Protein Tyrosine Phosphatase 1B Gene Research Articles

Distribution of genetic polymorphism of the PTP1B gene in diabetes mellitus patients taking insulin therapy in Indonesia: A narrative review

Background: Diabetes mellitus is a metabolic disease directly related to the onset of hyperglycemia, which occurs due to abnormalities in insulin secretion, insulin action, or both. Protein Tyrosine Phosphatase 1B (PTP1B) from insulin receptor signal transduction has a role in the pathogenesis of diabetes mellitus. Objective: To briefly present the distribution of genetic polymorphism of the PTP1B gene in diabetes mellitus patients taking insulin therapy. Method: A narrative review was conducted by collecting scientific journals in English from several leading platforms, such as PubMed, CrossRef, and Google Scholar, published from 2012 to 2023. Result: PTP1B can inhibit glucose transporter type 4 (GLUT4) activation in glucose uptake by cells, increasing glucose levels. The use of exogenous insulin becomes ineffective, and insulin resistance occurs. This study has limitations and needs additional prospective investigations to corroborate the findings. Conclusion: In some studies, PTP1B gene polymorphism in diabetes mellitus patients strongly correlates with insulin therapy. PTP1B gene polymorphism can cause insulin resistance because PTP1B and GLUT4 have the opposite effect.

The impact of vitamin D on type 2 diabetes management: boosting PTP1B gene expression and physical activity benefits in rats

BackgroundThe protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in the development of insulin resistance. Aerobic training (AT) and vitamin D (Vit D) supplementation have been shown to individually improve glucose tolerance and diabetes-related factors. However, the impact of their combined effect on PTP1B gene expression and serum irisin in the visceral adipose tissue remains unknown. This study aims to investigate whether 8 weeks of combined AT with Vit D supplementation can improve the expression of PTP1B in adipose tissue and serum irisin in obese rats with type 2 diabetes (T2D).MethodsFifty male Wistar rats were divided into two groups: diabetic (n = 40) and non-diabetic (ND; n = 10). The diabetic rats were further divided into four groups: aerobic training with vitamin D supplementation (D + AT + Vit D; n = 10), aerobic training only (D + AT; n = 10), vitamin D supplementation only (D + Vit D; n = 10), and control (D + C; n = 10). The D + Vit D and D + AT + Vit D groups received 5000 IU of vitamin D via injection once a week, while the D + AT and D + C groups received sesame oil. Diabetes was induced in all groups except the nondiabetic group by intraperitoneal (IP) injection of streptozotocin. At the end of the intervention, blood and adipose tissue samples were collected, and RNA was extracted from adipose tissue for real-time PCR analysis of PPTP1B gene expression.ResultsThere was an increase in serum Vit D and irisin levels and a decrease in HOMA-IR and PTP1B gene expression in the diabetic rat model treated with D + AT and injected with 50,000 IU/kg/week of Vit D. Comparatively, when treated with D + AT + Vit D, the downregulation of PTP1B was significantly higher (p = 0.049; p = 0.004), and there was a significant increase in irisin (p = 0.010; p = 0.001).ConclusionThe present study shows that the combined AT and Vit D supplementation positively impacts the expression of PTP1B in adipose tissue and serum irisin in rats with T2D. These findings suggest that combining AT with Vit D supplementation can provide a new and effective strategy to improve glucose tolerance and diabetes-related factors in individuals with T2D by regulating the expression of PTP1B in adipose tissue and promoting the synthesis of beneficial irisin protein.

Role of PTP1B in the Regulation of Cholesterol Homeostasis

Protein tyrosine phosphatase 1B (PTP1B), encoded by the PTPN1 gene, is a well‐known negative regulator of insulin signaling. Since insulin, via the activation of the insulin receptor, is involved in cholesterol synthesis by stimulating genes like HMG‐CoA reductase (HMGCR), we enquired whether PTP1B also played a role in the regulation of cholesterol homeostasis. Interestingly, knocking out PTP1B in hepatocytes, where most of the circulating cholesterol is synthesized, generates mice that have reduced circulating cholesterol levels. Moreover, SNPs in the human PTPN1 gene are associated with higher levels of low‐density lipoprotein cholesterol, total plasma cholesterol, and with the insulin sensitivity index and fasting glucose levels. As a first step, to better understand the function of PTP1B in cholesterol homeostasis, we used Mouse Embryonic Fibroblast (MEFs) cells derived from WT or PTP1B KO mice and measured cholesterol levels utilizing an Amplex red assay. As previously observed in liver PTP1B KO mice, we observed a ~ 50% decrease in cholesterol levels in PTP1B KO cells when compared to WT cells. Supporting this, Western blot analysis also indicated that proteins regulating cholesterol homeostasis are differently expressed in WT and KO MEFs at basal. We observed decreased expression of LDLR, PCSK9, HMGCR, SREBP1 and Cav‐1 in PTP1B KO cells. In addition, cholesterol treatment also showed a decreased adaptive response in PTP1B KO cells. Interestingly, Src, a substrate of PTP1B, was hyperphosphorylated in PTP1B KO MEFs treated with cholesterol and these cells were more sensitive to cholesterol‐induced toxicity as indicated by caspase‐3 cleavage at lower concentrations of cholesterol. Quantitative mass spectrometry analysis using isobaric tag for relative and absolute quantitation (iTRAQ) further revealed that several proteins involved in cholesterol homeostasis (e.g. NPC2, NPC1L1, DHCR7, NCEH1, ApoA, ApoB, ApoC, ApoE) were overexpressed in PTP1B KO MEFs. We also observed that proteins involved in retinoic acid homeostasis, which have also been involved in the regulation of insulin resistance and lipid homeostasis, were overexpressed in PTP1B KO MEFs. We are currently validating these findings and exploring underlying mechanisms by which PTP1B gene inactivation regulates cholesterol homeostasis in mammalian cells.

Association of protein tyrosine phosphatase1B gene polymorphism with the effects of weight reduction therapy on bodyweight and glycolipid profiles in obese patients.

Aims/IntroductionWeight reduction therapy is the primary treatment to prevent complications of obesity, such as lifestyle diseases and cardiovascular disease; however, to date, useful methods and genetic factors for predicting the outcomes of weight reduction therapy in obese patients have not been established. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator for insulin and leptin signaling, potentially modulates glucose and energy homeostasis. This study aimed to investigate the contribution of PTPN1 polymorphisms on weight reduction and diabetes in obese Japanese patients.Materials and MethodsPTPN1‐tagged single‐nucleotide polymorphisms (SNPs) rs3787348 and rs6067484 were genotyped in 447 obese Japanese patients from the general population. In this prospective cohort study, all obese patients underwent a 3‐month weight reduction therapy with lifestyle modifications, as recommended by guidelines.ResultsIn obese patients (male/female 196/251, age 50 ± 15 years, body mass index [BMI] 32 ± 6 kg/m2), the minor allele appeared at a frequency of 45.5% in rs3787348 SNP of the PTPN1 gene. The T allele of rs3787348 was significantly associated with a higher BMI (P = 0.041 in the additive model). The patients with the T allele in SNP rs3787348 of PTPN1 had significantly smaller reductions in BMI, bodyweight and waist circumference levels during weight reduction therapy (BMI G/G, −1.9 ± 0.2; G/T, −1.5 ± 0.1; T/T, −1.2 ± 0.1; P = 0.001 in the additive model).ConclusionsOur findings show that the SNP rs3787348 in PTPN1 was associated with the effects of weight reduction therapy on BMI and waist circumference among obese Japanese patients.

Roles of the PTP61F Gene in Regulating Energy Metabolism of Tribolium castaneum (Coleoptera: Tenebrionidae)

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator in the insulin signaling pathway. It belongs to a class of non-receptor phosphatases of protein tyrosine phosphatase and can catalyze the dephosphorylation of tyrosine to regulate cell differentiation, growth, and metabolism. However, few studies have focused on the role of PTP1B in regulating energy metabolism of insects. In this study, we investigated the expression profiles and the functions of a PTP1B gene (designated TcPTP61F) in the red flour beetle Tribolium castaneum. Quantitative real-time PCR analyzed showed that TcPTP61F was highly expressed in the pupal and adult stages. In adult tissues, TcPTP61F was prominently expressed in the tarsus and head. RNA interference-mediated silencing of TcPTP61F reduced the expression of eight genes in trehalose metabolic and glycolytic pathways. TcPTP61F depletion also caused a significant change in the distribution of trehalose, glucose, and glycogen. Additionally, knockdown of TcPTP61F inhibited the pyruvate kinase (PK) activity and significantly decreased the adenosine triphosphate (ATP) level. The results suggest that TcPTP61F is indispensible for trehalose and energy metabolism of T. castaneum.

Ficus deltoidea extract down-regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: a new insight into its antidiabetic mechanism.

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95% ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70% ethanol FD extract showed a significant PTP1B inhibition (92·0% inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70% ethanol extract led to the isolation of a new triterpene (3β,11β-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks' administration of 70% ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin-nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.

Reduced Insulin Resistance Contributes to the Beneficial Effect of Protein Tyrosine Phosphatase-1B Deletion in a Mouse Model of Sepsis.

Hyperglycemia is a common feature of septic patients and has been associated with poor outcome and high mortality. In contrast, insulin has been shown to decrease mortality and to prevent the incidence of multiorgan failure but is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of both insulin signaling and NO production, and has been shown to be an aggravating factor in septic shock. To evaluate the potential therapeutic effect of PTP1B blockade on glucose metabolism and insulin resistance in an experimental model of sepsis, we assessed the effect of PTP1B gene deletion in a cecal ligation and puncture (CLP) model of sepsis. PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation. These effects were associated with a reduction of sepsis-induced endothelial dysfunction/impaired NO production and especially of insulin-mediated dilatation. This modulation of insulin resistance may contribute to the beneficial effect of PTP1B blockade in septic shock, especially in terms of inflammation and cardiac metabolism.

Study of clinical significance of protein tyrosine phosphatase-1B gene polymorphism in essential hypertension and dyslipidemia

Objectives The aim of the study was to investigate the role of protein tyrosine phosphatase-1B (PTP-1B) gene polymorphism in essential hypertension and dyslipidemia. Background Essential hypertension is the most common chronic disease and an important risk factor for major health problems. PTP-1B has been recognized as a key modulator of several important physiological pathways. Multiple SNPs of PTP-1B have been shown to be associated with diseases accompanying insulin resistance, such as dyslipidemia and hypertension. Participants and methods The study included 57 individuals divided into two groups: group I comprised 37 hypertensive patients and group II comprised 20 healthy individuals as controls. The participants were subjected to the following: history taking and clinical examination, assessment of weight, height, and BMI, fasting blood sugar, lipid profile, renal function tests, and PCR-RFLP for determination of genotype and allele frequencies of the g54281T > A polymorphism of the PTP-1B gene. Results Group I had statistically higher fasting blood sugar, weight, BMI, and TG. The TT genotype recorded higher frequency in group II than in group I (70%, 43.2%, respectively). While, AA genotype showed higher frequency in group I than in group II (29.7%, 5%, respectively) and TA genotype was higher in group I than in group II (27%, 25%, respectively). However, the differences were without statistical significance. The T allele was more prevalent in group II (82.5%) than in group I (56.8) and the A allele was more prevalent in group I (43.2%) than in group II (17.5%). TA carried a 1.75-fold higher risk than TT [confidence interval (CI): 0.48-6.36], whereas AA carried a 9.63-fold higher risk than TT (CI: 1.10-84.23). The A allele carried a 3.59-fold higher risk than the T allele (CI: 1.41-9.16). In group I, AA genotype was higher in BMI than TT, also TA and AA genotypes were higher in TG than TT. Conclusion The g54281T > A polymorphism of the PTP-1B gene can be implicated in the pathogenesis of essential hypertension.

Analysis of protein tyrosine phosphatase 1B gene mutation in myeloproliferative neoplasms

Objective To analyse protein tyrosine phosphatase 1B (PTP1B) gene mutation in myeloproliferative neoplasms (MPN). Methods DNA sequencing technology was used to detect DNA sequences of PTP1B in MPN patients (n = 84) and normal controls (n = 37). Results For Exon1-6, Exon9 and Exon10, 84 cases of MPN patients and 37 cases of control group were not detected mutation. For EXON 8, 18 of 84 MPN patients had Exon8 C/T heterozygous mutation and 10 of 37 normal controls were detected C/T heterozygous mutation. There was no significant difference between MPN patients and normal controls (χ2= 0.453, P = 0.501). Exon7 was detected in 38 MPN patients and 2 cases of patients were found C/T heterozygous mutation ,while in the control group, 1 case with G/C heterozygous mutation. All of the cases were not detected homozygous mutation. Conclusion Using DNA sequencing technology to detect gene mutations of PTP1B, there is no significant difference between MPN patients and normal controls. Key words: Myeloproliferative neoplasms; Protein tyrosine phosphatase 1B; DNA sequencing

Nck1 depletion induces activation of the PI3K/Akt pathway by attenuating PTP1B protein expression.

BackgroundActivation of the PI3K/Akt pathway mediates crucial cellular functions regulated by receptor tyrosine kinases, such as cell growth, proliferation, survival and metabolism. Previously, we reported that the whole-body knockout of the Src homology domain-containing adaptor protein Nck1 improves overall glucose homeostasis and insulin-induced activation of the PI3K/Akt pathway in liver of obese mice. The aim of the current study is to elucidate the mechanism by which Nck1 depletion regulates hepatic insulin signaling.ResultsHere, we demonstrate that Nck1 regulates the activation of the PI3K/Akt pathway in a protein tyrosine phosphatase 1B (PTP1B)-dependent mechanism. Indeed, depletion of Nck1 by siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation. In accordance, primary hepatocytes isolated from Nck1−/− mice also display enhanced Akt activation in response to insulin. Activation of the PI3K/Akt pathway in Nck1-depleted HepG2 cells relies on higher levels of tyrosine-phosphorylated proteins and correlates with decreased PTP1B levels. Interestingly, Nck1 and PTP1B in cells are found in a common molecular complex and their interaction is dependent on the SH3 domains of Nck1. Finally, Nck1 depletion in HepG2 cells neither affects PTP1B gene transcription nor PTP1B protein stability, suggesting that Nck1 modulates PTP1B expression at the translational level.ConclusionOur study provides strong evidence supporting that the adaptor protein Nck1 interacts with PTP1B and also regulates PTP1B expression. In this manner, Nck1 plays a role in regulating the PI3K/Akt pathway.

Protein Tyrosine Phosphatase 1B Inhibition Protects against Podocyte Injury and Proteinuria

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed nonreceptor protein-tyrosine phosphatase that regulates various cellular functions, including migration. Recent studies suggest that an increased migratory phenotype of podocytes may be responsible for proteinuria and foot process effacement. The current study addresses the role of PTP1B in podocyte injury and proteinuria. PTP1B was markedly up-regulated in the glomerulus, notably in podocytes, in three rodent models of podocyte injury. Podocyte-specific ablation of the PTP1B gene ameliorated proteinuria induced by lipopolysaccharide and Adriamycin (doxorubicin). The use of a specific PTP1B inhibitor also protected against lipopolysaccharide-induced proteinuria. In contrast, podocyte-specific PTP1B transgenic male mice developed spontaneous proteinuria and foot process effacement. In cultured mouse podocytes, PTP1B knockdown and/or pretreatment with the PTP1B inhibitor blunted lipopolysaccharide-induced cell migration, activation of Src-family kinases (SFKs), and phosphorylation of focal adhesion kinase at Y397 (pFAK(Y397)), the latter being crucial for cell migration. Lipopolysaccharide-injected mice showed increased glomerular expression of active SFKs and pFAK(Y397), both of which were inhibited by podocyte-specific PTP1B knockout and the PTP1B inhibitor. Moreover, podocyte-specific PTP1B transgenic mice showed increased glomerular expression of active SFKs and pFAK(Y397). In summary, PTP1B up-regulation in podocytes induces a migratory response by activating SFKs and FAK, leading to foot process effacement and proteinuria. Pharmacological inhibition of PTP1B may have therapeutic potential in the treatment of proteinuric diseases.

Gene Deletion of Protein Tyrosine Phosphatase 1B Protects Against Sepsis-Induced Cardiovascular Dysfunction and Mortality

Cardiovascular dysfunction is a major cause of mortality in patients with sepsis. Recently, we showed that gene deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) improves endothelial dysfunction and reduces the severity of experimental heart failure. However, the cardiovascular effect of PTP1B invalidation in sepsis is unknown. Thus, we explored the beneficial therapeutic effect of PTP1B gene deletion on lipopolysaccharide (LPS)-induced cardiovascular dysfunction, inflammation, and mortality. PTP1B(-/-) or wild-type mice received LPS (15 mg/kg) or vehicle followed by subcutaneous fluid resuscitation (saline, 30 mL/kg). α-1-dependent constriction and endothelium-dependent dilatation, assessed on isolated perfused mesenteric arteries, were impaired 8 hours after LPS and significantly improved in PTP1B(-/-) mice. This was associated with reduced vascular expression of interleukin1-β, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, cyclooxygenase-2, and inducible nitric oxide synthase mRNA. PTP1B gene deletion also limited LPS-induced cardiac dysfunction assessed by echocardiography, left ventricular pressure-volume curves, and in isolated perfused hearts. PTP1B(-/-) mice also displayed reduced LPS-induced cardiac expression of tumor necrosis factor-α, interleukin1-β, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and Gp91phox, as well as of several markers of cellular infiltration. PTP1B deficiency also reduced cardiac P38 and extracellular signal-regulated protein kinase 1 and 2 phosphorylation and increased phospholamban phosphorylation. Finally, PTP1B(-/-) mice displayed a markedly reduced LPS-induced mortality, an effect also observed using a pharmacological PTP1B inhibitor. PTP1B deletion also improved survival in a cecal ligation puncture model of sepsis. PTP1B gene deletion protects against septic shock-induced cardiovascular dysfunction and mortality, and this may be the result of the profound reduction of cardiovascular inflammation. PTP1B is an attractive target for the treatment of sepsis.

Nck1 depletion induces activation of the PI3K/Akt pathway by attenuating PTP1B protein expression

Activation of the PI3K/Akt pathway mediates crucial cellular functions regulated by receptor tyrosine kinases, such as cell growth, proliferation, survival and metabolism. Previously, we reported that the whole-body knockout of the Src homology domain-containing adaptor protein Nck1 improves overall glucose homeostasis and insulin-induced activation of the PI3K/Akt pathway in liver of obese mice. The aim of the current study is to elucidate the mechanism by which Nck1 depletion regulates hepatic insulin signaling. Here, we demonstrate that Nck1 regulates the activation of the PI3K/Akt pathway in a protein tyrosine phosphatase 1B (PTP1B)-dependent mechanism. Indeed, depletion of Nck1 by siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation. In accordance, primary hepatocytes isolated from Nck1 -/- mice also display enhanced Akt activation in response to insulin. Activation of the PI3K/Akt pathway in Nck1-depleted HepG2 cells relies on higher levels of tyrosine-phosphorylated proteins and correlates with decreased PTP1B levels. Interestingly, Nck1 and PTP1B in cells are found in a common molecular complex and their interaction is dependent on the SH3 domains of Nck1. Finally, Nck1 depletion in HepG2 cells neither affects PTP1B gene transcription nor PTP1B protein stability, suggesting that Nck1 modulates PTP1B expression at the translational level. Our study provides strong evidence supporting that the adaptor protein Nck1 interacts with PTP1B and also regulates PTP1B expression. In this manner, Nck1 plays a role in regulating the PI3K/Akt pathway.

Hydrodynamic-based delivery of PTP1B shRNA reduces plasma glucose levels in diabetic mice

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling which is overexpressed in the liver of diabetic animals. The aims of this study were to generate liver-specific PTP1B knockout mice using a PTP1B‑short hairpin RNA (shRNA) plasmid and to investigate the effect of PTP1B inhibition on plasma glucose levels in streptozotocin-induced diabetic mice. We first validated the hydrodynamic tail vein injection in mice using a vector carrying the luciferase gene. Expression of the PTP1B gene was quantified by real-time PCR. The level of phosphorylated Akt was examined by western blot analysis. The injection of the plasmid containing firefly luciferase revealed that the highest transfer of the vector into the liver was obtained 24h after the injection of 20µg plasmid. The injection of PTP1B-shRNA, but not the scrambled shRNA plasmid, resulted in a reduction in PTP1B expression levels by up to 84% in the liver of the diabetic mice. Plasma glucose levels following the injection of PTP1B-shRNA remained significantly lower in the diabetic mice for 5days. In addition, mice receiving PTP1B-shRNA in the basal and insulin-stimulated states had higher levels of Akt phosphorylation in the liver cells compared with mice that were injected with the scrambled sequence (35 and 60%, respectively; p<0.01). Furthermore, PTP1B overexpression was observed in the muscle, liver, adipose, heart and kidney tissues of the diabetic mice. The data from this study demonstrate that PTP1B inhibition may be a promising approach for lowering plasma glucose levels in diabetic patients. However, further studies using non-viral carriers are required to deliver the plasmid safely into the liver.

Skeletal Muscle Protein Tyrosine Phosphatase 1B Regulates Insulin Sensitivity in African Americans

Protein tyrosine phosphatase 1B (PTP1B) is postulated to modulate insulin action by dephosphorylating the insulin receptor signaling proteins and attenuating insulin signaling. We sought to determine the relationship of skeletal muscle PTP1B to whole-body insulin sensitivity. We studied 17 African Americans with type 2 diabetes mellitus (T2DM) and 16 without diabetes. PTP1B gene expression and protein abundance were determined in the biopsied skeletal muscles at the baseline of a hyperinsulinemic-euglycemic clamp. PTP1B gene expression was significantly higher in subjects with T2DM versus control (P < 0.0001) and remained significantly different after adjusting for age and insulin sensitivity (P = 0.05). PTP1B gene expression was positively related to protein abundance (rs = 0.39; P = 0.03; adjusted for age and insulin sensitivity) and negatively related to insulin sensitivity (rs = −0.52; P = 0.002; adjusted for age). Overexpression and interference RNA of PTP1B were performed in primary human skeletal muscle culture. PTP1B overexpression resulted in reduction of Akt phosphorylation in the control subjects. Moreover, interference RNA transfection downregulated PTP1B expression and enhanced Akt phosphorylation in subjects with T2DM. These data show that skeletal muscle PTP1B gene expression is increased in African American subjects with T2DM, is negatively associated with whole-body insulin sensitivity, and contributes to modulation of insulin signaling.

Quercetin attenuates inflammation in human macrophages and adipocytes exposed to macrophage-conditioned media

Obesity is linked to chronic inflammation in white adipose tissue, which is exacerbated by infiltrating macrophages (MΦs). We recently demonstrated that an extract from grape powder (GPE), which is abundant in quercetin (QUE), reduced inflammation in human MΦs and prevented MΦ-mediated inflammation and insulin resistance in human adipocytes. However, we did not know how QUE individually affected these outcomes. We examined the extent to which QUE prevents inflammation in human MΦs (that is, differentiated U937 cell line) and cross-talk with human adipocytes (that is, primary cultures of newly differentiated human adipocytes). Treatment of MΦs with QUE attenuated the basal expression of inflammatory genes, such as tumor necrosis factor-α, interleukin (IL)-6, IL-8, IL-1β and interferon-γ inducible protein-10, and cyclooxygenase-2, a marker of prostaglandin production. QUE also attenuated the abundance of phosphorylated c-Jun N-terminal kinase (JNK) and c-Jun, and IκBα degradation in MΦs. Furthermore, conditioned media (CM) obtained from MΦs treated with QUE decreased the capacity of this CM to inflame adipocytes and cause insulin resistance as evidenced by decreased: (1) inflammatory gene expression, (2) phosphorylation of JNK and c-Jun, (3) serine residue 307 phosphorylation of insulin receptor substrate (IRS)-1, 4) protein tyrosine phosphatase-1B gene expression and 5) suppression of insulin-stimulated glucose uptake. Taken together, these data suggest that QUE is one of the bioactive components of GPE that prevents inflammation in MΦs and MΦ-mediated insulin resistance in adipocytes.

Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-α–mediated inflammation and insulin resistance in primary human adipocytes

Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes. However, we do not know how quercetin and trans-RSV individually affected these outcomes. The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-α (TNF-α)-an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals. Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-α. Subsequently, gene and protein markers of inflammation and insulin resistance were measured. Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-α-induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1. Quercetin attenuated TNF-α-mediated phosphorylation of extracellular signal-related kinase and c-Jun-NH₂ terminal kinase, whereas trans-RSV attenuated only c-Jun-NH₂ terminal kinase phosphorylation. Quercetin and trans-RSV attenuated TNF-α-mediated phosphorylation of c-Jun and degradation of inhibitory κB protein. Quercetin, but not trans-RSV, decreased TNF-α-induced nuclear factor-κB transcriptional activity. Quercetin and trans-RSV attenuated the TNF-α-mediated suppression of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ target genes and of PPARγ protein concentrations and transcriptional activity. Quercetin prevented the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1 and protein tyrosine phosphatase-1B gene expression and the suppression of insulin-stimulated glucose uptake, whereas trans-RSV prevented only the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1. These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-α-mediated inflammation and insulin resistance in primary human adipocytes.

Association of PTP1B gene polymorphism with obesity in Chinese children.

To investigate the distribution characteristics of protein tyrosine phosphatase 1B (PTP1B) gene IVS6+G82A and Pro303Pro polymorphisms in Chinese children and determine the effect of PTP1B gene IVS6+G82A and Pro303Pro polymorphisms on the pathogenesis of childhood obesity. A total of 147 Chinese obese and 118 healthy children were randomly selected and enrolled to identify IVS6+G82A and Pro303Pro genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Waist circumference (WC), waist to hip ratio (WHR), percentage of body fat (%BF),systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), serum triglycerides (TG), total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), plasma fasting insulin (FINS), homeostasis model assessment for insulin resistance (HOMA-IR), and plasma leptin were examined. The allele frequencies of IVS6+G82A and Pro303Pro were 59.5% and 19.4% in obese children, and 53.4% and 11.0% in healthy children, respectively. There were significant differences in allele frequencies of Pro303Pro polymorphism between the obese and the control group. Pro303Pro polymorphism was associated with body mass index, WC, TG, and LDL-C in the obese subjects. There was not difference in the genotype distributions or allele frequencies of IVS6+G82A polymorphism between the obese and the control group. Further analysis showed no association between the genotypes of IVS6+G82A and clinical characteristics in the obese subjects. The linkage disequilibrium analysis for IVS6+G82A and Pro303Pro (D': 0.441, r2: 0.027) was weak. PTP1B gene Pro303Pro polymorphism might be associated with the pathogenesis of obesity in children and could affect the lipid metabolism in Chinese obese children.

Palmitate Enhances Protein Tyrosine Phosphatase 1B (PTP1B) Gene Expression at Transcriptional Level in C2C12 Skeletal Muscle Cells

The factors responsible for regulating PTP1B expression in certain metabolic states have been unclear. We investigated the effects of palmitate on PTP1B gene transcription in C2C12 myotubes and myotubes co-cultured with J774A.1 macrophages. PTP1B mRNA and promoter activity levels were measured in C2C12 myotubes and direct or indirect co-culture of myotubes with macrophages using real time PCR and luciferase activity, respectively. Palmitate significantly induced PTP1B mRNA and promoter activity levels 1.36- and 1.32-fold, respectively, in C2C12 cells compared with the untreated myotubes. Palmitate showed a 2.3-fold increase in PTP1B mRNA level in myotubes co-cultured indirectly with macrophages. PTP1B promoter activity was also significantly induced by palmitate in direct (1.8-fold) and indirect (1.48-fold) co-culture of myotubes with macrophages. These data suggest that while palmitate treatment significantly induced PTP1B expression at the transcriptional level, the presence of an inflammatory process exerted by macrophages can augment this effect in the muscle cells.

Protein tyrosine phosphatase 1B gene polymorphisms and essential hypertension: A case-control study in Chinese population

Protein tyrosine phosphatase (PTP)- 1B, encoded by the PTPN1 gene, negatively regulates insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment. Several rare single nucleotide polymorphisms (SNP) have been linked to diseases accompanying insulin resistance such as Type 2 diabetes, obesity, and dyslipidemia in different populations. To investigate whether PTP-1B SNP are associated with hypertension and hypertension-related metabolic traits in Chinese subjects. A total of 239 Chinese patients with hypertension and 141 non-hypertensive subjects were screened. The genotypes of PTP-1B gene polymorphisms were determined by PCR-restriction fragment length polymorphism methods. The case-control study showed associations between the frequencies of T allelic g54281 T>A and A allele of I5/37C>A and hypertension (p<0.0001, p=0.0371, respectively). In addition, significant associations were observed between the IVS6+G82A polymorphism and waist circumference, total cholesterol, and LDL-cholesterol levels in hypertensive patients (p=0.0005 approximately 0.0260). And g54281 T allele was associated with higher plasma triglyceride (p=0.0390) and LDL-cholesterol concentration (p=0.0141), while g58585 T>C was associated with body mass index (BMI) (p=0.0308), waist circumference (p=0.0216), and homeostasis model assessment of insulin resistance (p=0.047). Multivariate logistic regression analysis showed that T allele carriers of g54281T>A and A allele carriers of I5/37C>A had higher risks of hypertension independent of age, gender, BMI, glucose levels, and lipids profiles [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.09- 2.96, p=0.02; OR: 1.66, 95% CI: 1.13-2.44, p=0.01, respectively]. PTP-1B polymorphisms contribute to pathogenesis of hypertension in Chinese subjects and PTP-1B SNP may be involved in the development of several features including dyslipidemia and obesity in hypertensive subjects.