellular PTP to be purified from human placental tissue. It has been proved that protein tyrosine phosphatase 1B played a significant role in the negative regulation of insulin signaling pathway and overexpression of PTP1B could lead to the decrease of insulin resistance. Therefore PTP1B has emerged as a novel promising therapeutic target for the treatment of type-2 diabetes mellitus. Computer aided drug design (CADD), chemical synthesis and biological activity assay resulted in the identification of a novel potent PTP1B inhibitor, compound 1a, which shared an IC50 value of 4.46 μM. Finally, the analysis of molecular dynamics simulation provided the theoretical basis for favorable activity of compound 1a.

Screening and Validating Insulin Signaling Pathway-Related Circulating circRNAs in Type 2 Diabetes

Background: The underlying molecular mechanism of type 2 diabetes (T2D) and insulin resistance is that abnormalities occur in the complex insulin signaling pathway. Circular RNAs (circRNAs) are involved in the development of diseases by regulating gene expression and become promising novel biomarkers for diseases. This study systematically screened and validated the insulin signaling pathway-related circulating circRNAs, which are associated with T2D. Methods: circRNA expression profiles were screened by microarray between five T2D patients and five healthy controls. Insulin signaling pathway-related circRNAs were then selected from those differently expressed circRNAs whose potential target miRNAs are involved in regulating key genes in the pathway. The expression of candidate circRNAs were validated in a second sample with 30 T2D cases and 30 controls by real-time quantitative polymerase chain reaction (RT-qPCR). Eventually, the association between circRNAs and T2D and their clinical significance were further confirmed in a large independent sample, including 103 T2D cases, 93 controls and 80 individuals with impaired fasting glucose (IFG) as prediabetes cases. Results: Four circRNAs including hsa_circ_0063425, hsa_circ_0056891, hsa_circ_0078166 and hsa_circ_0071336 were validated by RT-qPCR. Low expressed circ_0063425, hsa_circ_0056891 and hsa_circ_0071336 were independent predictor of T2D, IFG and insulin resistance. The three-circRNA panel had a high accuracy for diagnosing T2D and IFG in the training set and testing set, especially when body mass index (BMI) was integrated. Bioinformatics Gene Ontology and pathway analysis confirmed that these circRNAs involve in the regulation of insulin signaling pathway. Conclusion: circ_0063425, hsa_circ_0056891 and hsa_circ_0071336 are valuable circulating biomarkers for T2D, and may involve in regulating insulin signaling pathway. Funding Statement: This study was supported by the National Natural Science Foundation (81773511, 81573214), the Beijing Municipal Natural Science Foundation (7162020). Declaration of Interests: The authors state: None. Ethics Approval Statement: This study was approved by the university ethical committee and written informed consent was obtained from each participant before the investigation.

Polifenoller, Mikrobiyota ve Diyabet

Mikrobiyota; konak üzerinde/içinde yaşayan mikroorganizma topluluğu olarak tanımlanmaktadır. Son yıllarda bağırsak mikrobiyotasının fizyolojik etkileri en çeşitli ve fazla bakteri kolonizasyonuna sahip bölge olması nedeni ile oldukça ilgi görmektedir. Bağırsak mikrobiyotasındaki çeşitlilik ve denge; diyabet ve obezite gibi tüm dünyada epidemi boyutuna ulaşmış hastalıkların patogenizinde yer almaktadır. Doğum şekli, antibiyotik kullanımı, yaşam tarzı ve beslenme alışkanlıkları; mikrobiyota kompozisyonunu etkileyen faktörler arasındadır. Beslenme alışkanlıkları mikrobiyota kompozisyonunu etkileyen en önemli değiştirilebilir risk faktörü beslenme alışkanlıklarıdır. Yüksek posalı, düşük yağlı, Akdeniz tarzı beslenme ve pre- veprobiyotiklerin kullanımı intestinal mikrobiyota sağlığı, çeşitliliği ve dengesi üzerinde olumlu etkiye sahiptir. Kronik hastalıkların prevalansı ve disbiyoz gelişimi ile ters ilişki gösteren Akdeniz diyeti, DASH (Dietary Approaches to Stop Hypertension) diyeti gibi sağlıklı beslenme modelleri; polifenol içeriği yüksek sebze ve meyve tüketiminin fazla olduğu beslenme modelleridir. Polifenoller vücutta birçok biyolojik faaliyette rol alan biyoaktif besin bileşenleri olarak tanımlanmaktadır. Fenolik yapıdaki bu bileşiklerin %90-95’i kolonik mikrobiyota tarafından metabolize edilerek biyolojik aktif metabolitleri üretilir. Bu metabolitlerin kolonositler ve patojen bakteriler üzerine olan etkileri nedeni ile bağırsak mikrobiyotası ve polifenoller arasında çift yönlü bir ilişki vardır. Ayrıca polifenoller karbonhidratların metabolizması ve insülin sinyalizasyon yolaklarının regülasyonunun sağlanmasında ve antioksidan özellikleriyle β-hücre fonksiyonunun korunmasında etkin rol oynamaktadır. Polifenoller hem mikrobiyota kompozisyonu hem de diyabet patogenezindeki olumlu potansiyel etkileri nedeni ile hastalığın tedavisi ve önlenmesinde birincil, ikincil ve üçüncül koruma düzeyinde tıbbi beslenme tedavisinin önemli bir bileşenidir.

Effect of 8-Week Interval Training on Protein Tyrosine Phosphatase 1B Expression in Gastrocnemius Muscle and Insulin Resistance in Rats with Type 2 Diabetes

Background: Insulin resistance induced by genetic and metabolic disorders is the main cause of the prevalence or severity of type 2 diabetes (T2D). Protein tyrosine phosphatase 1B (PTP1B) plays a key role in regulating glucose homeostasis as a negative regulator of insulin signaling pathway. Objectives: This study aimed to assess the effect of interval training on PTP1B expression in gastrocnemius muscle and insulin resistance in male rats with T2D. Methods: T2D was induced by high fat diet (HFD) and intraperitoneal injection of STZ in 14 male Wistar rats and then they were divided randomly into exercise (n=7) or control (n=7) groups. Exercise rats completed an 8 weeks interval training (5 days/week) and control rats remained without training. Fasting glucose, serum insulin, and PTP1B expression in gastrocnemius muscle were measured 48 hours after the last exercise session. Insulin resistance was assessed using homeostasis model assessment of insulin resistance (HOMA-IR) formula based on fasting insulin and glucose levels. An independent t test was used to compare each parameter between 2 groups. A P value less than 0.05 was considered statistically significant. Results: Interval training resulted in a significant decrease in fasting glucose level (P&lt;0.0001) and insulin resistance (P=0.018) as well as an increase in serum insulin level (P&lt;0.0001). PTP1B expression in gastrocnemius muscle decreased significantly compared with control rats (P=0.003) Conclusion: Interval training can improve insulin resistance in T2D rats. This improvement may be attributed to the decrease in PTP1B expression in gastrocnemius muscle by interval training.

Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 μM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors.AbbreviationsBBBblood-brain barrierCDC25Bcell division cycle 25 homolog BCYP2D6Cytochrome P450 2D6 bindingDCCMdynamic cross-correlation mapDSDiscovery StudioH bondhydrogen bondHIAhuman intestinal absorptionLARleukocyte antigen-related phosphataseMDmolecular dynamicsMEG-2maternal-effect germ-cell defective 2MM-PBSAmolecular mechanics Poisson Boltzmann surface area)PCAprincipal component analysisPDBProtein Data BankpNPPp–nitrophenyl phosphatePPBplasma protein bindingPTP1Bprotein tyrosine phosphotase 1BRMSDroot mean square deviationRMSFroot mean square fluctuationSHP-1src homologous phosphatase-1SHP-2src homologous phosphatase-2SPCsingle-point chargeTCPTPT cell protein tyrosine phosphataseT2DMType 2 diabetes mellitusVDWvan der WaalsCommunicated by Ramaswamy H. Sarma

Insight into the PTP1B Inhibitory Activity of Arylbenzofurans: An In Vitro and In Silico Study.

Protein tyrosine phosphatase 1B (PTP1B) plays a specific role as a negative regulator of insulin signaling pathways and is a validated therapeutic target for Type 2 diabetes. Previously, arylbenzofurans were reported to have inhibitory activity against PTP1B. However, detailed investigation regarding their structure activity relationship (SAR) has not been elucidated. The main aim of this work was to investigate the PTP1B inhibitory activity of 2-arylbenzofuran analogs (sanggenofuran A (SA), mulberrofuran D2 (MD2), mulberrofuran D (MD), morusalfuran B (MB), mulberrofuran H (MH)) isolated from the root bark of Morus alba. All compounds demonstrated potent inhibitory activity with IC50 values ranging from 3.11 to 53.47 µM. Among the tested compounds, MD2 showed the strongest activity (IC50, 3.11 µM), followed by MD and MB, while SA and MH demonstrated the lowest activity. Lineweaver-Burk and Dixon plots were used for the determination of inhibition type whereas ligand and receptor interactions were investigated in modeled complexes via molecular docking. Our study clearly supports 2-arylbenzofuran analogs as a promising class of PTP1B inhibitors and illustrates the key positions responsible for the inhibitory activity, their correlation, the effect of prenyl/geranyl groups, and the influence of resorcinol scaffold, which can be further explored in-depth to develop therapeutic agents against T2DM.