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The MAPK Enhancing immune health is an essential secondary branch Enhance insulin signaling the insulin signaling pathway. It is activated independently of the PI3K pathway either through binding of growth factor receptor-bound protein 2 Grb2 to tyrosine-phosphorylated Shc, or through Sh2 binding to the insulin receptor.
The amino-terminal SH3 domain of Grb2 binds to proline-rich regions of proteins such as son-of-sevenless SOSa guanine nucleotide exchange factor that catalyzes the shift of membrane-bound Ras from an inactive form Ras-GDP to an active form Ras-GTP [18].
They act by regulating gene expression as well as extra-nuclear events, such as cytoskeletal reorganization, through the phosphorylation and activation of target proteins in both the cytosol and nucleus [11].
Many mechanisms exist to attenuate, finetune, and terminate insulin signaling, both at the level of the receptor and at various points in the cascade. The insulin receptor and IRS proteins are negatively regulated by multiple systems, such as ligand-induced downregulation, tyrosine protein phosphatases, and serine phosphorylation.
Phosphatases also regulate the subsequent steps in the associated protein kinase cascades. Negative feedback loops have been shown to play an essential role in finetuning this complex network [13,2]. Chronic exposure to insulin hyperinsulinemia results in a decrease of insulin receptors on the cell surface [19]as well as decreased IRS1 and IRS2 in vitro and in vivo in mice, which has been linked to insulin resistance in animal models [13].
The decrease in insulin receptors occurs through endocytosis by clathrin-coated vesicles. These receptors are then recycled or degraded within the lysosomes of the cell [20]. Receptor endocytosis has since been demonstrated to be a critical negative feedback mechanism that is relevant to the entire class of RTKs.
IRS signaling is negatively regulated by serine phosphorylation and kinases, such as ERK, S6 kinase, and c-Jun-N-terminal kinase JNKwhich are all activated by insulin. This is another negative feedback mechanism in the insulin signaling pathway [13]. The receptor for TNFα TNFRwhich predominantly functions in apoptosis and inflammation, induces IRS1 serine phosphorylation through JNK [13]causing insulin resistance in vitro, and in vivo in animal models as well as humans [21].
PTP1B is a major protein tyrosine phosphatase that dephosphorylates the insulin receptor. This protein resides in the endoplasmic reticulum and acts on the insulin receptor during internationalization and recycling of the receptor to the plasma membrane [22,23].
PTP1B also acts to dephosphorylate residues on activated IGF-1R and IRS proteins to reduce their activity. PTP1B knockout mice have been shown to be more sensitive to insulin and exhibit improved glucose tolerance [24,25].
Protein phosphatase 2A PP2A also plays a critical role in regulating the activities of many protein kinases involved in the insulin cascade, including Akt, PKC, and ERK [27]. Interestingly, PP2A has been demonstrated to be hyperactivated in diabetic states [28].
PH domain leucine-rich repeat protein phosphatases PHLPP-1 and PHLPP-2, members of the PP2C family, act to dephosphorylate both Akt and PKCs [30]. When PHLPP1 is over expressed in cells, the function of Akt and GSK3 activity is reduced. This results in a decrease in glycogen synthesis and glucose transport [31].
Obese and diabetic patients have been shown to have elevated levels of PHLPP1 in both adipose tissue and skeletal muscle which correlates with decreased Akt2 phosphorylation [31,32]. Negative regulation of the PI3K pathway occurs through dephosphorylation and subsequent inactivation of PIP3 by phospholipid phosphatases such as the tumor suppressor PTEN phosphatase and tensin homolog and SHIP2 SH2-containing inositol 5'-phosphatase PTEN dephosphorylates phosphoinositides on the 3'-position, whereas SHIP2 functions at the 5'-position [33].
Suppressor of Cytokine Signaling SOCS proteins also function to attenuate insulin receptor signaling. These are mediators of cytokine receptor signaling, such as leptin and IL-6 receptors that act through Janus kinases JAK and signal transduction, as well as activation of transcription STAT proteins [34,35].
SOCS1, SOCS3, SOCS6, and SOCS7 act by binding to the insulin receptor to inhibit signaling, as well as by targeting IRS-1 and IRS-2 for proteasomal degradation [35].
Type 2 diabetes is the primary disease associated with insulin and the insulin signaling pathways. This complex and heterogeneous disorder is caused by a combination of lifestyle and environmental factors, such as the typical western diet which is high in fats and sugarsinactivity, and obesity, and is further modified by various genetic determinants [36].
Type 2 Diabetes is caused by two factors, insulin sensitivity or insulin resistance attributed to dysregulation of the insulin receptor signaling cascade, and changes in the production and secretion of insulin by the beta cells of the pancreas in response to elevated glucose.
However, the relative impact of both defects on the development of diabetes has not yet been ascertained, nor have the specific molecular events at the tissue and cellular level [2]. As insulin receptors are present on many different cell types, dysregulation of the insulin signaling network effects multiple organs of the body in diabetes.
Heart attacks and strokes, precipitated by pathological blood clots thrombiare the leading cause of death in diabetic patients. The reason for this is twofold; firstly, patients with diabetes have an increased risk of developing more extensive atherosclerosis AS [37]and secondly, they possess "hyperactive" platelets, which are prone to forming thrombi.
The rupture of an atherosclerotic plaque, combined with this augmented propensity for platelets to form large occlusive thrombi, increases the risk of fatal thrombotic events in diabetic individuals. Endothelial dysfunction, as well as the hyperactive phenotype of diabetic platelets, are well reported [38,39,40]but the exact underlying mechanisms remain largely unknown.
Diabetic patients also have an increased risk of developing Alzheimer's Disease ADa neurodegenerative disorder, although the exact relationship between these two diseases is poorly understood. Insulin signaling dysfunction has been reported in the AD brain, however, whether this is a cause or consequence of the disease has not yet been ascertained [41,42].
There is growing evidence that abnormal insulin levels and dysregulated insulin signaling lead to cancer development and progression.
A higher incidence of cancer is found in obese patients and those with type 2 diabetes. Many of the proteins that play a role in the insulin signaling pathways are involved in promoting cell proliferation and mitosis, as well as preventing apoptosis, which may increase the risk of tumor formation and metastasis [43].
Despite the tremendous progress made in understanding insulin and insulin receptor signaling over the last decades, there is still much left to be uncovered regarding how these complex networks regulate cells in both normal and disease states.
We offer a wide range of research tools that be used for studing the insulin signalling pathway, glucose storage, glucose uptake, and protein lipid synthesis through Ras, Akt, mTor and MAPK.
Below we have listed some of our most popular antibodies and immunoassays. The Insulin Receptor The insulin receptor belongs to the superfamily receptor tyrosine kinases RTKs [3,4] and is activated by insulin, as well as insulin-like growth factors IGF Insulin Receptor Pathways When insulin binds to the extracellular α subunits of the insulin receptor, a conformational change is induced, which then results in the autophosphorylation of several tyrosine residues present in the β subunits.
Figure 1: The PI3K and MAPK pathways. Negative Regulation of Insulin Receptor Signaling and Signal Termination Many mechanisms exist to attenuate, finetune, and terminate insulin signaling, both at the level of the receptor and at various points in the cascade.
Negative Feedback Loops in Response to Insulin Negative feedback loops have been shown to play an essential role in finetuning this complex network [13,2].
Attenuation of Insulin Signaling by Protein and Phospholipid Phosphatases PTP1B is a major protein tyrosine phosphatase that dephosphorylates the insulin receptor. Other Negative Modulators of Insulin Receptor Signaling Suppressor of Cytokine Signaling SOCS proteins also function to attenuate insulin receptor signaling.
Figure 3: Negative regulators of the insulin signaling pathway. Dysregulated Insulin Signaling and Disease Type 2 Diabetes Type 2 diabetes is the primary disease associated with insulin and the insulin signaling pathways.
Thrombosis and Atherosclerosis Heart attacks and strokes, precipitated by pathological blood clots thrombiare the leading cause of death in diabetic patients. Cancer There is growing evidence that abnormal insulin levels and dysregulated insulin signaling lead to cancer development and progression.
Recommended Products We offer a wide range of research tools that be used for studing the insulin signalling pathway, glucose storage, glucose uptake, and protein lipid synthesis through Ras, Akt, mTor and MAPK. Popular Research Tools.
References James, D. et al. Insulin-regulatable Tissues Express a Unique Insulin-Sensitive Glucose Transport Protein. De Meyts, P. The Insulin Receptor and Its Signal Transduction Network. Ullrich, A. Human Insulin Receptor and Its Relationship to the Tyrosine Kinase Family of Oncogenes.
Ebina, Y. The Human Insulin Receptor cDNA: The Structural Basis for Hormone-Activated Transmembrane Signalling. Sun, X. Structure of the Insulin Receptor Substrate IRS-1 Defines a Unique Signal Transduction Protein.
: Enhance insulin signaling| MINI REVIEW article | C-reactive Protein Induces Phosphorylation of Insulin Receptor substrate-1 on Ser and Ser in L6 Myocytes, Thereby Impairing the Insulin Signalling Pathway That Promotes Glucose Transport. Shepherd, P. The Role of Phosphoinositide 3-kinase in Insulin Signalling. Journal of Molecular Endocrinology. Phosphoinositide 3-kinase: The Key Switch Mechanism in Insulin Signalling. The Biochemical Journal. Avruch, J. MAP Kinase Pathways: The First Twenty Years. Biochimica et Biophysica Acta. Cantley, L. The Phosphoinositide 3-kinase Pathway. Taniguchi, C. Critical Nodes in Signalling Pathways: Insights Into Insulin Action. Nature Reviews Molecular Cell Biology. Harris, T. and Lawrence, J. TOR Signaling. Science's Signal Transduction Knowledge Environment STKE. Cohen, P. and Frame, S. The Renaissance of GSK3. Svendsen, AM. Down-regulation of Cyclin G2 by Insulin, IGF-I Insulin-Like Growth Factor 1 and X10 AspB10 Insulin : Role in Mitogenesis. Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation. The Journal of Biological Chemistry. Skolnik, EY. The EMBO Journal. Gavin, G. Insulin-dependent Regulation of Insulin Receptor Concentrations: A Direct Demonstration in Cell Culture. Proceedings of the National Academy of Sciences of the United States of America. Carpentier, J. Insulin Receptor Internalization: Molecular Mechanisms and Physiopathological Implications. Hotamisligil, G. Mechanisms of TNF-alpha-induced Insulin Resistance. Exp Clin Endocrinol Diabetes. Elchebly, M. Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine phosphatase-1B Gene. Zhang, Z. Protein Tyrosine Phosphatases: Structure and Function, Substrate Specificity, and Inhibitor Development. Annual Review of Pharmacology and Toxicology. Haj, F. Imaging Sites of Receptor Dephosphorylation by PTP1B on the Surface of the Endoplasmic Reticulum. Klaman, L. Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-deficient Mice. Molecular and Cellular Biology. Brady, M. and Saltiel, A. The Role of Protein phosphatase-1 in Insulin Action. Recent Progress in Hormone Research. Millward, T. Regulation of Protein Kinase Cascades by Protein Phosphatase 2A. Trends in Biochemical Sciences. Kowluru, A. and Matti, A. Hyperactivation of Protein Phosphatase 2A in Models of Glucolipotoxicity and Diabetes: Potential Mechanisms and Functional Consequences. Biochemical Pharmacology. Ni, Y. FoxO Transcription Factors Activate Akt and Attenuate Insulin Signaling in Heart by Inhibiting Protein Phosphatases. Brognard, J. and Newton, A. PHLiPPing the Switch on Akt and Protein Kinase C Signaling. Trends in Endocrinology and Metabolism. Andreozzi, F. Increased Levels of the Akt-specific Phosphatase PH Domain Leucine-Rich Repeat Protein Phosphatase PHLPP -1 in Obese Participants Are Associated With Insulin Resistance. Cozzone, D. Maehama, T. and Dixon, J. PTEN: A Tumour Suppressor That Functions as a Phospholipid Phosphatase. Trends in Cell Biology. Emanuelli, B. SOCS-3 Inhibits Insulin Signaling and Is Up-Regulated in Response to Tumor Necrosis Factor-Alpha in the Adipose Tissue of Obese Mice. Howard, J. and Flier, J. Attenuation of Leptin and Insulin Signaling by SOCS Proteins. Qi, L. Genetic Predisposition, Western Dietary Pattern, and the Risk of Type 2 Diabetes in Men. The American Journal of Clinical Nutrition. Gleissner, C. Mechanisms by Which Diabetes Increases Cardiovascular Disease. Drug Discovery Today. Disease Mechanisms. Kaur, R. Endothelial Dysfunction and Platelet Hyperactivity in Type 2 Diabetes Mellitus: Molecular Insights and Therapeutic Strategies. Cardiovascular Diabetology. Li, Y. American Journal of Physiology. Heart and Circulatory Physiology. Vinik, A. Platelet Dysfunction in Type 2 Diabetes. Diabetes Care. Stanley, M. Changes in Insulin and Insulin Signaling in Alzheimer's Disease: Cause or Consequence? The Journal of Experimental Medicine. Gabbouj, S. Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway. Frontiers in Neuroscience. Poloz, Y. and Stambolic, V. Obesity and Cancer, a Case for Insulin Signaling. Show all. Main Menu Contact Us 0 Checkout. Anti-AKT Antibody A Anti-AKT Antibody [RM] A Anti-C Peptide Antibody A Anti-C Peptide Antibody [C-PEP] A Anti-Chromogranin A Antibody [RM] A Anti-Chromogranin A Antibody [DR] A Anti-ERK1 Antibody A Anti-ERK1 Antibody [E19] A Anti-Insulin Antibody [IN] A Anti-Insulin Antibody [7F8] A Anti-IDE Antibody A Anti-IGF1 Antibody A Anti-IGF1 Antibody [NYRhIGF1] A Anti-IGF1R Antibody A Anti-IGF2 Antibody A Anti-IGFBP3 Antibody A Anti-IGFBP4 Antibody A Anti-IRS-1 Antibody A Anti-IRS-1 phospho Ser Antibody A When we eat sugar, insulin is released to facilitate metabolism by binding directly to receptors on the outside of cells. Insulin receptors are present on all cells within the body, with fat cells adipocytes and liver cells hepatocytes having the highest amount. When insulin binds, it allows the cell to transport sugar glucose inside—this process lowers blood sugar levels. Without insulin, our cells cannot absorb or utilize sugar as an energy molecule. In summary, insulin regulates the metabolism of carbohydrates, protein, and fat for every cell within the body. Insulin sensitivity, commonly known as insulin resistance, is defined as impaired insulin signaling. Essentially, this term attempts to measure how well the body responds to insulin and sugar levels. This involves the complex interplay of many metabolic pathways, including: 8. Standard of care involves measuring your blood sugar level and a lab called an A1c. Studies are currently underway to evaluate if measuring other biomarkers, such as adiponectin, RBP4, chemerin, A-FABP, FGF21, fetuin-A, myostatin, IL-6, irisin, and the gut microbiome can be useful labs to follow in the future. Sugar causes certain neurons in the brain to release natural opioids and dopamine, thus triggering the same pleasure center circuitry that is activated by drugs and alcohol. One study demonstrated that fructose and alcohol follow a similar metabolism pathway in the liver, cause similar types of liver inflammation fatty liver , both cause increased visceral fat tissue, and activate the same hedonic pleasure pathway in the brain. While food and sugar themselves do not meet criteria as an addiction this is a heavily debated topic , our bodies are genetically designed to crave sugar and store this for future use. When humans would regularly experience extended times of fasting, and even starvation, we adapted by storing fat and glycogen for future use. This process of gaining and losing weight , from an evolutionary perspective, promoted our survival as a natural compensatory mechanism. As well defined by Dr. Goran, one of the leading experts on sugar, as we consume dangerously high amounts of sugar and sugar substitutes, our pancreas and hormones simply cannot compensate. Over time, the cells in our body grow less and less sensitive to insulin, further pressuring the pancreas. This triggers a vicious cycle that can fatigue the beta cells within the pancreas entirely, causing our bodies to stop producing insulin altogether. This process is evaluated by measuring insulin sensitivity. SFAs disrupt healthy insulin signaling by activating pro-inflammatory molecules. Reach instead for vegetables, olive oil, and lean meats like chicken and turkey. While studies in humans are still a bit controversial, increasing your omega-3 fatty acids can help. These include fish such as mackerel, salmon, chia seeds, walnuts, and seabass. They can also be taken in pill form as a supplement I personally take mg of EPA and mg of DHA every day. Foods rich in MUFAs are things like plant-based oils such as avocado, oil, and peanut oils. Intake of MUFAs is associated with improved insulin sensitivity. Albeit marketed as a healthy alternative to sugar, fructose and artificial sweeteners are directly related to metabolic syndrome, obesity, and insulin resistance. They disrupt our healthy gut microbiome, lead to decreased satiety feeling full , cause us to eat more, and alter how sugar is metabolized. Animal studies showed that feeding rodents a high-fat sucrose diet resulted in insulin resistance, high triglycerides, enhanced blood clotting, high blood pressure, and metabolic syndrome after just a few weeks! Completely remove things like aspartame and high fructose corn syrup commonly added to diet sodas, gum, and candy. Reach for bubbly water flavored with a real lime or lemon instead. Extensive studies show that both light continuous and high-intensity interval training improve insulin sensitivity, decrease fat tissue, and naturally treat metabolic syndrome. This can be as simple as going for a 1 mile walk every evening. For those who struggle with chronic pain or mobility issues, swimming and recumbent cycling can be excellent, low-impact forms of exercise. Reducing chronic inflammation and stress is important for optimal health outcomes. Learn how inflammation and stress affect your body long term and how to combat this. Studies show that those with shift work sleep disorder and circadian misalignment have worse signs of glucose control. This only perpetuates eating disorders and unhelpful, temporary diets. Changing your diet is a lifestyle change. Fruit is a healthy source of sugar, vitamins, flavinoids, and nutrients when consumed in moderation. According to the American Academy of Family Physicians, poor insulin sensitivity and resistance are linked to higher rates of diabetes, hypertension, dyslipidemia high levels of bad cholesterol and triglycerides , heart disease, and many other diseases. Decreased insulin sensitivity develops over many years, which is why having annual physicals and getting your labs checked every few years are so important. Those with a personal or family history of diabetes, obesity, polycystic ovarian syndrome PCOS , gestational diabetes, or heart disease would be well served to take preventative measures. Some medications can exacerbate insulin and sugar problems, such as Quetiapine Seroquel and Olanzapine Zyprexa , to name a few. If you take several medications and suffer from poor insulin sensitivity, ask for a consult with your pharmacist. adults have prediabetes or diabetes, based on their fasting glucose or A1c levels. Many genetic links have been identified, and the rates of insulin resistance are only increasing. Practicing the helpful tips in this article will help you avoid developing diabetes and re-establish a healthy relationship with food, sugar, and insulin. Signos uses an AI-driven app to provide real-time notifications about your glucose levels. As you eat and log meals in the app, it will notify you if your glucose levels spike in response to certain foods. Combined with a CGM, the app helps tailor personalized suggestions, including which foods trigger sugar spikes , when to eat them or not , and when to exercise. This keeps you within your optimal weight loss range and helps you make micro changes. Danielle Kelvas, MD, earned her medical degree from Quillen College of Medicine at East Tennessee State University in Johnson City, TN. Please note: The Signos team is committed to sharing insightful and actionable health articles that are backed by scientific research, supported by expert reviews, and vetted by experienced health editors. The Signos blog is not intended to diagnose, treat, cure or prevent any disease. If you have or suspect you have a medical problem, promptly contact your professional healthcare provider. Read more about our editorial process and content philosophy here. Take control of your health with data-backed insights that inspire sustainable transformation. Your body is speaking; now you can listen. Interested in learning more about metabolic health and weight management? Copyright © Signos Inc. This product is used to measure and analyze glucose readings for weight loss purposes only. It is not intended to diagnose, cure, mitigate, treat, or prevent pre-diabetes, diabetes, or any disease or condition, nor is it intended to affect the structure or any function of the body. Privacy Policy. How It Works. View Plans. Home How It Works FAQs Blog View Plans. How to Improve Insulin Sensitivity Increasing insulin sensitivity means your cells are able to use blood sugar more effectively, which helps your efforts to lose weight and burn fat. Reviewed by Danielle Kelvas, MD. Updated by. Science-based and reviewed. Foods to Avoid. Foods to Eat. Metabolic Health. Glucose Table of contents Example H2. Example H3. While this article itself is not directly about diabetes, we will cover some of the key principles of diabetes, such as sugar, insulin, insulin sensitivity, and how to increase insulin sensitivity What Is Insulin? This means the cell takes sugar and turns it into glycogen, so it can be stored and used later. In fat cells, insulin promotes storing sugar as fat. In muscle cells, insulin promotes protein synthesis and glycogenesis. In pancreas cells, insulin regulates the secretion of glucagon, which is a hormone that facilitates cells releasing stored sugar into the bloodstream. Insulin and glucagon are hormones that regulate each other. |
| Insulin Receptor Signaling in Normal and Insulin-Resistant States | The overexpression of IL6, in the liver, increased energy expenditure and insulin sensitivity in mice Sadagurski et al. Haywood, N. ChREBP is a glucose-responsive transcription factor that activates a lipogenic program similar to SREBP-1c, controlling Fasn, Scd1 , and Elovl6 gene expression Abstract Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum ER stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. CAS PubMed Google Scholar Keir, L. |
| 8 Ways to Boost Insulin Sensitivity | Signos | The best-characterized substrates are the IRS proteins Shc, SH2B2, and Cbl. Each contains either a phosphotyrosine-binding PTB domain IRS proteins, Shc or an SH2 domain SH2B2, Cbl that mediates receptor interaction. IRS protein and Shc PTB domains bind to the juxtamembrane autophosphorylation site pY within a canonical PTB domain binding site NPXpY. Regulation of glycogen metabolism by compartmentalized phosphorylation. Like other metabolic enzymes, control of glycogen metabolism is mediated by changes in phosphorylation of the enzymes glycogen synthase GS and glycogen phosphorylase GP through inhibition of kinases and activation of phosphatases. GS is inhibited by phosphorylation on up to nine amino acids, and insulin activates the enzyme by reversing this phosphorylation through a combination of kinase inhibition and phosphatase activation, primarily through protein phosphatase 1 PP1. Similarly, GP is activated by phosphorylation, and insulin inhibits the enzyme by reducing phosphorylation. These events occur in discrete cellular compartments owing to the presence of scaffolding proteins such as PTG Ppp1R3C and others, by binding to GS, GP, phosphorylase kinase PK , and AMPK, and targeting these proteins to glycogen itself. GS is also regulated by the binding of glucosephosphate G6P to an allosteric site that increases activity. Insulin receptor—mediated phosphorylation of IRS proteins occurs on at least nine tyrosines within sequence motifs that recognize and activate phosphatidylinositolkinase PI3K and downstream protein kinases. IRS-1 and IRS-2 are widely distributed, whereas IRS-3 and IRS-4 expression is more limited Although the IRS proteins are homologous and possess similar tyrosine phosphorylation motifs, knockout studies suggest complementary roles. IRS-1—deficient mice exhibit pre- and postnatal growth retardation due to IGF-1 resistance, as well as insulin resistance and impaired glucose tolerance, primarily in muscle and fat 43 , IRS-2—deficient mice exhibit hepatic insulin resistance, with some growth defects in the brain, β cells, and retinal cells Shc isoforms also undergo tyrosine phosphorylation by binding to the insulin receptor through their PTB domain. This adaptor protein interacts directly with the triad of phosphotyrosines in the activation loop as a homodimer, in which each member interacts with a separate receptor β subunit, then undergoes phosphorylation on a single tyrosine SH2B2 thereupon serves as an adaptor for c-Cbl phosphorylation through the adaptor protein CAP SORBS1 , leading to downstream activation of G proteins including TC10 RhoQ see below. This pathway occurs largely in lipid raft domains of the adipocyte plasma membrane Following dissociation of insulin, phosphorylation of the insulin receptor and its substrates is rapidly reversed by protein tyrosine phosphatases PTPases. Although the substrate specificity of PTPases has proven difficult to evaluate, several identified PTPases can catalyze IR dephosphorylation, and some are upregulated in insulin-resistant states 48 — Most attention has focused on the phosphatase PTP-1b encoded by Ptpn1. Disrupting Ptpn in mice increases insulin-dependent tyrosine phosphorylation of the insulin receptor and IRS proteins, leading to improved insulin sensitivity 51 , PTP-1b—deficient mice are resistant to diet-induced obesity, suggesting that PTP-1b deletion in the brain may influence energy uptake and expenditure via leptin signaling 52 , IRS proteins and the insulin receptor also undergo serine phosphorylation that is generally associated with reduced insulin action Serine phosphorylation of the receptor or substrates blocks insulin action by decreasing tyrosine phosphorylation and sequestering tyrosines by promoting interaction with proteins Multiple intracellular kinases are implicated in this serine phosphorylation 7 , 56 , including some activated by insulin, such as Akt 57 , JNK 58 , ERK 59 , and PI3K 60 , which potentially provide feedback inhibition. Moreover, serine kinases activated in obesity or by inflammation, especially PKCε 7 , can phosphorylate and inhibit substrate tyrosine phosphorylation However, the physiological relevance of these negative phosphorylation events remains uncertain 62 , Several polymorphisms in human IRS-1 G R and A P observed in T2D produce decreased associated PI3K activity These polymorphisms are associated with insulin resistance, hyperinsulinemia, adiposity, dyslipidemia, and risk of coronary disease, along with reduced IRS-1 protein levels and decreased IRS-1—associated PI3K activity Other polymorphisms associated with obesity or T2D have been detected for SH2B2 , SORBS1 , and Cbl The class 1 form of PI3K consists of a p85 regulatory unit encoded by PIK3R1 and a p catalytic subunit PIK3CA and is activated by the two SH2 domains in the regulatory subunit interacting with tyrosine-phosphorylated IRS proteins 68 , The eight identified isoforms of regulatory subunits derive from three genes that undergo alternative splicing p85α and p85β contain an SH3 domain, a BCR homology domain flanked by two proline-rich domains, two SH2 domains, and an inter-SH2 domain containing the p binding region The shorter splicing variants of regulatory subunits p55α and p50α lack the N-terminal half. p85α is ubiquitously expressed, while p55α and p50α play specific roles Transcriptional control of metabolism by insulin. Insulin increases the expression of lipogenic genes while inhibiting the expression of gluconeogenic genes in hepatocytes. Akt phosphorylates the transcription factor FOXO1, leading to the exclusion of the protein from the nucleus, and thus reducing transcription of gluconeogenic genes such as PEPCK, G6P, and others. Akt can also phosphorylate mTORC1, which in turn phosphorylates S6K. S6K activation leads to the activation of the SREBP pathway. mTORC1 also phosphorylates lipin, which inhibits SREBP action. Phosphorylation of this protein maintains a cytoplasmic localization, thus preventing its inhibitory activity. PI3K catalyzes the phosphorylation of phosphoinositides on the 3-position to generate PI- 3 P, PI- 3,4 P 2 , and PI- 3,4,5 P 3. These lipids bind to the pleckstrin homology PH domains of target proteins, altering activity or subcellular localization. This pathway can be terminated by phosphoinositide phosphatases 73 , such as PTEN 74 and SHIP2 encoded by Inppl1 Disrupting Inppl1 yields mice with increased insulin sensitivity Polymorphisms in INPPL1 are associated with increased incidence of hypertension, obesity, T2D, and metabolic syndrome Serine phosphorylation events are initiated downstream of insulin receptor substrate tyrosine phosphorylation via PI3K and small GTPase activation Figure 1B. The best-characterized pathway in insulin signaling involves the AGC kinase Akt. Ser appears to be phosphorylated mainly by the rapamycin-insensitive mTOR complex mTORC2 The mechanism of mTORC2 regulation remains uncertain. Akt amplifies multiple pathways in insulin action Targeted deletion of Akt isoforms produces insulin resistance and glucose intolerance 83 , 84 , and Akt mutations have been identified in patients with severe insulin resistance 85 , whereas an activating mutation produced hypoglycemia However, studies using Akt inhibitors and activators have not uniformly inhibited or mimicked insulin actions In part, variability may reflect the presence of three Akt isoforms Although Akt1 impacts cell survival and growth, Akt2 appears to play a more prominent role in the liver Stable expression of a constitutively active, membrane-bound form of Akt in 3T3L1 murine adipocytes resulted in increased glucose transport and persistent localization of GLUT4 to the plasma membrane 89 — 91 , but did not fully reproduce insulin action. Conversely, expression of a dominant-interfering Akt mutant inhibited insulin-stimulated GLUT4 translocation. Parenthetically, full expression of insulin action likely requires other signaling pathways Other AGC kinases activated downstream of PI3K include the protein kinase C PKC family, particularly PKC-ζ. Overexpressing PKC-ζ or PKC-λ resulted in GLUT4 translocation 93 , 94 , whereas expressing a dominant-interfering PKC-λ blocked insulin action Akt phosphorylates a variety of substrates, including glycogen synthase kinase-3 GSK3 96 , the forkhead FOXO transcription factors, cAMP regulatory element—binding protein CREB 87 , 97 , 98 , and the GAP proteins TSC2, AS, and RalGAPA Once activated at the plasma membrane, phosphorylated Akt can translocate to the cytoplasm or nucleus, depending on cell type Although PI3K activity is clearly necessary for insulin action, several lines of evidence suggest that additional signals may also be required. Activation of PI3K with other hormones, such as PDGF and IL-4, does not stimulate glucose transport in adipocytes Likewise, adding a PI- 3,4,5 trisphosphate PIP 3 analog alone did not effect glucose transport , and two insulin receptor mutants that produced complete PI3K activation failed to mediate full insulin action As mentioned above, insulin initiates additional pathways by recruiting other adaptor proteins, particularly SH2B2, which binds to the activated insulin receptor Upon phosphorylation, SH2B2 recruits a complex of SORBS1 and c-Cbl 38 , , triggering insulin receptor—catalyzed tyrosine phosphorylation of c-Cbl, which then interacts with the adaptor protein Crk in complex with C3G, a guanyl nucleotide exchange factor GEF C3G in turn activates the small GTPase TC10 RhoQ , SORBS1 expression correlates well with insulin responsiveness and increases when cells are treated with insulin-sensitizing thiazolidinediones 66 , Once activated, Ras operates as a molecular switch, converting upstream tyrosine phosphorylation into a serine kinase cascade via stepwise activation of Raf and the MAPKs MEK, ERK1, and ERK2 , The MAPKs can phosphorylate cytoplasmic substrates or translocate into the nucleus and catalyze the phosphorylation of transcription factors Elk1, p62 TCF , and others , initiating a transcriptional program that commits the cell to a proliferative or differentiative cycle. Insulin also controls protein synthesis via a process closely linked with nutrient sensing, involving the protein kinase mTORC1. mTORC1 is a PI3K family member but appears to serve primarily as a protein kinase. Insulin-mediated mTOR stimulation involves PI3K and other inputs — Akt phosphorylates and inhibits the GTPase-activating protein GAP tuberosclerosis complex 2 TSC2 , which forms a complex with the scaffolding protein TSC1 that negatively controls the small GTPase Rheb, a key regulator of the mTORC1 complex , mTOR regulates mRNA translation via phosphorylation and activation of the p70 ribosomal S6 kinase, as well as the phosphorylation of the eIF-4E inhibitor PHAS1 also called 4E-BP1; EIF4EBP1. Controlling transport processes, especially the uptake of nutrients into cells for storage, is a key aspect of insulin action. This occurs via the translocation of facilitative GLUT4 glucose transporters from intracellular sites to the plasma membrane. The GLUT4 protein consists of 12 transmembrane helices, with C- and N-terminal tails both oriented on the cytoplasmic side of the vesicle or plasma membrane. GLUT4 continuously recycles between the cell surface and various intracellular compartments in the basal state. Insulin markedly increases the rate of GLUT4 vesicle exocytosis 99 , After endocytosis, GLUT4 returns to the plasma membrane via sorting endosomes or intracellular compartments. In the basal state, at least half of the GLUT4 population is found in a specialized vesicle compartment, and stimulation with insulin depletes a proportion of these GLUT4-enriched vesicles storage GSVs , directing them to the plasma membrane. Control of GLUT4 sorting and GSV trafficking relies on activity of several small GTPases that assemble effectors mediating vesicle budding, transport, tethering, and fusion. Small GTPases are active in the GTP-bound state, and inactive upon hydrolysis of GTP to GDP due to the intrinsic activity of the proteins. GTPases are activated by GEF recruitment and inhibited by GAPs. As a general rule, upstream GEFs and GAPs regulate GTPases that control different steps in GLUT4 sorting in adipocytes and muscle cells Insulin activates TC10 via recruitment of the GEF C3G The Akt substrate AS is a RabGAP that targets Rab8 and Rab14 in muscle cells, and Rab10 in adipocytes , Insulin-mediated activation of Rab8 and Rab14 was observed in muscle cells, but Rab10 activation has not been detected , Nevertheless, Rab10 is a bona fide target of AS , and necessary for maximal GLUT4 exocytosis in response to insulin. Several lines of evidence indicate that Rab10 cycling may increase glucose uptake GLUT4 tethering relies on the exocyst, an evolutionarily conserved octameric complex that assembles at sites of exocytosis and tethers exocytic vesicles on the plasma membrane , The exocyst mediates initial contact between exocytic vesicles and the plasma membrane and can thus tether GSVs before the final membrane fusion step. Inhibiting exocyst assembly in adipocytes disrupts GSV fusion without affecting their translocation, demonstrating that this complex is necessary for vesicle targeting to the plasma membrane Insulin regulates exocyst-mediated targeting through exocyst assembly, recognition of the exocyst by GSVs, and disengagement to enable fusion — Once activated, TC10 binds to the exocyst scaffolding subunit Exo70, which assembles the complex at the plasma membrane , , , GSVs recognize the exocyst via the small GTPase RalA, which is present on GLUT4-containing vesicles. Insulin controls RalA activity primarily by inhibiting the RalGAP complex, comprising a regulatory subunit RalGAPB and a catalytic subunit RalGAPA that specifically inactivates Ral GTPases. RalGAP function requires RalGAPB, and deleting RalGAPB leads to RalGAPA instability Akt-catalyzed phosphorylation of RalGAPA on three residues inhibits the complex and allows for RalA-GTP binding Moreover, targeted knockout of Exo70 blocks glucose uptake in vivo Conditional knockout of RalGAPB leads to RalA activation in both adipocytes and muscle , along with a dramatic increase in glucose uptake and improved glucose tolerance Once activated, RalA interacts with exocyst subunits Sec5 and Exo84 , , Although the precise role of these two RalA-binding proteins remains uncertain, both are required for insulin-stimulated glucose uptake In addition to suppressing lipolysis, insulin stimulates fatty acid uptake The fatty acid transporters CD36 and FATP1 are both implicated, and studies show that insulin can increase the translocation of these transporters from intracellular vesicles to the cell surface to enhance fatty acid uptake in fat and muscle cells , Likewise, although the pathways involved remain unclear, insulin can increase amino acid uptake in these cells, potentially reflecting increased protein synthesis downstream of mTORC1 activation Insulin acutely controls metabolic enzyme activity through a combination of changes in phosphorylation, gene expression, and interaction with allosteric regulators to coordinate an increase in energy storage and decrease in utilization. Upon entering the cell, glucose is rapidly phosphorylated by hexokinase and either stored as glycogen via the activity of glycogen synthase or oxidized to generate ATP synthesis via enzymes such as pyruvate kinase. In muscle, liver, and adipose tissue, glucose is stored as glycogen and triglycerides. Insulin stimulates glycogen accumulation through coordinated increases in glucose transport and glycogen synthesis Figure 2. Hormonal activation of glycogen synthase involves both allosteric interaction with glucosephosphate and dephosphorylation promoted by kinase inhibition including PKA, AMPK, or GSK3; refs. Insulin also reduces the activities of other GSKs, notably PKA and AMPK PP1 activation correlates well with changes in glycogen synthase activity However, insulin does not appear to globally activate PP1, but rather targets specific pools of the phosphatase localized on the glycogen particle. The compartmentalized, insulin-mediated activation of PP1 is due to glycogen-targeting subunits that serve as molecular scaffolds, incorporating the enzyme with its substrates in a macromolecular complex Four different proteins G M , G L , PTG, and R 6 reportedly target PP1 to glycogen. Overexpressing these scaffolding proteins dramatically increases glycogen levels Overexpressing PTG makes glycogen stores refractory to breakdown by agents that raise intracellular cAMP levels, suggesting that PTG locks the cell into a glycogenic mode, whereas PTG knockouts dramatically reduce glycogen levels The mechanism by which insulin activates glycogen-associated PP1 remains unknown. Moreover, the genes encoding some of the scaffolding proteins are regulated, raising the possibility that transcriptional control constitutes a portion of glycogen synthesis regulation. In adipocytes, glucose is stored primarily as lipid, the result of increased uptake of glucose and activation of lipid synthetic enzymes, including pyruvate dehydrogenase, fatty acid synthase, and acetyl-CoA carboxylase, through dephosphorylation. Although insulin undoubtedly promotes dephosphorylation of these enzymes, the pathways mediating these effects are not well understood. Insulin also inhibits lipolysis in adipocytes, primarily by inhibiting the enzyme hormone-sensitive lipase HSL PKA and AMPK also regulate HSL activation via phosphorylation, while insulin inhibits HSL via a combination of kinase inhibition and phosphatase activation, and a major pathway involves reductions in cAMP levels due to the activation of the cAMP-specific phosphodiesterases PDE4 and PDE3B in fat cells , Although these phosphodiesterases can be phosphorylated and presumably regulated via Akt , Akt knockout did not compromise the insulin-mediated inhibition of HSL in adipocytes , indicating that the pathways responsible for this important action of insulin remain unknown. Insulin inhibits hepatic and renal glucose production and release by blocking gluconeogenesis and glycogenolysis through phosphorylation and dephosphorylation as described above , controlling substrates via crosstalk with other tissues, and regulating expression of genes encoding key hepatic enzymes — Controversy remains regarding the importance of direct insulin action in controlling hepatic glucose output. Insulin dramatically inhibits the transcription of PEPCK , encoding phosphoenolpyruvate carboxylase, the rate-limiting step in gluconeogenesis. Insulin also counteracts glucagon action by decreasing transcription of FBP1 encoding bisphosphatase and G6P glucosephosphatase and increases transcription of genes encoding glycolytic enzymes such as glucokinase and pyruvate kinase and lipogenic enzymes such as fatty acid synthase and acetyl-CoA carboxylase , Stable podocyte cell lines were made through transduction of lentiviruses to stably express the ER stress-specific promoter sequences ATF6 or ERSE driving the firefly luciferase reporter, together with renilla luciferase expressed independently as an internal control. We tested these assays using thapsigargin and tunicamycin, traditionally used as chemical inducers of ER stress. Both thapsigargin and tunicamycin induced time-dependent increases in ATF6-driven Fig. Peak activity was observed at 16 hr; after this time luciferase activity declined, likely due to a reduction in luciferase protein as induction of the UPR halts general protein translation. Stimulation of ER stress in podocytes. Full blot shown in Supplementary Fig. d Representative images of the CHOP immunoassay acquired with the IN Cell Analyzer. DAPI staining in the blue channel was used to segment the nuclei and was then mapped onto the green channel CHOP immunofluorescence , shown by the inner line, and CHOP fluorescence intensity in the nucleus quantified. AFU, arbitrary fluorescence units. Palmitate, one of the most abundant free fatty acids in blood plasma 21 , has been found in higher quantities in the blood of patients with type 2 diabetes 22 , and has been shown to induce insulin resistance in immortalized human podocytes Furthermore, palmitate has previously been shown to induce ER stress and cell death in podocytes This endogenous ER stressor induced time-dependent increases in ATF6-driven Fig. In addition to monitoring gene transcription using commercially-available luciferase assays, we developed a high content imaging-based assay. This enabled us to monitor the upregulation of ER stress-inducible proteins downstream of the increase in transcription, and to do so in single cells rather than in the whole cell population. All three ER stressors induced a robust dose-dependent upregulation of CHOP expression in the nucleus of podocytes after 24 hr Fig. At this timepoint, although ER stress was induced, no cell loss was observed; at 48 hr and beyond, a notable loss of cells was observed as apoptosis was initiated Supplementary Fig. Western blotting confirmed that total cellular CHOP expression was significantly increased in podocytes in response to all three stressors after 24 hr Fig. Podocytes are insulin-responsive cells, and mice with podocyte-specific IR knockdown develop significant albuminuria 8. Disruption of the PI 3-kinase PI3K -Akt signalling pathway through genetic ablation of the IR or PI3K subunits causes ER stress 11 , and we therefore hypothesised that improving insulin sensitivity would protect podocytes from ER stress. We began by examining a podocyte cell line with stable over-expression of IR Expression of the IR in these wild-type wt -IR cells was found to be three-fold higher than in wt podocytes by western blot Fig. Concomitant with the increase in IR expression, wt-IR were more sensitive to insulin, as shown recently 25 , and we demonstrate this here using high content immunofluorescence imaging of insulin-induced phosphorylation of Akt at Ser Fig. IR over-expression protects against ER stress. A Bonferroni post-hoc comparison revealed no significant difference between wt and wt-IR cells at each insulin concentration. c ATF6-driven luciferase activity for wt and wt-IR podocytes treated with diabetic media relative to normal growth media. d ERSE-driven luciferase activity for wt and wt-IR podocytes treated with diabetic media relative to normal growth media. h Composite graph of curves shown in e , f and g. We recently developed conditions for culturing podocytes which mimic those experienced by podocytes during diabetes, an environment rich in glucose, insulin and inflammatory cytokines, TNFα and IL-6, which promotes insulin resistance We observed that incubating podocytes with diabetic media during differentiation increased both ATF6- and ERSE-luciferase activity, but this was unaffected by IR over-expression Fig. Similarly, diabetic media significantly increased nuclear CHOP expression, and this acted synergistically to upregulate CHOP induced by a range of palmitate concentrations Fig. Conversely, CHOP induction was significantly attenuated in podocytes over-expressing the IR, in both untreated and palmitate-treated cells Fig. Notably, treatment of wt-IR podocytes with a range of palmitate concentrations on a background of diabetic media displayed CHOP induction indistinguishable from wt treated in the absence of diabetic media Fig. This protection from ER stress translated into protection from apoptosis Fig. We additionally assessed markers of ER stress by western blotting. Induction of GRP78 expression and phosphorylation of PERK in response to palmitate treatment on a background of diabetic media were completely suppressed by IR over-expression Supplementary Fig. PTP1B acts as a negative regulator of the insulin signalling pathway by dephosphorylating the IR and IR substrate 1 IRS1 We created a PTP1B knockdown cell line by transducing immortalised podocytes with a lentivirus to stably express PTP1B shRNA. Knockdown of PTP1B protects against ER stress. Quantification of PTP1B in cells treated with scrambled scr shRNA also shown. Data expressed as the percentage of cells positive for pAkt in the nucleus. c ATF6-driven luciferase activity for wt and PTP1B kd podocytes treated with diabetic media relative to normal growth media. d ERSE-driven luciferase activity for wt and PTP1B kd podocytes treated with diabetic media relative to normal growth media. Furthermore, in podocytes incubated with diabetic media, ATF6-driven luciferase activity was significantly reduced in PTP1B knockdown kd cells relative to wild-type cells Fig. A similar trend was seen for ERSE-driven luciferase activity, but this was not found to be significant Fig. Although diabetic media upregulated CHOP expression in wt podocytes, interestingly the same CHOP induction was not observed in PTP1B kd podocytes, and there was no significant difference between untreated wt and PTP1B kd cells with regards to CHOP expression in the nucleus Fig. This again indicates that PTP1B knockdown protects podocytes from ER stress. We observed a trend for PTP1B knockdown to suppress apoptosis in podocytes treated with a range of palmitate concentrations, but this was not found to be significant Fig. The frequency distribution plot in Fig. Cells were sorted in silico into AFU bins based on the amount of PTP1B expressed, and mean CHOP expression for cells within each bin was determined. A positive correlation was observed between PTP1B and CHOP expression, which increased when cells were treated with palmitate Fig. This indicates that the degree of CHOP upregulation in a single cell is proportional to the amount of PTP1B present, and that this effect is increased when cells are treated with palmitate. The amount of PTP1B in podocytes positively correlates with ER stress. a Immunofluorescent staining of wt and PTP1B kd cells for PTP1B. b Frequency distribution plot of unadjusted PTP1B intensity values for single cells sorted into AFU bins. c Nuclear PTP1B and CHOP paired single cell values were sorted based on the amount of PTP1B into AFU bins. WT and PTP1B kd cells were combined in silico to yield a wide range of PTP1B intensity values for cells untreated or palmitate-treated. Within each bin, the mean CHOP value was calculated and plotted. Our final strategy to improve podocyte insulin sensitivity was to make a cell line with stable knockdown of PTEN using shRNA. PTEN kd podocytes exhibited a significantly increased sensitivity to insulin, shown by increased Akt phosphorylation Fig. Knockdown of PTEN in podocytes increases ER stress. A Bonferroni post-hoc comparison revealed no significant difference between wt and PTEN kd cells at each insulin concentration. c ATF6-driven luciferase activity for wt and PTEN kd podocytes treated with diabetic media relative to normal growth media. d ERSE-driven luciferase activity for wt and PTEN kd podocytes treated with diabetic media relative to normal growth media. Inset Bar graph of 10 3. Unexpectedly, however, ER stress induction was increased in PTEN kd cells. Although the observed increase in ATF6-driven luciferase activity in PTEN kd compared to wt was not significant Fig. Importantly, there was no significant increase in CHOP expression for PTEN kd podocytes treated with diabetic media compared with untreated PTEN kd podocytes Fig. To investigate this further we treated PTEN kd cells with MEK and ERK inhibitors along with a range of palmitate concentrations, and found that inhibiting the ERK signalling pathway resulted in a significant reduction in nuclear CHOP in PTEN-depleted podocytes Fig. Defective insulin signalling in podocytes is associated with the development of ER stress 11 , and we hypothesised that by improving insulin sensitivity, podocytes would be protected from ER stress. We tested this in three genetic models of improved insulin sensitivity. Here we demonstrate that IR over-expression protects podocytes from ER stress and apoptosis, induced by either palmitate or by culturing in a diabetic environment rich in glucose, insulin and inflammatory cytokines, TNFα and IL-6 Fig. When insulin sensitivity is improved at the level of the IR in podocytes, either through IR over-expression or PTP1B knockdown, podocytes are protected from the development of ER stress. However, knockdown of PTEN, which improves insulin sensitivity through the PI3K-Akt pathway downstream of insulin, potentiates ER stress. Inhibition of mitogen-activated protein kinase kinase MEK or extracellular signal-regulated kinase ERK protects podocytes from ER stress. IRS, insulin receptor substrate. PTP1B knockdown, which also improved insulin sensitivity, also protected podocytes from the development of ER stress Fig. Since PTP1B attenuates insulin signalling by dephosphorylating IR and IRS1, both IR over-expression and PTP1B knockdown act to improve insulin sensitivity at the level of the IR. However, it is clear that PTP1B has a wide range of roles, not all related to insulin signalling. Studies in other cell types suggest that PTP1B could be an active player in the UPR; for example PTP1B knock-out from mouse embryonic fibroblasts MEFs impaired IRE1-induced ER stress PTP1B is resident at the ER, an ideal site for its involvement in the UPR; it dephosphorylates the IR at membrane contact sites, either ER-plasma membrane sites or ER-endosomal sites when the IR is internalised 28 , Furthermore, PTP1B deficiency in the liver protects against high fat-induced ER stress 30 , This correlates with our observation, that PTP1B knockdown protects podocytes from ER stress, but other, apparently unrelated PTP1B activities, such as its role in the downregulation of VEGF signalling 32 , make the possibility of PTP1B as a good therapeutic drug target for the prevention of ER stress, podocyte injury and the development of DN more complicated. PTEN was originally identified as a tumour suppressor protein and has been found to be deleted or mutated in many cancers However, unexpectedly, PTEN knockdown actually increased the development of ER stress rather than reducing it Fig. One of the many cellular effects of Akt signalling is a general increase in protein translation level, increasing protein load in the ER and making the development of ER stress more likely as the cell struggles to cope. Following this, PTEN might operate to reduce protein load by tempering Akt activity. Our high throughput CHOP assay has enabled us to understand the relationship between ER stressor concentration and ER stress response in more detail, and we found particularly that CHOP expression was increased in untreated PTEN kd podocytes, and across multiple palmitate concentrations. Our findings clearly indicate that the protection from ER stress bestowed on podocytes from improving insulin sensitivity is not straightforward. We show that improving insulin sensitivity at the level of the insulin receptor protects against ER stress. However, by genetically suppressing a downstream element of the insulin signalling network, PTEN, ER stress is enhanced. This indicates that there are critical nodes in the network that need to be dynamically controlled. In our genetic model we switched on the PI3K pathway constantly preventing upstream pathway modulation. A number of key pathways in the podocyte have been elegantly shown to be dependent on dynamic control, with either too much or too little activity being detrimental. These include VEGF-A 38 , mammalian target of rapamycin mTOR 39 , and mTORC1 Insulin signals through the Raf-MEK-ERK pathway as well as the PI3K-Akt pathway in podocytes 8 , and much cross-talk is known to occur between the two pathways Palmitate has been shown to have a number of molecular targets in different cell types; it is understood to disrupt calcium handling 42 , as well as activate mTORC1 43 and FOXO1 Future work will focus on the interplay between the PI3K-Akt and Raf-MEK-ERK signalling pathways and how their dynamic regulation can influence the ER stress response. Here we report the development of a robust antibody-based high content imaging assay for ER stress in podocytes. This assay monitors the increase in nuclear CHOP fluorescence, which is quantifiable when cells are segmented using a DAPI or other nuclear stain, using simple automated algorithms. Immortalised podocytes are grown in black-walled well plates optimised for imaging, making this assay amenable to the assessment of novel compounds to prevent ER stress in drug screens, potentially even in other cell types grown in culture. Furthermore, this assay enabled us to monitor the ER stress response in single cells rather than in the whole cell population, used here to consider the contribution of the quantity of PTP1B present in each podocyte, and the positive correlation between this measure and ER stress. To develop the CHOP assay we first screened more than 25 commercial antibodies specific for components of the UPR for their ability to recognise an expected change in protein fluorescence localisation or intensity. Only one other assay, the Herp assay, responded to thapsigargin and tunicamycin as would be predicted, by upregulating Herp expression in the cytoplasm Supplementary Fig. However, Herp was not observed to be upregulated in response to the endogenous ER stressor, palmitate, and so this assay was not taken any further. In conclusion, we have developed a robust high content imaging assay for ER stress in podocytes, which we have used alongside established ER stress-specific luciferase assays to explore the relationship between insulin sensitivity and ER stress. We hypothesised that by improving insulin sensitivity, podocytes would be protected from ER stress, with the corollary that the reduced insulin sensitivity in type 2 diabetes would predispose podocytes to ER stress, increasing GFB permeability and promoting DN. Consistent with this working hypothesis, we found that improving insulin sensitivity at the level of the IR, by over-expression of a positive regulator the IR itself or knockdown of a negative regulator PTP1B , protected podocytes from ER stress induced by palmitate or diabetic media. Conversely, we also found that knockdown of a negative regulator of the PI3K-Akt pathway, PTEN, actually increased ER stress despite also improving insulin sensitivity. Our study suggests that effectors other than Akt mediate the protective effect of insulin against ER stress, and also highlights the potential for enhancing insulin receptor activity to prevent podocyte injury and the development of DN. Mouse podocytes immortalised by transduction with a temperature sensitive large T antigen SV40 construct as previously described 45 , 46 , were used as wt cells and as a background for making wt-IR, PTEN kd and PTP1B kd cell lines. G Addgene plasmid and psPAX2 Addgene plasmid as previously reported PTEN and PTP1B were stably knocked down using MISSION® shRNA lentiviral particles PLKO-puro plasmid backbone, Sigma-Aldrich and selected with 0. Transduced cells were selected with 0. All transcriptional reporter lines additionally expressed renilla luciferase CLS-RCL, QIAGEN as an internal positive control. For treatment with thapsigargin Sigma-Aldrich , tunicamycin Tocris or palmitate the ER stressors , the media was removed 18 hr luciferase assay or 24 hr high content imaging before lysis or fixation respectively, and replaced with fresh media containing the appropriate concentration of ER stressor. Palmitate was prepared as described 48 ; sodium palmitate and bovine serum albumin fatty acid-free were purchased from Sigma-Aldrich. Protein expression was analysed from whole cell lysates as previously described 25 , using primary antibodies recognising GRP78 BiP C50B12 , Cell Signaling Technology CST , CHOP DDIT3, ab, Abcam , PTEN , Cell Signaling Technology , PTP1B N-terminal, SAB, Sigma-Aldrich , insulin receptor β 4B8 , Cell Signaling Technology , β-actin A Sigma-Aldrich , and GAPDH E, EnoGene , p-PERK , CST , total PERK , CST. Each plate was then read consecutively with the luciferase and renilla-specific substrates on a MLX Luminometer Dynex Technologies. After stimulation, cells were fixed and analysed as described Lastly, the cells were washed twice with PBS; the second wash remained on the cells for imaging. Imaging in live cells was carried out for apoptosis. Experiments were carried out with treatments in duplicate or triplicate wells. Three fields were imaged per well such that — cells were typically imaged per well. Image analysis was performed using IN Cell Analyzer Workstation Multi-Target Analysis algorithms using DAPI staining to segment the nucleus. For PTP1B, raw nuclear intensity values in arbitrary fluorescence units AFU were used. For pAkt, frequency distribution plots for wt cells of nuclear fluorescence intensity values for unstimulated and highest insulin concentration were used to determine appropriate cut-offs for cells positive for pAkt in the nucleus. Multiple experiments were combined by normalising the datasets to the lowest unstimulated values for each cell type. Cells were fixed and permeabilised, then co-stained with CHOP and PTP1B antibodies, followed by Alexa Fluor goat anti-mouse or anti-rabbit , respectively, and DAPI. Four fields per well were imaged using the IN Cell Analyzer system GE Healthcare. A perl script available on request was used to extract nuclear CHOP and nuclear PTP1B fluorescence intensity values for single cells. Perl software version: Strawberry Perl 5. WT and PTP1B kd cells were combined in silico to yield a broad range of PTP1B values. Cells were sorted based on the amount of PTP1B expressed and placed into AFU bins. Mean CHOP values within each bin were determined and standard deviation values calculated. Marshall, S. Diabetic nephropathy in type 1 diabetes: has the outlook improved since the s? Diabetologia 55 , — Article CAS PubMed Google Scholar. Rosolowsky, E. et al. Risk for ESRD in type 1 diabetes remains high despite renoprotection. Article CAS PubMed PubMed Central Google Scholar. United States Renal Data System. pdf Andersen, A. Diabetic nephropathy in Type 1 insulin-dependent diabetes: an epidemiological study. Diabetologia 25 , — Krolewski, A. The changing natural history of nephropathy in type I diabetes. Wolf, G. From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54 , — Reddy, G. The podocyte and diabetes mellitus: is the podocyte the key to the origins of diabetic nephropathy? Article PubMed Google Scholar. Welsh, G. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. Cao, Y. Role of endoplasmic reticulum stress in apoptosis of differentiated mouse podocytes induced by high glucose. Tao, J. Endoplasmic reticulum stress is involved in podocyte apoptosis induced by saturated fatty acid palmitate. CAS PubMed Google Scholar. Madhusudhan, T. Defective podocyte insulin signalling through pXBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Article Google Scholar. Zhuang, A. Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy? Kim, T. Herp enhances ER-associated protein degradation by recruiting ubiquilins. Back, S. Endoplasmic reticulum stress and type 2 diabetes. Zinszner, H. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. Oyadomari, S. Cell Death Differ. Gotoh, T. hspDnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria. Chen, Y. Down-regulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats. Coward, R. The human glomerular podocyte is a novel target for insulin action. Tejada, T. Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death. Kidney Int. Hagenfeldt, L. Uptake of individual free fatty acids by skeletal muscle and liver in man. Miles, J. Nocturnal and postprandial free fatty acid kinetics in normal and type 2 diabetic subjects: effects of insulin sensitization therapy. Diabetes 52 , — Lennon, R. Saturated fatty acids induce insulin resistance in human podocytes: implications for diabetic nephropathy. Transplant 24 , — Sieber, J. Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids. AJP: Renal Physiology , F—F CAS Google Scholar. Lay, A. et al Prolonged exposure of podocytes to insulin induces insulin resistance through lysosomal and proteasomal degradation of the insulin receptor. Diabetologia Galic, S. Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. Gu, F. Protein-tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress. Stuible, M. In control at the ER: PTP1B and the down-regulation of RTKs by dephosphorylation and endocytosis. Trends Cell Biol. Popov, D. Endoplasmic reticulum stress and the on site function of resident PTP1B. Delibegovic, M. Liver-specific deletion of protein-tyrosine phosphatase 1B PTP1B improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. Diabetes 58 , — |
| Hello. We're improving abcam.com and we'd welcome your feedback. | Quiroga, R. Coward, R. mTORC1 also phosphorylates lipin, which inhibits SREBP action. Mason, C. JCI insight 3 , e |
Enhance insulin signaling -
iv Decreased IRS1 and IRS2 expression levels are observed in the tissues of animals and patients with hyperinsulinemia or type 2 diabetes Kerouz et al. vi p38 MAPK also mediates the induction of inflammatory cytokines that promote insulin resistance Li et al.
The activation of JNK induces IRS1 phosphorylation at S and desensitizes insulin action in the liver and other tissues, acting as a mechanism for insulin resistance Lee et al. The deletion of Jnk1 Mapk8 , in mice, reduced blood glucose levels and improved insulin sensitivity following HFD treatment Tuncman et al.
Indeed, either MKP3 or PP2A interacts with Foxo1 and contributes to Foxo1 dephosphorylation at S and activation Yan et al. Currently, there are about protein kinases found in mouse or human genome sequences. Thus, the dephosphorylation of Foxo1 at the conserved Akt phosphorylation sites T 24 , S , and S enhances Foxo1 stability and transcriptional activity, stimulating gluconeogenesis and resulting in hyperglycemia.
An increase in nuclear dephosphorylated Foxo1-S levels was detected in the liver and heart of animals with type 2 diabetes Altomonte et al. The aberrant activation of Foxo1 disrupts metabolic homeostasis and promotes organ failure, by regulating the expression of a number of target genes Fig.
Foxo1 promotes hepatic glucose production via the expression of Pepck and G6pase and inhibits lipogenesis, resulting from the suppression of Srebp1c , and glucokinase and fatty acid synthase Zhang et al. Recently, we have identified a novel Foxo1 target gene — hemeoxygenase 1 Hmox1 , an enzyme catalyzing the degradation of heme to produce biliverdin, iron, and carbon monoxide.
Heme is a component of the mitochondrial electron transport chain complexes III and IV, and constitutive Foxo1 activation, following the loss of Irs1 and Irs2 , is a key component for heme degradation and impairment of mitochondrial biosynthesis and function Cheng et al.
This impairment results in reduced fatty acid oxidation and ATP generation, significantly contributing to triglyceride accumulation, resulting in organ steatosis or energy deficiency, as often observed in type 2 diabetes mellitus. The phosphorylation of Foxo1 at S by Akt promotes Foxo1 cytoplasmic retention and ubiquitination, which serve as a central mechanism controlling Foxo1 stability and activity Guo However, Foxo1 can also be phosphorylated at different serine or threonine residues by other protein kinases, enhancing transcriptional activity.
For example, mammalian sterile like kinase 1 MST1 promotes Foxo1 phosphorylation at S , which promotes neuronal cell apoptosis Yuan et al. In addition to the phosphorylation-based pathway, the activity of Foxo1 can also be regulated by other post-translational modifications, including methylation, glycosylation, and acetylation Fig.
Human Foxo1 phosphorylation, ubiquitination, methylation, acetylation, and glycosylation at amino acid residues via different pathways and enzymes. However, whether PRMT1 expression and Foxo1 methylation are altered in diabetics is unclear.
The glycosylation of Foxo1 at threonine T via O -GlcNac modification in response to glucose increased Foxo1 transcriptional activity for the expression of gluconeogenic genes Pepck and G6pase and anti-oxidative stress genes Mnsod Sod2 and catalase Housley et al.
The flux of glucose through the hexosamine biosynthetic pathway provides a substrate for the glucosaminephosphate forming UDP-GlcNAc UDP- N -acetylglucosamine. O -GlcNAc modification of proteins results in an enzymatic addition of the N -acetyl glucosamine GlcNAc moiety of UDP-GlcNAc on the hydroxyl oxygen of serines and threonines Kuo et al.
Foxo1-T is GlcNAcylated in the liver and it is a modification that is increased in diabetic animals Housley et al. In contrast, recent studies indicate that the acetylation of Foxo1 suppresses Foxo1 activity, while deacetylation by SIRT1 increases it Matsuzaki et al.
Moreover, Foxo1 is deacetylated and activated by class IIa histone deacetylases HDACs , promoting hepatic glucose production Mihaylova et al.
Nuclear HDAC4, HDAC5, and HDAC7 are phosphorylated and excluded from the nucleus by AMP-dependent protein kinase AMPK , but fasting hormone glucagon rapidly dephosphorylates and translocates the HDACs to the nucleus, where they associate with the promoters of gluconeogenic enzymes, such as Pepck and G6pase.
In turn, HDAC4 and HDAC5 recruit HDAC3, which results in acute transcriptional induction of these genes via the deacetylation and activation of Foxo transcription factors. The loss of class IIa HDACs in murine liver results in the inhibition of Foxo target genes and lowers blood glucose levels Mihaylova et al.
Moreover, with food intake, cells accumulate acetyl-CoA from glucose oxidation, providing substrate for the acetylation of Foxo1 and suppression of Foxo1 activity, in addition to insulin-induced inhibitory phosphorylation. Thus, Foxo1 merges the nutritional and hormonal signaling into a well-controlled metabolic regulation Fig.
It is of note that Foxo1 stimulates the expression of manganese superoxide dismutase MnSOD and catalase and enhances antioxidant responses. In rodents, the activation of Foxo1 following Irs2 deficiency in the brain enhanced longevity, but promoted obesity and diabetes Taguchi et al.
Also, the activation of Foxo1 enhanced myocardial survival upon the induction of oxidative stress Sengupta et al. Mice lacking systemic Foxo1 display embryonic lethality, since Foxo1 is required for endothelial cell lineage during cardiovascular development Hosaka et al. Together, these data indicate that the activation of Foxo1 is required for the maintenance of the life cycle under stressful conditions, such as prolonged fasting, in the liver for hepatic glucose production and activation of anti-oxidative mechanisms promoting survival in C.
However, Foxo1 is activated through multiple layers of regulatory mechanisms, contributing to the development of type 2 diabetes mellitus and organ failure, following insulin resistance. Human appetite is tightly controlled by the action of insulin in the CNS. The hypothalamus at the base of the forebrain comprises numerous small nuclei, each with distinct connections and neurochemistry, which regulate food intake, hormone release, sleep and wake cycles, and other biological functions.
A low dose of insulin delivery by i. infusion decreased both food intake and hepatic glucose production, effects which were blocked by PI3K inhibitors Woods et al. Combined with evidence that mice with neuron-specific Ir deletion are overweight and insulin resistant Bruning et al.
The functional significance of brain insulin signaling is further evidenced by the deletion of Irs2 in the hypothalamus resulting in hyperglycemia and obesity in mice Lin et al.
However, both leptin and insulin promoted IRS2 tyrosine phosphorylation and PI3K activation in the brain Warne et al.
Hypothalamic neurons expressing Agouti-regulated peptide Agrp stimulate food intake orexigenic: appetite stimulant during the fasting state.
Foxo1 stimulates orexigenic Agrp expression, an effect reversed by leptin delivery, in which the activation of Stat3 abrogates Foxo1 occupancy on the Agrp promoter region Kitamura et al.
The deletion of Foxo1 in AGRP neurons of mice resulted in reduced food intake, leanness, and decreased hepatic glucose production, involving the suppression of a G-protein-coupled receptor Gpr17 , a Foxo1 target gene in AGRP neurons Ren et al. By antagonizing the effect of Agrp, hypothalamic neurons expressing pro-opiomelanocortin Pomc inhibit food intake during the feeding state anorexic: lack of appetite.
The deletion of Foxo1 in POMC neurons resulted in reduced food intake and body weight, by increasing the expression of obesity susceptibility gene, carboxypeptidase E Cpe , and subsequent production of β-endorphin, which mediates anorexigenic effects in mice Plum et al.
A key feature of metabolic syndrome is hyperlipidemia, which probably results from insulin resistance in adipose tissue. Insulin promotes fat cell differentiation, enhances adipocyte glucose uptake, and inhibits adipocyte lipolysis. Mice lacking adipocyte Torc2 exhibited hyperglycemia, hyperinsulinemia, failure to suppress lipolysis in response to insulin, elevated circulating fatty acid and glycerol levels, and insulin resistance in the skeletal muscle and liver Kumar et al.
These data indicate that when insulin action fails in the adipose tissue, adipocyte development is retarded and lipids are unable to convert from carbohydrates for storage.
Thus, both glucose and lipids will redistribute into the circulation and organs, resulting in hyperlipidemia and fatty organs. These studies significantly underscore the contribution of insulin resistance in adipose tissue, via the inactivation of Akt signaling, to the control of systemic nutrient homeostasis.
Adipose tissue is also an endocrine organ secreting cytokines and hormones, including TNFα TNF , IL6, leptin, adiponectin, and many other factors, influencing food intake, systemic insulin sensitivity, and nutrient homeostasis.
However, obesity from fat expansion disrupts a proper balance of cytokine and hormone generation, promoting insulin resistance. For example, TNFα, IL6, and leptin are pro-inflammatory factors and their levels are markedly increased in obesity, where the levels of adiponectin, which has anti-inflammatory effects on the enhancement of insulin sensitivity, are markedly reduced Hotamisligil et al.
The overexpression of IKKb for the activation of NFκB a key player in the control of pro-inflammatory responses in the liver of mice is sufficient for inducing insulin resistance and type 2 diabetes Cai et al. TNFα reduces IRS1 protein levels by the activation of JNK or S6K, resulting in insulin resistance Gao et al.
Thus, the suppression of inflammation increases insulin sensitivity and reduces metabolic dysfunction in type 2 diabetes mellitus Hotamisligil et al. However, the outcome of anti-inflammatory therapy in treating insulin resistance deserves a cautionary note for several reasons, which are as follows: i inflammation is involved in the deployment and mobilization of immune cell leukocytes to defend against infections or toxins.
The overexpression of IL6, in the liver, increased energy expenditure and insulin sensitivity in mice Sadagurski et al. ii During physical exercise, inflammatory factors, such as TNFα and IL6, are secreted resulting in the inhibition of anabolic metabolism insulin action and promoting catabolic metabolism fat lipolysis to meet the fuel requirements of the muscle.
iii NFκB is essential for hepatocyte proliferation and survival, and mice lacking the p65 subunit of NFκB die of liver failure Geisler et al. iv Inflammation not only triggers pro-inflammatory responses, but also activates anti-inflammatory processes.
Together, these data indicate that a balance between inflammation and anti-inflammation is required for proper insulin actions and nutrient homeostasis. Thus, correcting the imbalance of hormones, nutrients, and inflammation may provide opportunities and challenges for the prevention and treatment of metabolic syndrome and type 2 diabetes.
In general, excess energy storage in tissues, particularly lipids, is now believed to be a primary factor contributing to metabolic syndrome Reaven a. Free fatty acids derived from nutritional intake or conversion from carbohydrates not only act as an important energy source, but also act as signaling molecules in the modulation of intracellular protein kinases PKC, JNK, etc.
for the inactivation of insulin signaling Oh et al. Excess lipid accumulation in several organs, including adipose tissue, liver, muscle, heart, and blood vessels, results in insulin resistance and triggers metabolic inflammation, a low-grade and chronic inflammatory response Samuel et al.
An acute lipid or fatty acid infusion or chronic HFD directly induces insulin resistance in mice via the activation of PKCθ Griffin et al. Saturated fatty acids also interact with a liver-secreted glycoprotein fetuin A that binds and activates Toll-like receptor 4, resulting in NFκB activation Pal et al.
In contrast, unsaturated fatty acids interact with the G-protein-coupled receptor GRP, inhibiting inflammation and obesity and increasing insulin sensitivity Ichimura et al.
In the liver, lipid accumulation hepatic steatosis is a risk factor for non-alcoholic steatohepatitis, fibrosis, cirrhosis, and liver cancer Kumashiro et al. Hyperglycemia is caused by insulin resistance not only in the brain and adipose tissue, but also in the liver, which is a central organ controlling blood glucose and lipid homeostasis.
Insulin promotes the synthesis of the macromolecules glycogen, lipids and protein in the liver and suppresses hepatic glucose production by inhibiting gluconeogenesis. The deletion of either Irs1 or Irs2 in the liver maintained glucose homeostasis, but the deletion of both Irs1 and Irs2 L-DKO mice blocked the induction of Akt and Foxo1 phosphorylation by insulin or feeding and resulted in unrestrained gluconeogenesis for hepatic glucose production, resulting in hyperglycemia, with a reduction in hepatic lipogenesis and blood lipid levels Kubota et al.
Moreover, a HFD severely impaired IRS2 expression and tyrosine phosphorylation in the hepatocytes of liver-specific Irs1 null mice and the mice developed severe diabetes Guo et al. Overnutrition or a HFD can modify intracellular signaling, affecting IRS2 expression and functionality, altering metabolic gene expression, and impairing glucose homeostasis.
Hepatic insulin resistance also results in insulin resistance in other tissues, which is demonstrated in L-DKO mice. The L-DKO mice exhibited not only inhibition of the hepatic Akt signaling cascade, but also blunted brain i. insulin action on the reduction of hepatic glucose production in i.
clamp experiments Guo et al. Moreover, L-DKO mice exhibited features of heart failure, probably secondary to hyperinsulinemia, resulting in cardiac IRS1 and IRS2 suppression Qi et al.
Similarly, mice lacking hepatic Ir displayed pro-atherogenic lipoprotein profiles with reduced HDL cholesterol and VLDL particles, and within 12 weeks of being placed on an atherogenic diet, they developed severe hypercholesterolemia Biddinger et al.
These data indicate that hepatic insulin resistance is sufficient to produce dyslipidemia and increased risk of atherosclerosis and cardiac dysfunction. The role of Foxo1 activation in the control of the development of diabetes is supported by findings in L-TKO mice, which lack Irs1 , Irs2 , and Foxo1 genes in the liver.
L-TKO mice demonstrated a significant reversal of elevated blood glucose levels, glucose intolerance, and the fasting—feeding effect on hepatic gene expression, which were observed in L-DKO mice Dong et al. Similarly, mice lacking both Akt1 and Akt2 in the liver Akt-DLKO or lacking Pdk1 or Mtorc2 which blocks Akt activation developed a similar diabetic phenotype to that seen in L-DKO mice Mora et al.
Moreover, mice lacking Akt1 , Akt2 , and Foxo1 TLKO rescued diabetes in the Akt-DLKO mice Lu et al. It is of interest that, L-TKO and TLKO mice had normal glucose tolerance and responses to the fasting—feeding challenge and suppressed Pepck and G6Pase gene expression to a degree similar to that of control mice Chai et al.
It is likely that hepatic Foxo1 deletion may sensitize brain insulin signaling to reduce hepatic glucose production, even though Akt activity is not controlled. The loss of Irs1 and Irs2 in the liver and brain resulted in hyperglycemia, while loss in other tissues, such as the heart and pancreas, resulted in organ failure.
Thus, it is likely that diabetes may serve as a link to the development of heart failure via the loss of IRS proteins. The heart is an insulin-responsive and energy-consuming organ that requires a constant fuel supply to maintain intracellular ATP levels for myocardial contraction.
The deletion of both cardiac Irs1 and Irs2 H-DKO mice: heart-specific double Irs1 and Irs2 gene knockout diminished cardiac Akt and Foxo1 phosphorylation and resulted in heart failure and death of male animals at 7—8 weeks of age Qi et al. The deletion of both Irs1 and Irs2 in the skeletal and cardiac muscle caused heart failure and diminished Akt and Foxo1 phosphorylation in the skeletal muscle, but the mice had normal blood glucose levels and insulin sensitivity Long et al.
In contrast, cardiac muscle requires either IRS1 or IRS2 for the maintenance of endogenous Akt activity and Foxo1 inactivation to promote cardiac function and survival. The overexpression of cardiac Foxo1, which caused heart failure in mice Evans-Anderson et al.
The loss of Irs1 and Irs2 following chronic insulin stimulation and p38 MAK activation contributes to insulin resistance in the heart Qi et al. Based on our recent studies, we proposed that the regulation of IRS1 and IRS2 has a major role in the control of cardiac homeostasis, metabolism, and function.
This concept was based on the following observations: i metabolic adaptation during physiological conditions phase I ; ii metabolic remodeling following the development of insulin resistance and mild cardiac dysfunction phase II ; and iii maladaptive metabolic and cardiac remodeling, leading to cardiac failure and sudden death phase III.
During phase I in the postprandial setting, insulin stimulates glucose transport and oxidation, resulting in effective cardiac utilization of glucose as a substrate for the supply of ATP.
In phase II when insulin resistance occurs, the heart undergoes adaptive responses to limit glucose utilization insulin-dependent and responds to lipid oxidation less insulin-dependent. The heart is capable of generating ATP for myocardial contraction and changes in gene expression patterns, with unaltered cardiac morphology.
During this period, the metabolic adaptation or remodeling compensates for cardiac energy demand, even without overt indications of heart failure. During phase III in H-DKO mice, when maladaptive metabolic remodeling occurs, there is a lack of compensation for cardiac energy demand, secondary to the loss of Irs1 and Irs2 , with Akt inactivation, utilization of both glucose and fatty acids being restrained, resulting in hyperlipidemia and cardiac ATP deficiency and sudden death Qi et al.
In this phase, the failing heart may exhibit a loss of mitochondrial biogenesis, a process required for fatty acid and glucose utilization via mitochondrial oxidative phosphorylation.
In addition, unknown myocardial factors, which are derived from the loss of Irs1 and Irs2 and released to cardiofibroblasts, may also contribute to the onset of interstitial fibrosis. Pancreatic β-cell failure is essential for the development of hyperglycemia in type 1 diabetes, but β-cell failure is also observed in patients with type 2 diabetes Rhodes , Rhodes et al.
The β-cells secret insulin, reducing blood glucose levels, and the α-cells secret glucagon, increasing blood glucose levels to meet bodily metabolic requirements. Recent studies have shown that insulin enhances glucose-stimulated insulin secretion in healthy humans Bouche et al.
However, whether insulin has a direct autocrine action on β-cells in promoting insulin secretion is unclear Rhodes et al. The deletion of whole-body Irs2 in mice resulted in diabetes owing to pancreatic β-cell failure Withers et al. On the other hand, the deletion of Irs2 in β-cells triggered β-cell repopulation or regeneration, leading to a restoration of insulin secretion and resolution of diabetes in aged mice Lin et al.
Conversely, the inactivation of Foxo1 in β-cells resulted in reduced β-cell mass, hyperglycemia, and hyperglucagonemia, owing to the dedifferentiation of β-cells into progenitor-like cells or pancreatic α-cells Talchai et al.
On the other hand, antagonizing glucagon receptor action in type 1 diabetes induced by streptozotocin and type 2 diabetes mellitus in mice markedly reduced blood glucose levels and completely prevented diabetes Liang et al. Thus, an abnormality at the level of the pancreas is critical for the development of diabetes, and the correction of the imbalance of hormones between insulin β-cells and glucagon α-cells may provide a potential strategy to prevent diabetes.
Skeletal muscle is an important fuel storage tissue for glucose uptake, converting it to glycogen and triglycerides, a process stimulated by insulin. Skeletal muscle demonstrates remarkable metabolic flexibility to consume and store glucose and lipids.
Mice lacking muscular Ir display elevated fat mass, serum triglyceride levels, and free fatty acid levels, but blood glucose levels, serum insulin levels, and glucose tolerance are normal.
Thus, insulin resistance in muscle contributes to the altered fat metabolism associated with type 2 diabetes, but tissues other than muscle appear to be more involved in insulin-regulated glucose disposal than previously recognized Bruning et al.
Mice lacking Mtorc2 exhibited decreased insulin-stimulated phosphorylation of Akt-S and glucose uptake and mild glucose intolerance Kumar et al. Mice lacking both Irs1 and Irs2 in the skeletal and cardiac muscle died at 3 weeks of age, and had a much shorter lifespan than mice lacking both Irs1 and Irs2 in only the cardiac muscle H-DKO mice , which died at 7 weeks of age Qi et al.
Mice lacking both Irs1 and Irs2 in the skeletal and cardiac muscle did not develop hyperglycemia or hyperinsulinemia, though insulin-induced glucose uptake was diminished. However, AMP levels were elevated in the skeletal muscle, resulting in the activation of AMPK Long et al.
AMPK stimulates glucose uptake in an insulin-independent manner, by phosphorylating and activating the Rab GAP family member AS, which promotes Glut4 translocation Taylor et al. AMPK also induces acetyl-CoA carboxylase ACC phosphorylation and inhibits ACC activity, preventing the conversion of acetyl-CoA to malonyl-CoA, disrupting lipid synthesis, and enhancing fatty acid oxidation Hoehn et al.
Together, these studies underscore the flexibility of skeletal muscle in the control of glucose homeostasis and longevity. Since skeletal muscle actively secretes hormones myokines , such as irisin, a hormone that systemically regulates glucose homeostasis and obesity Bostrom et al. Vasodilator actions of insulin are mediated by PI3K-dependent signaling pathways that stimulate the production of nitric oxide from vascular endothelium Muniyappa et al.
Insulin resistance in vascular endothelium stimulates vasoconstriction, promotes hypertension and atherosclerosis, and impairs systemic insulin sensitivity and glucose homeostasis.
The inactivation of IR in vascular endothelium diminished insulin-induced eNOS phosphorylation and blunted aortic vasorelaxant responses to acetylcholine and calcium ionophore in normal mice Duncan et al.
Vascular endothelium deficient in Irs2 or both Irs1 and Irs2 reduced endothelial Akt and eNOS phosphorylation and impaired skeletal muscle glucose uptake, resulting in systemic insulin resistance Kubota et al. The activation of Foxo following the deficiency of Irs2 or both Irs1 and Irs2 may play a key role in the stimulation of endothelial cell dysfunction.
In fact, the deletion of Foxo1 , Foxo3 , and Foxo4 in the endothelium enhanced eNOS phosphorylation, reduced inflammation and oxidative stress of endothelial cells, and prevented atherosclerosis in HFD or LDL receptor null mice Tsuchiya et al.
Endothelium-targeted deletion of Ir or Foxo genes in mice barely disrupted glucose homeostasis Duncan et al. RTEF1 has the potential to interact with the IRE and Foxo1 in cells Messmer-Blust et al.
Thus, vascular endothelium serves as an organ that potentially regulates glucose homeostasis. Insulin promotes the formation of bone and differentiation of osteoblasts that synthesize osteocalcin, a bone-derived insulin secretagogue that regulates pancreatic insulin secretion and systemically controls glucose homeostasis.
Mice lacking Ir in osteoblasts exhibited reduced bone formation, increased peripheral adiposity, and insulin resistance, primarily by reduced gene expression and activity of osteocalcin Ferron et al.
The results of these studies indicate that in osteoblasts insulin may stimulate osteocalcin by suppressing Foxo1, which affects bone remodeling and glucose homeostasis control. Foxo1 inhibits osteocalcin expression and activity by increasing the expression of ESP, a protein tyrosine phosphatase that inhibits the bioactivity of osteocalcin by favoring its carboxylation.
Moreover, osteoblast-specific Foxo1 null mice exhibit increased osteocalcin expression and insulin production and reduced blood glucose levels Rached et al.
Collectively, these data indicate that bone serves as an endocrine organ involved in the control of glucose homeostasis, through bone—pancreas crosstalk, in which Foxo1 plays a key role in insulin action regulating osteocalcin expression and activity in osteoblasts. A large body of evidence related to the mechanisms of diabetes, obesity, and cardiovascular diseases has been derived from mouse studies.
Also, experimental mice have immune gene transcriptional programs that are divergent from those of humans Shay et al. Humans live in a mobile environment. Recent studies have indicated that gastrointestinal microbiota may trigger inflammation and insulin resistance Kau et al.
Since tissue-specific deletion of a gene of interest is dependent on the tissue specificity and intensity of Cre-recombinase expression, a tissue-specific promoter that drives Cre-recombinase is critical to achieve a partial or complete deletion of the target gene to affect the phenotype observed in animals.
For example, myosin heavy chain-Cre-driven Irs1 and Irs2 deletion is almost complete and the heart failure phenotype striking, while myocyte enhancer factor-Cre-driven Irs1 and Irs2 deletion is partial and there is no observed phenotype. Similarly, adiponectin-Cre-driven Ir gene deletion is much stronger than aP2-Cre-driven Ir gene deletion and a diabetic phenotype is evident.
The interpretation of the role of insulin in adipose tissue and contribution to nutrient homeostasis may be affected. For example, RIP-cre is a rat insulin promoter-driven Cre transgenic mouse model, but Cre exhibits leaky expression in the hypothalamus of the brain Lin et al. Thus, the deletion of Irs2 by the RIP-Cre system resulted in a phenotype that is derived not only from pancreatic β-cells, but also from the brain hypothalamus Rhodes et al.
Thus, tissue specificity and intensity of Cre-recombinase expression, though advancing our understanding of mouse genetic engineering, also have a significant role in the analysis of gene function.
Insulin inhibits hepatic glucose production and stimulates lipid synthesis, and the deletion of Ir or both Irs1 and Irs2 in the liver of mice results in hyperglycemia, hyperinsulinemia, and hypolipidemia Michael et al.
A valid question is whether the mouse disease models created by genetic engineering accurately reflect the clinical features of metabolic syndrome and type 2 diabetes.
Although the inhibition of this signaling branch also limits hepatic TOCR2 or Akt-stimulated lipogenesis, suppression in adipose tissue may block the insulin inhibitory effect on fat lipolysis, contributing to hyperlipidemia in patients with type 2 diabetes mellitus, in whom other alternative pathways promoting lipogenesis remain active.
For example, insulin-independent mTORC1 activation and carbohydrate-activated lipogenic gene expression profiles via Chrebp and AMPK facilitate the progression of lipogenesis in patients with metabolic syndrome and type 2 diabetes mellitus Fig.
The identification of these and other novel mediators in the control of lipid homeostasis is important for understanding disease mechanisms and developing interventions for the control of metabolic syndrome, type 2 diabetes mellitus, and their complications.
Bariatric surgery, designed to achieve and sustain substantial weight loss and reduce food intake, effectively prevents and remediates type 2 diabetes Sjostrom et al. Moreover, gastric bypass surgery reduces adverse cardiovascular events, not only in obese adults Sjostrom et al.
The actions of metabolic surgery on metabolic control are unclear Rubino et al. Mouse studies have demonstrated that Akt inactivation and Foxo1 activation following the suppression of IRS1 and IRS2 act as a fundamental mechanism for insulin resistance, which occurs in insulin-responsive tissues, impairing systemic glucose and lipid homeostasis and body weight control and serving as an important mechanism for the development of metabolic syndrome.
Metabolic syndrome includes insulin resistance in different organs of the body, such as the brain, liver, pancreas, adipose tissue, muscle, and the cardiovascular system. Hyperinsulinemia, pro-inflammation, and overnutrition are important environmental factors that affect this system, contributing to type 2 diabetes and cardiovascular dysfunction.
Although genome-wide association analyses have identified a number of genes that control the development of diabetes and obesity Doria et al. Current anti-diabetic therapeutics, such as glucagon-like peptide, pioglitazone, and metformin, as well as metabolic surgery, may affect this pathway directly or indirectly, helping to correct the imbalance of hormones, nutrients, and inflammation.
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported. This research was also supported by resources and the use of facilities at the Central Texas Veterans Health Care System, Temple, Texas, USA.
Nature Genetics 12 — Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Medicine 15 — Lancet — Current Biology 7 — American Journal of Physiology. Endocrinology and Metabolism E — E Nature — Journal of Biological Chemistry — Cell Metabolism 14 — Nature Medicine 11 — Drug Discovery Today.
Disease Mechanisms 7 e — e Journal of Clinical Investigation — Cell Metabolism 8 — Annual Review of Physiology 68 — Cell Metabolism 7 — PNAS 96 — Boden G Obesity, insulin resistance and free fatty acids. Current Opinion in Endocrinology, Diabetes, and Obesity 18 — Diabetes 54 — PNAS — Diabetes 62 A Molecular and Cellular Biology 25 — Cell Metabolism 7 95 — Molecular Cell 2 — Science — Burcelin R Regulation of metabolism: a cross talk between gut microbiota and its human host.
Physiology 27 — Endocrinology and Metabolism E Nature Medicine 15 — Diabetes Care 35 — Diabetologia 55 — Endocrine Reviews 29 — A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.
Diabetes Care 14 — Cell Metabolism 8 65 — Diabetes 57 — Estall JL The Foxo family: partners in crime or silent heroes.
Endocrinology — Circulation Research — Nature Medicine 17 — Cell — Endocrinology and Metabolism E84 — E Gastroenterology — Diabetes 48 — Circulation — Guo S Molecular basis of insulin resistance: the role of IRS and Foxo1 in the control of diabetes mellitus and its complications.
Disease Mechanisms 10 e27 — e Molecular Endocrinology 20 — Molecular and Cellular Biology 29 — Cell Metabolism 15 — Journal of Endocrinology — Cell Metabolism 11 70 — Nature Reviews.
Immunology 8 — This complex and heterogeneous disorder is caused by a combination of lifestyle and environmental factors, such as the typical western diet which is high in fats and sugars , inactivity, and obesity, and is further modified by various genetic determinants [36]. Type 2 Diabetes is caused by two factors, insulin sensitivity or insulin resistance attributed to dysregulation of the insulin receptor signaling cascade, and changes in the production and secretion of insulin by the beta cells of the pancreas in response to elevated glucose.
However, the relative impact of both defects on the development of diabetes has not yet been ascertained, nor have the specific molecular events at the tissue and cellular level [2].
As insulin receptors are present on many different cell types, dysregulation of the insulin signaling network effects multiple organs of the body in diabetes. Heart attacks and strokes, precipitated by pathological blood clots thrombi , are the leading cause of death in diabetic patients.
The reason for this is twofold; firstly, patients with diabetes have an increased risk of developing more extensive atherosclerosis AS [37] , and secondly, they possess "hyperactive" platelets, which are prone to forming thrombi.
The rupture of an atherosclerotic plaque, combined with this augmented propensity for platelets to form large occlusive thrombi, increases the risk of fatal thrombotic events in diabetic individuals.
Endothelial dysfunction, as well as the hyperactive phenotype of diabetic platelets, are well reported [38,39,40] , but the exact underlying mechanisms remain largely unknown. Diabetic patients also have an increased risk of developing Alzheimer's Disease AD , a neurodegenerative disorder, although the exact relationship between these two diseases is poorly understood.
Insulin signaling dysfunction has been reported in the AD brain, however, whether this is a cause or consequence of the disease has not yet been ascertained [41,42].
There is growing evidence that abnormal insulin levels and dysregulated insulin signaling lead to cancer development and progression.
A higher incidence of cancer is found in obese patients and those with type 2 diabetes. Many of the proteins that play a role in the insulin signaling pathways are involved in promoting cell proliferation and mitosis, as well as preventing apoptosis, which may increase the risk of tumor formation and metastasis [43].
Despite the tremendous progress made in understanding insulin and insulin receptor signaling over the last decades, there is still much left to be uncovered regarding how these complex networks regulate cells in both normal and disease states.
We offer a wide range of research tools that be used for studing the insulin signalling pathway, glucose storage, glucose uptake, and protein lipid synthesis through Ras, Akt, mTor and MAPK. Below we have listed some of our most popular antibodies and immunoassays.
The Insulin Receptor The insulin receptor belongs to the superfamily receptor tyrosine kinases RTKs [3,4] and is activated by insulin, as well as insulin-like growth factors IGF Insulin Receptor Pathways When insulin binds to the extracellular α subunits of the insulin receptor, a conformational change is induced, which then results in the autophosphorylation of several tyrosine residues present in the β subunits.
Figure 1: The PI3K and MAPK pathways. Negative Regulation of Insulin Receptor Signaling and Signal Termination Many mechanisms exist to attenuate, finetune, and terminate insulin signaling, both at the level of the receptor and at various points in the cascade. Negative Feedback Loops in Response to Insulin Negative feedback loops have been shown to play an essential role in finetuning this complex network [13,2].
Attenuation of Insulin Signaling by Protein and Phospholipid Phosphatases PTP1B is a major protein tyrosine phosphatase that dephosphorylates the insulin receptor.
Other Negative Modulators of Insulin Receptor Signaling Suppressor of Cytokine Signaling SOCS proteins also function to attenuate insulin receptor signaling. Figure 3: Negative regulators of the insulin signaling pathway. Dysregulated Insulin Signaling and Disease Type 2 Diabetes Type 2 diabetes is the primary disease associated with insulin and the insulin signaling pathways.
Thrombosis and Atherosclerosis Heart attacks and strokes, precipitated by pathological blood clots thrombi , are the leading cause of death in diabetic patients.
Cancer There is growing evidence that abnormal insulin levels and dysregulated insulin signaling lead to cancer development and progression. Recommended Products We offer a wide range of research tools that be used for studing the insulin signalling pathway, glucose storage, glucose uptake, and protein lipid synthesis through Ras, Akt, mTor and MAPK.
Popular Research Tools. References James, D. et al. Insulin-regulatable Tissues Express a Unique Insulin-Sensitive Glucose Transport Protein. De Meyts, P. The Insulin Receptor and Its Signal Transduction Network. Ullrich, A. Human Insulin Receptor and Its Relationship to the Tyrosine Kinase Family of Oncogenes.
Ebina, Y. The Human Insulin Receptor cDNA: The Structural Basis for Hormone-Activated Transmembrane Signalling. Sun, X. Structure of the Insulin Receptor Substrate IRS-1 Defines a Unique Signal Transduction Protein. White, M. and Yenush, L. The IRS-signaling System: A Network of Docking Proteins That Mediate Insulin and Cytokine Action.
Current Topics in Microbiology and Immunology. Ravichandran, K. Signaling via Shc Family Adapter Proteins. D'Alessandris, C. C-reactive Protein Induces Phosphorylation of Insulin Receptor substrate-1 on Ser and Ser in L6 Myocytes, Thereby Impairing the Insulin Signalling Pathway That Promotes Glucose Transport.
Shepherd, P. The Role of Phosphoinositide 3-kinase in Insulin Signalling. Journal of Molecular Endocrinology. Phosphoinositide 3-kinase: The Key Switch Mechanism in Insulin Signalling.
The Biochemical Journal. Avruch, J. MAP Kinase Pathways: The First Twenty Years. Biochimica et Biophysica Acta. Cantley, L. The Phosphoinositide 3-kinase Pathway.
Taniguchi, C. Critical Nodes in Signalling Pathways: Insights Into Insulin Action. Nature Reviews Molecular Cell Biology. Harris, T. and Lawrence, J. TOR Signaling. Science's Signal Transduction Knowledge Environment STKE. Cohen, P. and Frame, S. The Renaissance of GSK3.
Svendsen, AM. Down-regulation of Cyclin G2 by Insulin, IGF-I Insulin-Like Growth Factor 1 and X10 AspB10 Insulin : Role in Mitogenesis. Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation.
The Journal of Biological Chemistry. Skolnik, EY. The EMBO Journal. Gavin, G. Insulin-dependent Regulation of Insulin Receptor Concentrations: A Direct Demonstration in Cell Culture. Proceedings of the National Academy of Sciences of the United States of America.
Carpentier, J. Insulin Receptor Internalization: Molecular Mechanisms and Physiopathological Implications. Hotamisligil, G. Mechanisms of TNF-alpha-induced Insulin Resistance.
Exp Clin Endocrinol Diabetes. Elchebly, M. Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine phosphatase-1B Gene. Zhang, Z. Protein Tyrosine Phosphatases: Structure and Function, Substrate Specificity, and Inhibitor Development. Annual Review of Pharmacology and Toxicology.
Haj, F. Imaging Sites of Receptor Dephosphorylation by PTP1B on the Surface of the Endoplasmic Reticulum. Klaman, L. Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-deficient Mice.
Molecular and Cellular Biology. Brady, M. and Saltiel, A. The Role of Protein phosphatase-1 in Insulin Action. Recent Progress in Hormone Research. Millward, T. Regulation of Protein Kinase Cascades by Protein Phosphatase 2A. Trends in Biochemical Sciences. Kowluru, A. and Matti, A.
Hyperactivation of Protein Phosphatase 2A in Models of Glucolipotoxicity and Diabetes: Potential Mechanisms and Functional Consequences. Biochemical Pharmacology. Ni, Y. FoxO Transcription Factors Activate Akt and Attenuate Insulin Signaling in Heart by Inhibiting Protein Phosphatases.
Brognard, J. and Newton, A. PHLiPPing the Switch on Akt and Protein Kinase C Signaling. Trends in Endocrinology and Metabolism.
Andreozzi, F. Increased Levels of the Akt-specific Phosphatase PH Domain Leucine-Rich Repeat Protein Phosphatase PHLPP -1 in Obese Participants Are Associated With Insulin Resistance. Cozzone, D. Maehama, T. and Dixon, J. PTEN: A Tumour Suppressor That Functions as a Phospholipid Phosphatase.
Trends in Cell Biology. Emanuelli, B. SOCS-3 Inhibits Insulin Signaling and Is Up-Regulated in Response to Tumor Necrosis Factor-Alpha in the Adipose Tissue of Obese Mice.
Howard, J. and Flier, J.
Research Article Metabolism Therapeutics Free access Discovery, Ehnance and Early Development, MRL, Merck and Co. Address correspondence to: James Mu, Gateway Blvd. Phone: Find articles by Wang, Y.
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