Regulation Of Insulin Signaling Research Articles

Torso, a Drosophila receptor tyrosine kinase, plays a novel role in the larval fat body in regulating insulin signaling and body growth

Torso is a receptor tyrosine kinase whose localized activation at the termini of the Drosophila embryo is mediated by its ligand, Trunk. Recent studies have unveiled a second function of Torso in the larval prothoracic gland (PG) as the receptor for the prothoracicotropic hormone, which triggers pupariation. As such, inhibition of Torso in the PG prolongs the larval growth period, thereby increasing the final pupa size. Here, we report that Torso also acts in the larval fat body, regulating body size in a manner opposite from that of Torso in PG. We confirmed the expression of torso mRNA in the larval fat body and its reduction by RNA interference (RNAi). Fat body-specific knockdown of torso, by either of the two independent RNAi transgenes, significantly decreased the final pupal size. We found that torso knockdown suppresses insulin/target of rapamycin (TOR) signaling in the fat body, as confirmed by repression of Akt and S6K. Notably, the decrease in insulin/TOR signaling and decrease of pupal size induced by the knockdown of torso were rescued by the expression of a constitutively active form of the insulin receptor or by the knockdown of FOXO. Our study revealed a novel role for Torso in the fat body with respect to regulation of insulin/TOR signaling and body size. This finding exemplifies the contrasting effects of the same gene expressed in two different organs on organismal physiology.

Heat Stress‐induced Insulin Sensitivity in Oxidative Skeletal Muscle

Heat‐related complications continue to be a major health concern for humans and animals and lead to potentially life‐threatening conditions ranging from heat exhaustion, heat stroke and even death. Heat stress have been shown to alter metabolic and energetic parameters in mammals and may alter glucose metabolism and insulin sensitivity. Therefore, the purpose of this investigation was to determine the extent to which short‐term HS altered markers of insulin signaling in oxidative skeletal muscle. To address this, crossbred gilts (n=8/group) were assigned to thermoneutral (TN; 24° C), HS (37° C), or pair‐fed to HS and kept under TN conditions (PFTN) groups for 12 hours. Following treatment, animals were euthanized and the semitendinosus red (STR) was recovered. HS‐induced changes were not caused by reduced feed intake as TN and PFTN were similar for nearly all measures. Twelve hours of HS increased insulin receptor protein abundance by 54% (p<0.05) and phosphorylated insulin receptor substrate (pIRS1S307) by 56% (p<0.05) compared to TN. Phosphorylation of IRS1 at this site is a negative regulator of insulin signaling. Relative protein abundance and phosphorylation of phosphoinositide 3‐kinase (PI3K) and 3‐phosphoinositide dependent protein kinase‐1 (PDK1) were similar between groups. Phosphorylation of protein kinase B (pAKTs473) was decreased by 53% (p<0.05) in HS compared to TN, which indicates that insulin signaling was suppressed through pIRS1. Conversely, HS increased phosphorylation of protein kinase C (PKC)λ/ζ and pPKCδ protein abundance by 128% and 205%, respectively, compared to TN which are known to stimulate pIRS1S307. Sarcolemma glucose transporter‐4 (Glut4) was decreased by 47% (p<0.05) in HS group compared to TN suggesting reduced glucose uptake. These data suggest that HS induces insulin sensititvity by disturbing insulin signaling via an AKT‐mediated pathway.Support or Funding InformationThis work is supported by USDA grants 2014‐67015‐21627 and 2011‐67003‐30007

Insulin‐dependent glucose uptake is regulated by mitochondrial Ca2+ handling in skeletal muscle fibers

IntroductionThe mitochondria functions rapidly to respond to high energy food supply but the role of mitochondrial Ca2+ levels in the context of insulin signaling has not been explored.Material and MethodsMice were fed with normal chow diet (NCD) or high fat diet (HFD) for 1 (St‐HFD) or 8 (Lt‐HFD) weeks, (short‐ and long‐term) respectively. Changes in calcium levels, mitochondria membrane potential and glucose uptake were evaluated in living fibers from Flexor digitorum brevis muscle using fluorescent dyes.ResultsInsulin induced an increase in cytoplasmic and mitochondrial Ca2+ in adult fibers that was significantly smaller in fibers from short‐term HFD fed mice and completely inhibited in Lt‐HFD. In fibers from NCD fed mice, insulin‐dependent mitochondrial Ca2+ uptake was blunted by both inositol‐1,4,5‐trisphosphate receptor inhibition and knockdown. The mitochondrial potential was larger in fibers from short‐term HFD fed mice v/s NCD derived fibers and the recruited of active mitochondria was increased. The glucose analogue (2‐NBDG) uptake and the redistribution of GLUT4myc‐eGFP chimera induced by insulin were decreased in the absence of mitochondrial Ca2+ uptake in conditions of type 1inositol 1,4,5‐trisphosphate receptor knockdown.DiscussionThese effects suggest a role for mitochondrial Ca2+ uptake in a retrograde regulation of insulin signaling by mitochondria.Support or Funding InformationFinanced by FONDECYT 11130267, 1151293, PIA‐ACT1111

Insulin Signaling Regulation of Sortilin 1 and Glut4 Storage Vesicle Formation in NIH 3T3‐L1 Adipocytes and Mouse Adipose Tissue

Type‐II diabetes is associated with impaired insulin‐stimulated glucose uptake into the muscle and adipose tissues. Insulin regulates glucose uptake in adipocytes and muscle cells by promoting the plasma membrane translocation of the glucose transporter 4 (Glut4)‐containing storage vesicles, which is defective in type‐II diabetes. The intracellular trafficking receptor Sortilin 1 is an essential component of the Glut4 storage vesicles in adipocytes and mediates the insulin responsiveness of Glut4 translocation to the plasma membrane. Knockdown of Sortilin 1 impaired Glut4 storage vesicle formation and resulted in Glut4 degradation in NIH 3T3‐L1 cells. The objective of this study is to investigate the effect and molecular mechanism of insulin regulation of Sortilin 1 in differentiated 3T3‐L1 adipocytes and in mouse adipose tissue. Adipose Sortilin 1 and Glut4 protein levels were determined in obese and diabetic mice. The effects of insulin and insulin signaling inhibitors on Sortilin 1 mRNA and protein levels were determined in differentiated 3T3‐L1 adipocytes. The potential role of Sortilin 1 phosphorylation in mediating insulin regulation of Sortilin 1 was further investigated. Results showed that insulin induced Sortilin 1 protein, but not mRNA, in 3T3‐L1 adipocytes. Treatment of PI3K or AKT inhibitors decreased Sortilin 1 protein, but not mRNA in 3T3‐L1 cells. In addition, treatment of pro‐inflammatory cytokine TNFα impaired Insulin signaling and decreased Sortilin 1 protein in 3T3‐L1 adipocytes. Consistently, Sortilin 1 protein was down‐regulated in the white and brown adipose of obese and diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. In addition, intraperitoneal injection of a PI3K inhibitor in lean mice caused rapid downregulation of Sortilin 1 protein in the adipose tissue without alteration of Sortilin 1 mRNA levels. LC‐MS/MS analysis further revealed novel serine phosphorylation sites on Sortilin 1 protein. Additional mechanistic studies suggest that Sortilin 1 phosphorylation affects Sortilin1 protein trafficking function and stability, and potentially mediates insulin regulation of Sortilin 1. In conclusion, we have identified Sortilin 1 as a novel target of insulin signaling in adipose tissue, and suggest that insulin resistance may be responsible for the Sortilin 1 downregulation and impaired Glut4 storage vesicle formation in obesity and diabetes.Support or Funding InformationAmerican Diabetes Association, NIDDK

Glucose-regulated protein 78 (GRP78) binds directly to PIP3 phosphatase SKIP and determines its localization.

Skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP3 phosphatase, has been implicated in the regulation of insulin signaling in skeletal muscle. SKIP interacts with Pak1 and glucose-regulated protein 78 (GRP78), both of which are necessary for the regulation of insulin signaling. In this study, we showed that GRP78 directly binds to the SKIP C-terminal homology (SKICH) domain of SKIP and that this binding is necessary for the localization of SKIP at the ER. In addition, invitro binding analysis showed that GRP78 and Pak1 competitively bind to SKIP. Taken together, these findings suggest a model by which GRP78 regulates intracellular localization of SKIP and how SKIP binds to Pak1 on insulin stimulation.

The neuropilin-like protein ESDN regulates insulin signaling and sensitivity.

Insulin effects on cell metabolism, growth, and survival are mediated by its binding to, and activation of, insulin receptor. With increasing prevalence of insulin resistance and diabetes there is considerable interest in identifying novel regulators of insulin signal transduction. The transmembrane protein endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a novel regulator of vascular remodeling and angiogenesis. Here, we investigate a potential role of ESDN in insulin signaling, demonstrating that Esdn gene deletion promotes insulin-induced vascular smooth muscle cell proliferation and migration. This is associated with enhanced protein kinase B and mitogen-activated protein kinase activation as well as insulin receptor phosphorylation. Likewise, insulin signaling in the liver, muscle, and adipose tissue is enhanced in Esdn(-/-) mice, and these animals exhibit improved insulin sensitivity and glucose homeostasis in vivo. The effect of ESDN on insulin signaling is traced back to its interaction with insulin receptor, which alters the receptor interaction with regulatory adaptor protein-E3 ubiquitin ligase pairs, adaptor protein with pleckstrin homology and Src homology 2 domain-c-Cbl and growth factor receptor bound protein 10-neuronal precursor cell-expressed developmentally downregulated 4. In conclusion, our findings establish ESDN as an inhibitor of insulin receptor signal transduction through a novel regulatory mechanism. Loss of ESDN potentiates insulin's metabolic and mitotic effects and provides insights into a novel therapeutic avenue.

Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart.

The leading cause of death in diabetic patients is diabetic cardiomyopathy, in which alteration of Akt signal plays an important role. Inpp5f is recently found to be a negative regulator of Akt signaling, while its expression and function in diabetic heart is largely unknown. In this study, we found that in both the streptozotocin (STZ) and high fat diet (HFD) induced diabetic mouse models, Inpp5f expression was coordinately regulated by insulin, blood glucose and lipid levels. Increased Inpp5f was inversely correlated with the cardiac function. Further studies revealed that Insulin transcriptionally activated Inpp5f in an Sp1 dependent manner, and increased Inpp5f in turn reduced the phosphorylation of Akt, forming a negative feedback loop. The negative feedback plays a protective role under diabetic condition. However, high blood glucose and lipid, which are characteristics of uncontrolled diabetes and type 2 diabetes, increased Inpp5f expression through activation of NF-κB, blunts the protective feedback. Thus, our study has revealed that Inpp5f provides as a negative feedback regulator of insulin signaling and downregulation of Inpp5f in diabetes is cardioprotective. Increased Inpp5f by hyperglycemia and hyperlipidemia is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease.

Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis.

Altered hepatic lipogenesis is associated with metabolic diseases such as obesity and hepatosteatosis. Insulin resistance and compensatory hyperinsulinaemia are key drivers of these metabolic imbalances. Fas apoptosis inhibitory molecule (FAIM), a ubiquitously expressed antiapoptotic protein, functions as a mediator of Akt signalling. Since Akt acts at a nodal point in insulin signalling, we hypothesize that FAIM may be involved in energy metabolism. In the current study, C57BL/6 wild-type (WT) and FAIM-knockout (FAIM-KO) male mice were fed with normal chow diet and body weight changes were monitored. Energy expenditure, substrate utilization and physical activities were analysed using a metabolic cage. Liver, pancreas and adipose tissue were subjected to histological examination. Serum glucose and insulin levels and lipid profiles were determined by biochemical assays. Changes in components of the insulin signalling pathway in FAIM-KO mice were examined by immunoblots. We found that FAIM-KO mice developed spontaneous non-hyperphagic obesity accompanied by hepatosteatosis, adipocyte hypertrophy, dyslipidaemia, hyperglycaemia and hyperinsulinaemia. In FAIM-KO liver, lipogenesis was elevated as indicated by increased fatty acid synthesis and SREBP-1 and SREBP-2 activation. Notably, protein expression of insulin receptor beta was markedly reduced in insulin target organs of FAIM-KO mice. Akt phosphorylation was also lower in FAIM-KO liver and adipose tissue as compared with WT controls. In addition, phosphorylation of insulin receptor substrate-1 and Akt2 in response to insulin treatment in isolated FAIM-KO hepatocytes was also markedly attenuated. Altogether, our data indicate that FAIM is a novel regulator of insulin signalling and plays an essential role in energy homoeostasis. These findings may shed light on the pathogenesis of obesity and hepatosteatosis.

MiR-322 regulates insulin signaling pathway and protects against metabolic syndrome-induced cardiac dysfunction in mice

We identified murine miR-322, orthologous to human miR-424, as a new regulator of insulin receptor, IGF-1 receptor and sirtuin 4 mRNA in vitro and in vivo in the heart and found that miR-322/424 is highly expressed in the heart of mice. C57Bl/6N mice fed 10weeks of high fat diet (HFD) presented signs of cardiomyopathy and a stable miR-322 cardiac level while cardiac function was slightly affected in 11week-old ob/ob which overexpressed miR-322. We thus hypothesized that mmu-miR-322 could be protective against cardiac consequences of hyperinsulinemia and hyperlipidemia. We overexpressed or knocked-down mmu-miR-322 using AAV9 and monitored cardiac function in wild-type C57Bl/6N mice fed a control diet (CD) or a HFD and in ob/ob mice. The fractional shortening progressively declined while the left ventricle systolic diameter increased in HFD mice infected with an AAVcontrol or with an AAVsponge (decreasing miR-322 bioavailability) but also in ob/ob mice infected with AAVsponge. Similar observations were also found in CD-fed mice infected with AAVsponge. On the contrary over-expressing miR-322 with AAVmiR-322 was efficient in protecting the heart from HFD effects in C57Bl/6N mice. This cardioprotection could be associated with the regulation of identified targets IGF1R, INSR and CD1, a decrease in insulin signaling pathway and an enrichment of genes involved in mitochondrial function and fatty acid oxidation as demonstrated by transcriptome analysis. Altogether, these results emphasize miR-322 as a new potential therapeutic target against cardiac consequences of metabolic syndrome, which represents an increasing burden in the western countries.

Disease onset and aging in the world of circular RNAs.

Circular ribonucleic acids (circRNAs) are non-coding RNAs of approximately 100 nucleotides in length with thousands of members in mammalian cells. The presence of circRNAs is believed to be even greater than that of messenger RNAs. Identification of circRNAs occurred approximately 37 years ago with the subsequent demonstration that covalent bonds are necessary for the unique circular structure of these ribonucleic acids. However, present understanding of the complex biological role of circRNAs remains limited and requires further elucidation. CircRNAs may impact aging, multiple disorders, function as biomarkers, and are able to regulate gene expression by acting as effective microRNA (miRNA) sponges. New work suggests that circRNAs are vital for the modulation of cellular senescence and programmed cell death pathways such as apoptosis. These non-coding RNAs can control cell cycle progression, cellular proliferation, and cellular survival impacting disorders linked to aging, cardiovascular disease, and atherosclerosis through pathways that involve cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase inhibitor 1 (p21), and mammalian forkhead transcription factors. In addition, circRNAs can oversee cellular metabolism and disorders such as diabetes mellitus through the regulation of insulin signaling as well as limit tumor progression through Wnt signaling and β-catenin pathways. Further understanding of the biology of circRNAs offers great promise for the targeting of novel strategies against a wide spectrum of disease entities.

Correlation of Glypican-4 Level with Basal Active Glucagon-Like Peptide 1 Level in Patients with Type 2 Diabetes Mellitus.

BackgroundPrevious studies have reported that glypican-4 (GPC4) regulates insulin signaling by interacting with insulin receptor and through adipocyte differentiation. However, GPC4 has not been studied with regard to its effects on clinical factors in patients with type 2 diabetes mellitus (T2DM). We aimed to identify factors associated with GPC4 level in T2DM.MethodsBetween January 2010 and December 2013, we selected 152 subjects with T2DM and collected serum and plasma into tubes pretreated with aprotinin and dipeptidyl peptidase-4 inhibitor to preserve active gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). GPC4, active GLP-1, active GIP, and other factors were measured in these plasma samples. We performed a linear regression analysis to identify factors associated with GPC4 level.ResultsThe subjects had a mean age of 58.1 years, were mildly obese (mean body mass index [BMI], 26.1 kg/m2), had T2DM of long-duration (mean, 101.3 months), glycated hemoglobin 7.5%, low insulin secretion, and low insulin resistance (mean homeostatic model assessment of insulin resistance [HOMA-IR], 1.2). Their mean GPC4 was 2.0±0.2 ng/mL. In multivariate analysis, GPC4 was independently associated with age (β=0.224, P=0.009), and levels of active GLP-1 (β=0.171, P=0.049) and aspartate aminotransferase (AST; β=–0.176, P=0.043) after being adjusted for other clinical factors.ConclusionGPC4 was independently associated with age, active GLP-1, and AST in T2DM patients, but was not associated with HOMA-IR and BMI, which are well known factors related to GPC4. Further study is needed to identify the mechanisms of the association between GPC4 and basal active GLP-1 levels.

Euonymus alatus: A Review on Its Phytochemistry and Antidiabetic Activity.

Euonymus alatus (E. alatus) is a medicinal plant used in some Asian countries for treating various conditions including cancer, hyperglycemia, and diabetic complications. This review outlines the phytochemistry and bioactivities of E. alatus related to antidiabetic actions. More than 100 chemical constituents have been isolated and identified from E. alatus, including flavonoids, terpenoids, steroids, lignans, cardenolides, phenolic acids, and alkaloids. Studies in vitro and in vivo have demonstrated the hypoglycemic activity of E. alatus extracts and its certain constituents. The hypoglycemic activity of E. alatus may be related to regulation of insulin signaling and insulin sensitivity, involving PPARγ and aldose reductase pathways. Further studies on E. alatus and its bioactive compounds may help to develop new agents for treating diabetes and diabetic complications.

CDK4 is an essential insulin effector in adipocytes.

Insulin resistance is a fundamental pathogenic factor that characterizes various metabolic disorders, including obesity and type 2 diabetes. Adipose tissue contributes to the development of obesity-related insulin resistance through increased release of fatty acids, altered adipokine secretion, and/or macrophage infiltration and cytokine release. Here, we aimed to analyze the participation of the cyclin-dependent kinase 4 (CDK4) in adipose tissue biology. We determined that white adipose tissue (WAT) from CDK4-deficient mice exhibits impaired lipogenesis and increased lipolysis. Conversely, lipolysis was decreased and lipogenesis was increased in mice expressing a mutant hyperactive form of CDK4 (CDK4(R24C)). A global kinome analysis of CDK4-deficient mice following insulin stimulation revealed that insulin signaling is impaired in these animals. We determined that insulin activates the CCND3-CDK4 complex, which in turn phosphorylates insulin receptor substrate 2 (IRS2) at serine 388, thereby creating a positive feedback loop that maintains adipocyte insulin signaling. Furthermore, we found that CCND3 expression and IRS2 serine 388 phosphorylation are increased in human obese subjects. Together, our results demonstrate that CDK4 is a major regulator of insulin signaling in WAT.

A very low carbohydrate ketogenic diet increases hepatic glycosphingolipids related to regulation of insulin signalling

Low carbohydrate ketogenic diet (KD) produces several ameliorating effects against metabolic abnormalities found in obese patients. However, mechanisms underlying the effect of KD are poorly understood. We report here that KD increases gangliosides, which were recently identified as a novel modulator involved in the regulation of cellular insulin signalling. We found that the ob/ob mice had low liver ganglioside content, whereas feeding KD increased this to approximately equivalent levels observed in wild-type mice. This result indicates that KD improves the low level expression of gangliosides in ob/ob mouse liver. On the other hand, feeding KD specifically increased only monosialoganglioside GM3 in wild-type mice. This work revealed the potential utility of low carbohydrate diet including KD as a functional food targeting insulin-related metabolic abnormalities.

Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of type 2 diabetes; however, the enzyme has been classified by some as an "undruggable target". Here we describe studies directed toward the development of agents that covalently capture the sulfenyl amide "oxoform" of PTP1B generated during insulin signaling events. The sulfenyl amide residue found in oxidized PTP1B presents a unique electrophilic sulfur center that may be exploited in drug and probe design. Covalent capture of oxidized PTP1B could permanently disable the intracellular pool of enzyme involved in regulation of insulin signaling. Here, we employed a dipeptide model of oxidized PTP1B to investigate the nucleophilic capture of the sulfenyl amide residue by structurally diverse 1,3-diketones. All of the 1,3-diketones examined here reacted readily with the electrophilic sulfur center in the sulfenyl amide residue to generate stable covalent attachments. Several different types of products were observed, depending upon the substituents present on the 1,3-diketone. The results provide a chemical foundation for the development of agents that covalently capture the oxidized form of PTP1B generated in cells during insulin signaling events.

Inhibition of PTP1b in the amygdala reduces food intake, body weight and modulates glycemic homeostasis in obese rats

Background The control of food intake depends, in part, of the action and signaling of hormones, such as insulin in hypothalamic neurons. In obesity, inflammatory cytokines activate protein phosphatases, such as protein tyrosine phosphatase 1B (PTP1B). PTP1B interacts with the insulin receptor (IR) and the insulin receptor substrate (IRS1), inhibiting them in hypothalamus. Other brain regions, that are part of the dopaminergic reward system, such as the amygdala, participate of the control of energy balance in parallel to the hypothalamus. Insulin exerts its anorexigenic effect also through the amygdala and, in obesity, this effect is abolished. However, it is not known whether PTP1B is expressed and participates of the regulation of insulin signaling in amygdala.

A bis-Schiff base of isatin improves methylglyoxal mediated insulin resistance in skeletal muscle cells.

Methylglyoxal (MGO) is a highly reactive advanced glycation end products (AGEs) precursor and its abnormal accumulation causes damage to various tissues and organs. In our previous study, we synthesized a novel MGO inhibitor, MK-I-81, a bis-Schiff base derivative of isatin. In this study we demonstrate the mechanism of action of MK-I-81, on insulin resistance in skeletal muscle cells. MK-I-81 reduced AGEs formation and restored proximal insulin signaling by modulating IRS-1 phosphorylation. MK-I-81 also alleviated MGO mediated diminished distal insulin signaling by increasing protein kinase B and glycogen synthase kinase 3-beta phosphorylation. We also observed that MK-I-81 prevented reduced glucose uptake and glycogen synthesis induced by MGO in muscle cells. We found that the mechanism of action by which MK-I-81 reduced insulin resistance was suppression of production of MGO mediated ROS production in C2C12 cells. We evaluated deactivation of PKC-α and receptor for advanced glycation end products (RAGE) after treatment of cells with MK-I-81. MK-I-81 also reduced MGO mediated IRS-1, PKC-α and RAGE interaction in muscle cells. MK-I-81 also promoted nuclear factor erythroid 2-related factor-2 phosphorylation, heme oxygenase-1 and glyoxalase expression levels. We conclude that MK-I-81 can be a potential therapeutic target to address AGEs mediated insulin resistance. A novel Advanced Glycation End products (AGEs) inhibitor, MK-I-81 (a bis Schiff base of isatin), restored AGEs mediated down regulation of insulin signaling via modulating key molecules of proximal and distal insulin signaling. MK-I-81 also increased glucose uptake and glycogen synthesis in muscle cells. Novel bis-Schiff base of isatin showed significant antioxidant activity and also reduced receptor for AGEs (RAGE) expression and PKC-alpha activation therefore; MK-I-81 reduces AGEs induced insulin resistance.

Protein Tyrosine Phosphatase 1B (PTP1B) in the immune system

Protein Tyrosine Phosphatase 1B (PTP1B) is best known for its role in insulin and leptin signalling. Its ability to directly dephosphorylate the insulin receptor (IR) has made it a prime target for the development of anti-diabetic drugs. In recent times the role of PTP1B has been substantially expanded from a simple regulator of insulin signalling to a complex and dynamic regulator of multiple signalling pathways including the Janus kinase and signal transducer and activator of transcription (JAK-STAT) signalling, thus providing a link between metabolism and inflammation. Here, we review the inflammation associated with obesity and diabetes and the role that PTP1B may play in the development and regulation of this inflammation. We will discuss the role of PTP1B in both the innate and adaptive immune system and how the development of tissue specific knock out models have allowed us to delineate this complex system. Finally, we discuss how this new knowledge may allow us to develop safe and effective treatments for a multitude of conditions, including type 2 diabetes mellitus (T2DM), autoimmunity, and chronic inflammation.

Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts.

BackgroundObesity, defined as pathologically increased body mass index (BMI), is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed.MethodsWhole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals.ResultsExtensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS).ConclusionsWhereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0141-x) contains supplementary material, which is available to authorized users.

Mitochondrial-generated ROS down regulates insulin signaling via activation of the p38MAPK stress response pathway

Impairment of insulin signaling and hepatic insulin resistance has been attributed to ROS-mediated activation of p38MAPK stress response signaling. Our research focused on whether (a) ROS generated by mitochondrial electron transport chain complex I (ETC-CI) dysfunction, via the use of Rotenone, inactivates insulin signaling; and (b) the p38MAPK pathway is involved in the ROS-induced impairment of insulin signaling. Our results show that in primary mouse hepatocytes the CI inhibitor, Rotenone, (a) induces IRS-1 Ser307 phosphorylation that is blocked by the anti-oxidant NAC or by the p38MAPK inhibitors, SB203580 and SB202190; (b) inhibits insulin-stimulated AKT-Ser473 and GSK3β-Ser9 phosphorylations, in a manner that is not responsive to reversal by the anti-oxidant NAC or by the p38MAPK inhibitors, SB203580 and SB202190. We conclude that rotenone-induced insulin resistance involves a p38MAPK-dependent mechanism for the inhibition of the proximal end of insulin signaling (IRS1), and a p38MAPK-independent mechanism for the inhibition of the distal end (AKT and GSK3β). Our study suggests that ROS generated by inhibition of ETC CI, promotes hepatic insulin resistance partly via activation of the p38MAPK stress-response pathway.