Role In Insulin Signaling Research Articles

Insulin signaling is acutely required for long-term memory in Drosophila.

Memory formation has been shown recently to be dependent on energy status in Drosophila. A well-established energy sensor is the insulin signaling (InS) pathway. Previous studies in various animal models including human have revealed the role of insulin levels in short-term memory but its role in long-term memory remains less clear. We therefore investigated genetically the spatial and temporal role of InS using the olfactory learning and long-term memory model in Drosophila. We found that InS is involved in both learning and memory. InS in the mushroom body is required for learning and long-term memory whereas long-term memory specifically is impaired after InS signaling disruption in the ellipsoid body, where it regulates the level of p70s6k, a downstream target of InS and a marker of protein synthesis. Finally, we show also that InS is acutely required for long-term memory formation in adult flies.

Effect of Irbesartan on Chemerin in the Renal Tissues of Diabetic Rats

Background/Aims: Chemerin was introduced as a novel adipokine that plays a crucial role in insulin signaling and diabetic nephropathy. Serum chemerin levels are significantly elevated in type 2 diabetes patients with macroalbuminuria. However, the underlying mechanisms remain unclear. We conducted a preliminary investigation of the effects of the renin-angiotensin system (RAS) on chemerin expression in streptozotocin-induced diabetic rats. Methods: Streptozotocin-induced diabetic rats were randomized into control, diabetic, and irbesartan-treated groups. Real-time polymerase chain reaction was used to detect mRNA expression of chemerin, angiotensin II type 1a receptor (AT1a), angiotensin II type 1b receptor (AT1b) and angiotensin II type 2 receptor (AT2). Immunohistochemical staining was used to detect chemerin in renal tissues. Results: Expression levels of chemerin in renal tissues were significantly elevated in the diabetic group compared to the control group. In the irbesartan-treated group, chemerin expression levels and RAS-related protein levels (i.e. AT1a and AT1b) were markedly decreased compared to the diabetic group. Irbesartan treatment reduced chemerin overexpression and RAS-related protein levels in diabetic rats (i.e. AT1a and AT1b). Conclusion: Irbesartan may inhibit intrarenal RAS in diabetic rats, which may affect the expression of chemerin in the kidneys; however, the precise underlying mechanism remains to be determined.

Insulin Increases Sestrin 2 Content by Reducing Its Degradation through the PI 3 K/mTOR Signaling Pathway.

Sestrin (SESN) is known as a cysteine sulfinic acid reductase. Recently, nonredox functions of SESN in metabolic regulation and antitumor property have been recognized. While mechanisms underlying the expression of SESN are not fully understood. Here we report that insulin markedly increased SESN2 level in HepG2 cells through mTOR activation. To determine whether insulin affects SESN2 degradation, we assessed SESN2 turnover by applying the protein synthesis inhibitor, cycloheximide (CHX), and found that following insulin treatment SESN2 protein levels were reduced significantly slower than non-insulin-treated cells. Furthermore, the proteasomal inhibitor, MG132, dramatically increased SESN2 protein and its ubiquitination level while in the presence of MG132 insulin did not further increase SESN2 content, suggesting that insulin increases SESN2 content mainly via inhibiting its proteasomal degradation. We then explored the potential feedback role of SESN2 in insulin signaling by SESN2 siRNA knockdown in HepG2 cells. Following SESN2 knockdown insulin-stimulated PKB phosphorylation was enhanced and accompanied by reduced PTEN content. Taken together, our study suggests that insulin upregulates SESN2 content via the PI3K/mTOR signaling pathway and this effect is attributed to decreased SESN2 degradation. Furthermore, SESN2 via modulating PTEN plays a negative feedback role in insulin signaling.

Aging and insulin signaling differentially control normal and tumorous germline stem cells

Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age-dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC–male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging.

Structure and ligand-based design of mTOR and PI3-kinase inhibitors leading to the clinical candidates VS-5584 (SB2343) and SB2602.

Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical effectors in a commonly deregulated cell signaling pathway in human cancers. The abnormal activation of the PI3K/mTOR pathway has been shown to play a role in initiation, progression, and metastasis of human tumors. Being one of the most frequently activated pathways in cancer, much effort has been directed toward inhibition of the PI3K/mTOR pathway as a novel oncology therapy. Previous work by a number of groups has revealed several selective PI3K and dual mTOR/PI3K inhibitors. However, there are few reports of therapeutic agents with a pan-PI3K/mTOR inhibitory profile within a narrow concentration range. We therefore initiated a drug discovery project with the aim of discovering dual mTOR/PI3K inhibitors which would equipotently inhibit the 4 isoforms of PI3K, α, β, γ, and δ, and mTOR a compelling profile for powerful blockage of the PI3K/mTOR pathway. A pharmacophore model was generated and used for designing a series of novel compounds, based on a purine scaffold, which potently inhibited mTOR and PI3Ks. These compounds contained a phenol headgroup essential for binding to the target proteins. Early efforts concentrated on finding replacements for the phenol as it was rapidly conjugated resulting in a short half-life in vivo. Compounds with a variety of headgroups were docked into the PI3Kα and mTOR ATP-binding sites, and aminopyrimidine and aminopyrazine were found to make excellent phenol replacements. Further structure guided optimization of side chains in the 8- and 9-positions of the purine resulted in potent inhibitors with good PKDM properties. As the PI3 kinases play a role in insulin signaling, it is believed that targeting mTOR selectively may give the benefit of blocking the AKT-pathway while avoiding the potential side effects associated with PI3K inhibition. As a result we designed a further series of selective mTOR kinase inhibitors. The project was successfully concluded by progressing both a dual mTOR/PI3K inhibitor, SB2343, and a selective mTOR inhibitor, SB2602, into preclinical development. SB2343 has since entered phase 1 clinical development as VS-5584.

Abstract NG05: Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53 null tumors

Abstract NG05: Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53 null tumors

Saturated fatty acid-induced miR-195 impairs insulin signaling and glycogen metabolism in HepG2 cells

MicroRNAs (miRNAs) play an important role in insulin signaling and insulin secretion, but the role of miRNAs in the association between obesity and hepatic insulin resistance is largely unknown. This study reports that saturated fatty acid (SFA) and high fat diet (HFD) significantly induce miR-195 expression in hepatocytes, and that the insulin receptor (INSR), not insulin receptor substrate-1 (IRS-1), is a direct target of miR-195. Furthermore, the ectopic expression of miR-195 suppresses the expression of INSR, thereby impairing the insulin signaling cascade and glycogen synthesis in HepG2 cells. These findings suggest that the dysregulation of miR-195 by SFA is a detrimental factor for hepatic insulin sensitivity.

IRS1 gene polymorphisms Gly972Arg and Ala513Pro are not associated with insulin resistance and type 2 diabetes risk in non-obese Turkish population

Insulin receptor substrate 1 (IRS1), plays a critical role in insulin signaling and its control has an important place in the development of insulin resistance. The tyrosine phosphorylation of IRS1 serves as docking molecules for downstream effectors such as Phosphatidylinositol 3-kinase and phosphotyrosine phosphatase-2. We focused on the Gly972Arg and Ala513Pro variants of the IRS1 gene, since these specific allelic variants are located near the Tyr-Met-X-Met (YMXM) motifs around Tyr987 and Tyr612. Thus, we aimed to investigate the effects of Gly972Arg/Ala513Pro polymorphisms in IRS1 gene on development of insulin resistance and the risk of type 2 diabetes in a non-obese Turkish population. This work included 306 individuals comprising 178 subjects with type 2 diabetes and 128 healthy subjects matched for body mass index. Gly972Arg/Ala513Pro polymorphisms had no effect on type 2 diabetes risk and its phenotypes (P>0.05). Although IRS1 gene and its variants are associated with type 2 diabetes and insulin resistance in several studies worldwide, our data showed that there is no association between Gly972Arg and Ala513Pro variants in IRS1 and disease in Turkish population.

Insulin signaling in the aging of healthy and proteotoxically stressed mechanosensory neurons.

Insulin signaling is central to cellular metabolism and organismal aging. However, the role of insulin signaling in natural and proteotoxically stressed aging neurons has yet to be fully described. We studied aging of Caenorbaditis elegans mechanosensory neurons expressing a neurotoxic expanded polyglutamine transgene (polyQ128), or lacking this proteotoxicity stressor (polyQ0), under conditions in which the insulin signaling pathway was disrupted by RNA interference (RNAi). We describe specific changes in lifespan, mechanosensory neuronal morphologies, and mechansensory function following RNAi treatment targeting the insulin signaling pathway. Overall, we confirmed that transcription factor DAF-16 is neuroprotective in the proteotoxically stressed model, though not strikingly in the naturally aging model. Decreased insulin signaling through daf-2 RNAi improved mechanosensory function in both models and decreased protein aggregation load in polyQ128, yet showed opposing effects on accumulation of neuronal aberrations in both strains. Decreased daf-2 signaling slightly enhanced mechanosensation while greatly enhancing branching of the mechanosensory neuron axons and dendrites in polyQ0 animals, suggesting that branching is an adaptive response in natural aging. These effects in polyQ0 did not appear to involve DAF-16, suggesting the existence of a non-canonical DAF-2 pathway for the modulation of morphological adaptation. However, in polyQ128 animals, decreased daf-2 signaling significantly enhanced mechanosensation while decreasing neuronal aberrations. Unlike other interventions that reduce the strength of insulin signaling, daf-2 RNAi dramatically redistributed large polyQ128 aggregates to the cell body, away from neuronal processes. Our results suggest that insulin signaling strength can differentially affect specific neurons aging naturally or under proteotoxic stress.

Induction of miR-29a by saturated fatty acids impairs insulin signaling and glucose uptake through translational repression of IRS-1 in myocytes.

MicroRNAs have been shown to play an important role in insulin signaling but their biological function in insulin resistance induced by saturated fatty acids (SFA) remains largely unknown. Here, we report that SFA palmitate and high fat diet (HFD) significantly increase expression of miR-29a in myocytes. miR-29a targets IRS-1 3'UTR directly and represses IRS-1 expression at the translational level. Furthermore, the ectopic expression of miR-29a impairs insulin signaling and glucose uptake in myocytes through a substantial decrease in IRS-1. These findings suggest that the up-regulation of miR-29a by SFA is causally related to the development of insulin resistance in myocytes.

Correction

HomeHypertensionVol. 63, No. 4Correction Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection Originally published1 Apr 2014https://doi.org/10.1161/HYP.0000000000000006Hypertension. 2014;63:e92This article corrects the followingInsulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile DysfunctionIn the Hypertension article by Zhang et al (Zhang Y, Yuan M, Bradley KM, Dong F, Anversa P, Ren J. Insulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function. Hypertension. 2012;59:680–693 ), corrections were needed.Data presented in Figure 6 were incorrect and were not found until after the article was published. The corrected Figure 6 appears here. Also, the following text has been added to the figure legend: vertical lines denote source of noncontinuous gels.The authors apologize for the errors.This correction has been made to the current online version of the article, which is available at http://hyper.ahajournals.org/content/59/3/680.full.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesInsulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile DysfunctionYingmei Zhang, et al. Hypertension. 2012;59:680-693 April 2014Vol 63, Issue 4 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/HYP.0000000000000006 Originally publishedApril 1, 2014 PDF download Advertisement

Acute and long-term effects of arsenite in HepG2 cells: modulation of insulin signaling

Epidemiological studies have indicated a relationship between the prevalence of diabetes and exposure to arsenic. Mechanisms by which arsenic may cause this diabetogenic effect are largely unknown. The phosphoinositide 3'-kinase (PI3K)/Akt signaling pathway plays an important role in insulin signaling by controlling glucose metabolism, in part through regulating the activity of FoxO transcription factors. The present study aimed at investigating the effect of short and long-term exposure to arsenite on insulin signaling in HepG2 human hepatoma cells, the role of PI3K/Akt signaling therein and the modulation of target genes controlled by insulin. Exposure of cells to arsenite for 24h rendered cells less responsive toward stimulation of Akt by insulin. At the same time, short-term exposure to arsenite induced a concentration-dependent increase in phosphorylation of Akt at Ser-473, followed by phosphorylation of FoxO proteins at sites known to be phosphorylated by Akt. Phosphorylation of FoxOs was prevented by wortmannin, pointing to the involvement of PI3K. Arsenite exposure resulted in attenuation of FoxO DNA binding and in nuclear exclusion of FoxO1a-EGFP. A 24-h exposure of HepG2 cells to submicromolar concentrations of arsenite resulted in downregulation of glucose 6-phosphatase (G6Pase) and selenoprotein P (SelP) mRNA levels. Curiously, arsenite had a dual effect on SelP protein levels, inducing a small increase in the nanomolar and a distinct decrease in the micromolar concentration range. Interestingly, arsenite-induced long-term effects on G6Pase and SelP mRNA or SelP protein levels were not blocked by the PI3K inhibitor, wortmannin. In conclusion, arsenite perturbs cellular signaling pathways involved in fuel metabolism: it impairs cellular responsiveness toward insulin, while at the same time stimulating insulin-like signaling to attenuate the expression of genes involved in glucose metabolism and the release of the hepatokine SelP, which is known to modulate peripheral insulin sensitivity.

The l-arginine/nitric oxide pathway is impaired in overweight/obese pregnant women.

To evaluate the l-arginine/NO system and its role in insulin signaling and endothelial function during the pregnancy of women of different BMI categories. Twelve women with BMI⩾25 were compared with 10 normal-weight women in a fasting condition after the infusion of l-arginine (20g in 3h) and after the evaluation of the flow-mediated vasodilation (FMD) of the brachial artery between the 9th-12th and 24th-27th weeks. Blood samples for insulin and nitrite/nitrate (NOx) were collected at baseline and after 1, 2 and 3h after initiating the infusion. In both trimesters, the baseline NOx levels were similar among groups. In the 1st trimester of the lean women, there was a NOx increase in response to l-Arg (AUC: 1328; 3, 3173), which had increased by the 2nd trimester (AUC: 3884; 1905, 7686); in overweight/obese women, no responses to l-Arg were found in the 1st or 2nd trimesters. In the 1st trimester, the insulin levels were significantly reduced in both groups after l-Arg infusion. Although the insulin levels in all BMI categories were higher in the 2nd trimester, such levels during weeks 24-27 were suppressed only in normal-weight women after l-Arg infusion. The FMD was higher during both trimesters in the lean controls and was impaired in the overweight/obese subjects. NO availability is impaired in overweight/obese women during pregnancy, which affects endothelial functioning and interferes with insulin regulation. These mechanisms could be involved in the development of hypertensive disorders and glucose intolerance in this population.

Effect of PIP3 on Adhesion Molecules and Adhesion of THP-1 Monocytes to HUVEC Treated with High Glucose

Background: Phosphatidylinositol-3,4,5-triphosphate (PIP3), a well-known lipid second messenger, plays a key role in insulin signaling and glucose homeostasis. Using human umbilical vein endothelial cells (HUVEC) and THP-1 monocytes, we tested the hypothesis that PIP3 can downregulate adhesion molecules and monocyte adhesion to endothelial cells. Methods: HUVEC and monocytes were exposed to high glucose (HG, 25 mM, 20 h) with or without PIP3 (0-20 nM), or PIT-1 (25 µM), an inhibitor of PIP3. Results: Both HG and PIT-1 caused a decrease in cellular PIP3 in monocytes and HUVEC compared to controls. Treatment with PIT-1 and HG also increased the ICAM-1 (intercellular adhesion molecule 1) total protein expression as well as its surface expression in HUVEC, CD11a (a subunit of lymphocyte function-associated antigen 1, LFA-1) total protein expression as well as its surface expression in monocytes, and adhesion of monocytes to HUVEC. Exogenous PIP3 supplementation restored the intracellular PIP3 concentrations, downregulated the expression of adhesion molecules, and reduced the adhesion of monocytes to HUVEC treated with HG. Conclusion: This study reports that a decrease in cellular PIP3 is associated with increased expression of adhesion molecules and monocyte-endothelial cell adhesion, and may play a role in the endothelial dysfunction associated with diabetes.

Novel Factors in the Pathogenesis of Psoriasis and Potential Drug Candidates Are Found with Systems Biology Approach

Psoriasis is a multifactorial inflammatory skin disease characterized by increased proliferation of keratinocytes, activation of immune cells and susceptibility to metabolic syndrome. Systems biology approach makes it possible to reveal novel important factors in the pathogenesis of the disease. Protein-protein, protein-DNA, merged (containing both protein-protein and protein-DNA interactions) and chemical-protein interaction networks were constructed consisting of differentially expressed genes (DEG) between lesional and non-lesional skin samples of psoriatic patients and/or the encoded proteins. DEGs were determined by microarray meta-analysis using MetaOMICS package. We used STRING for protein-protein, CisRED for protein-DNA and STITCH for chemical-protein interaction network construction. General network-, cluster- and motif-analysis were carried out in each network. Many DEG-coded proteins (CCNA2, FYN, PIK3R1, CTGF, F3) and transcription factors (AR, TFDP1, MEF2A, MECOM) were identified as central nodes, suggesting their potential role in psoriasis pathogenesis. CCNA2, TFDP1 and MECOM might play role in the hyperproliferation of keratinocytes, whereas FYN may be involved in the disturbed immunity in psoriasis. AR can be an important link between inflammation and insulin resistance, while MEF2A has role in insulin signaling. A controller sub-network was constructed from interlinked positive feedback loops that with the capability to maintain psoriatic lesional phenotype. Analysis of chemical-protein interaction networks detected 34 drugs with previously confirmed disease-modifying effects, 23 drugs with some experimental evidences, and 21 drugs with case reports suggesting their positive or negative effects. In addition, 99 unpublished drug candidates were also found, that might serve future treatments for psoriasis.

The Akt substrate Girdin is a regulator of insulin signaling in myoblast cells

Akt kinases are important mediators of the insulin signal, and some Akt substrates are directly involved in glucose homeostasis. Recently, Girdin has been described as an Akt substrate that is expressed ubiquitously in mammals. Cells overexpressing Girdin show an enhanced Akt activity. However, not much is known about Girdin's role in insulin signaling. We therefore analyzed the role of Girdin in primary human myotubes and found a correlation between Girdin expression and insulin sensitivity of the muscle biopsy donors, as measured by a hyperinsulinemic–euglycemic clamp. To understand this finding on a cellular level, we then investigated the function of Girdin in C2C12 mouse myoblasts. Girdin knock-down reduced Akt and insulin receptor substrate-1 phosphorylation. In contrast, stable overexpression of Girdin in C2C12 cells strikingly increased insulin sensitivity through a massive upregulation of the insulin receptor and enhanced tyrosine phosphorylation of insulin receptor substrate-1. Furthermore, Akt and c-Abl kinases were constitutively activated. To investigate medium-term insulin responses we measured glucose incorporation into glycogen. The Girdin overexpressing cells showed a high basal glycogen synthesis that peaked already at 1nM insulin. Taken together, we characterized Girdin as a new and major regulator of the insulin signal in myoblasts and skeletal muscle.

Inhibition of EGF Signaling Protects the Diabetic Retina from Insulin-Induced Vascular Leakage

Diabetes mellitus is a disease with considerable morbidity and mortality worldwide. Breakdown of the blood-retinal barrier and leakage from the retinal vasculature leads to diabetic macular edema, an important cause of vision loss in patients with diabetes. Although epidemiologic studies and randomized clinical trials suggest that glycemic control plays a major role in the development of vascular complications of diabetes, insulin therapies for control of glucose metabolism cannot prevent long-term retinal complications. The phenomenon of temporary paradoxical worsening of diabetic macular edema after insulin treatment has been observed in a number of studies. In prospective studies on non-insulin-dependent (type 2) diabetes mellitus patients, a change in treatment from oral drugs to insulin was often associated with a significant increased risk of retinopathy progression and visual impairment. Although insulin therapies are critical for regulation of the metabolic disease, their role in the retina is controversial. In this study with diabetic mice, insulin treatment resulted in increased vascular leakage apparently mediated by betacellulin and signaling via the epidermal growth factor (EGF) receptor. In addition, treatment with EGF receptor inhibitors reduced retinal vascular leakage in diabetic mice on insulin. These findings provide unique insight into the role of insulin signaling in mediating retinal effects in diabetes and open new avenues for therapeutics to treat the retinal complications of diabetes mellitus.

Fatty acids differentially regulate insulin resistance through endoplasm reticulum stress-mediated induction of tribbles homologue 3: a potential link between dietary fat composition and the pathophysiological outcomes of obesity

Previous studies have shown that saturated fatty acids cause insulin resistance (IR) that is prevented by unsaturated fatty acids. Tribbles homologue 3 (TRIB3) is a putative endogenous inhibitor of insulin signalling, but its role in insulin signalling is controversial. This study aimed to determine whether fatty acids regulate IR via TRIB3. We treated HepG2 cells with saturated and unsaturated fatty acids and evaluated TRIB3 expression. We then tested whether regulation of TRIB3 occurred through endoplasmic reticulum (ER) stress, and whether modulating TRIB3 and ER stress marker genes was necessary and/or sufficient for regulation of insulin signalling. To test the in vivo significance of this mechanism, we fed mice obesogenic diets with different fatty acid profiles and assessed physiological variables of diabetes, ER stress markers and Trib3 expression in the liver. Our data show that fatty acids differentially regulate IR through ER stress-mediated induction of TRIB3. Intriguingly, a standard and widely used obesogenic diet high in unsaturated fats failed to induce ER stress, TRIB3 or IR. However, an alternative obesogenic diet with lower unsaturated fat recapitulated the cell studies by causing ER stress, TRIB3 induction and IR. This study revealed a novel mechanism linking dietary fat composition to IR. Given the emerging roles for ER stress in non-alcoholic liver disease, we conclude that dietary fat composition rather than total amount may mediate hepatic pathology associated with obesity.

PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.

Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2

Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steric conformation and electronic configuration of thiazolidinedione (TZD) compounds. The top three candidates were tested using an in vitro biological assay after synthesis. Finally, we report a novel inhibitor, Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 μM. Its IC50 values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine the catalytic domains of PTP1B and SHP-2 by molecular dynamics (MD) simulations.