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Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.
Samovski D, Dhule P, Pietka T, Jacome-Sosa M, Penrose E, Son NH, Flynn CR, Shoghi KI, Hyrc KL, Goldberg IJ, Gamazon ER, Abumrad NA
(2018) Diabetes 67: 1272-1284
MeSH Terms: Animals, CD36 Antigens, CHO Cells, Carbohydrate Metabolism, Cells, Cultured, Cricetinae, Cricetulus, Diabetes Mellitus, Type 2, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Receptor, Insulin, Signal Transduction
Show Abstract · Added May 26, 2018
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
© 2018 by the American Diabetes Association.
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20 MeSH Terms
Insulin exits skeletal muscle capillaries by fluid-phase transport.
Williams IM, Valenzuela FA, Kahl SD, Ramkrishna D, Mezo AR, Young JD, Wells KS, Wasserman DH
(2018) J Clin Invest 128: 699-714
MeSH Terms: Animals, Antigens, CD, Biological Transport, Capillaries, Diabetes Mellitus, Glucose, Glucose Clamp Technique, Humans, Hyperinsulinism, Image Processing, Computer-Assisted, Insulin, Intravital Microscopy, Kinetics, Male, Mice, Mice, Inbred C57BL, Models, Theoretical, Muscle, Skeletal, Protein Binding, Receptor, Insulin, Rhodamines
Show Abstract · Added March 14, 2018
Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Here, we present an intravital microscopy technique to measure the rate of insulin efflux across the endothelium of SkM capillaries. This method involves development of a fully bioactive, fluorescent insulin probe, a gastrocnemius preparation for intravital microscopy, an automated vascular segmentation algorithm, and the use of mathematical models to estimate endothelial transport parameters. We combined direct visualization of insulin efflux from SkM capillaries with modeling of insulin efflux kinetics to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism supported this result. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.
1 Communities
1 Members
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21 MeSH Terms
In vivo evaluation of IGF1R/IR PET ligand [F]BMS-754807 in rodents.
Prabhakaran J, Dewey SL, McClure R, Simpson NR, Tantawy MN, Mann JJ, Pham W, Kumar JSD
(2017) Bioorg Med Chem Lett 27: 941-943
MeSH Terms: Animals, Fluorine Radioisotopes, Heterografts, Humans, Mice, Positron-Emission Tomography, Pyrazoles, Radioligand Assay, Rats, Receptor, IGF Type 1, Receptor, Insulin, Triazines
Show Abstract · Added March 21, 2018
In vivo evaluation of [F]BMS-754807 binding in mice and rats using microPET and biodistribution methods is described herein. The radioligand shows consistent binding characteristics, in vivo, in both species. Early time frames of the microPET images and time activity curves of brain indicate poor penetration of the tracer across the blood brain barrier (BBB) in both species. However, microPET experiments in mice and rats show high binding of the radioligand outside the brain to heart, pancreas and muscle, the organs known for higher expression of IGF1R/1R. Biodistribution analysis 2h after injection of [F]BMS-754807 in rats show negligible [F]defluorination as reflected by the low bone uptake and clearance from blood. Overall, the data indicate that [F]BMS-754807 can potentially be a radiotracer for the quantification of IGF1R/IR outside the brain using PET.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents.
Scarlett JM, Rojas JM, Matsen ME, Kaiyala KJ, Stefanovski D, Bergman RN, Nguyen HT, Dorfman MD, Lantier L, Wasserman DH, Mirzadeh Z, Unterman TG, Morton GJ, Schwartz MW
(2016) Nat Med 22: 800-6
MeSH Terms: Adipose Tissue, Animals, Blood Glucose, Blotting, Western, Body Composition, Brain, Carbon Radioisotopes, Deoxyglucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diet, High-Fat, Disease Models, Animal, Ependymoglial Cells, Fibroblast Growth Factor 1, Forkhead Box Protein O1, Glucose Tolerance Test, Heart, Heat-Shock Proteins, Hyperglycemia, Hypothalamus, Injections, Intraventricular, Liver, Male, Mice, Mice, Knockout, Mice, Obese, Muscle, Skeletal, Myocardium, Neoplasm Proteins, Proto-Oncogene Proteins c-fos, Rats, Rats, Zucker, Real-Time Polymerase Chain Reaction, Receptor, Insulin, Remission Induction
Show Abstract · Added May 16, 2019
Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.
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MeSH Terms
InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.
Ma Y, Tang N, Thompson RC, Mobley BC, Clark SW, Sarkaria JN, Wang J
(2016) Clin Cancer Res 22: 1767-76
MeSH Terms: Animals, Antineoplastic Agents, Cell Line, Tumor, Disease Models, Animal, Drug Resistance, Neoplasm, ErbB Receptors, Gefitinib, Glioblastoma, Humans, Insulin, Insulin-Like Growth Factor I, Mice, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Quinazolines, Receptor, IGF Type 1, Receptor, Insulin, Signal Transduction, Tumor Burden, Xenograft Model Antitumor Assays
Show Abstract · Added April 18, 2017
PURPOSE - Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma.
EXPERIMENTAL DESIGN - We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R).
RESULTS - Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors.
CONCLUSIONS - Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.
©2015 American Association for Cancer Research.
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20 MeSH Terms
Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation.
Gong Y, Ma Y, Sinyuk M, Loganathan S, Thompson RC, Sarkaria JN, Chen W, Lathia JD, Mobley BC, Clark SW, Wang J
(2016) Neuro Oncol 18: 48-57
MeSH Terms: Animals, Antigens, CD, Brain Neoplasms, Cell Proliferation, Cell Survival, Female, Glioblastoma, Humans, Insulin, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Mice, Nude, Proto-Oncogene Proteins c-akt, Receptor, Insulin, Receptors, Somatomedin, Signal Transduction, Tumor Cells, Cultured
Show Abstract · Added July 23, 2015
BACKGROUND - Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells.
METHODS - In the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo.
RESULTS - We showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth.
CONCLUSIONS - Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.
© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
1 Communities
3 Members
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17 MeSH Terms
Striatal dopamine homeostasis is altered in mice following Roux-en-Y gastric bypass surgery.
Reddy IA, Wasserman DH, Ayala JE, Hasty AH, Abumrad NN, Galli A
(2014) ACS Chem Neurosci 5: 943-51
MeSH Terms: Adiposity, Anastomosis, Roux-en-Y, Animals, Body Weight, Caloric Restriction, Corpus Striatum, Diet, High-Fat, Dopamine, Gastric Bypass, Homeostasis, Immunoblotting, Male, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Norepinephrine, Obesity, Phosphorylation, Receptor, Insulin, Tyrosine 3-Monooxygenase
Show Abstract · Added January 21, 2015
Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity. Importantly, weight loss following RYGB is thought to result in part from changes in brain-mediated regulation of appetite and food intake. Dopamine (DA) within the dorsal striatum plays an important role in feeding behavior; we therefore hypothesized that RYGB alters DA homeostasis in this subcortical region. In the current study, obese RYGB-operated mice consumed significantly less of a high-fat diet, weighed less by the end of the study, and exhibited lower adiposity than obese sham-operated mice. Interestingly, both RYGB and caloric restriction (pair feeding) resulted in elevated DA and reduced norepinephrine (NE) tissue levels compared with ad libitum fed sham animals. Consequently, the ratio of NE to DA, a measure of DA turnover, was significantly reduced in both of these groups. The RYGB mice additionally exhibited a significant increase in phosphorylation of tyrosine hydroxylase at position Ser31, a key regulatory site of DA synthesis. This increase was associated with augmented expression of extracellular-signal-regulated kinases ERK1/2, the kinase targeting Ser31. Additionally, RYGB has been shown in animal models and humans to improve insulin sensitivity and glycemic control. Curiously, we noted a significant increase in the expression of insulin receptor-β in RYGB animals in striatum (a glucosensing brain region) compared to sham ad libitum fed mice. These data demonstrate that RYGB surgery is associated with altered monoamine homeostasis at the level of the dorsal striatum, thus providing a critical foundation for future studies exploring central mechanisms of weight loss in RYGB.
1 Communities
4 Members
1 Resources
20 MeSH Terms
Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone.
Thrailkill K, Bunn RC, Lumpkin C, Wahl E, Cockrell G, Morris L, Kahn CR, Fowlkes J, Nyman JS
(2014) J Diabetes Res 2014: 703589
MeSH Terms: Animals, Biomechanical Phenomena, Body Size, Bone and Bones, Female, Genotype, Glucose, Insulin, Male, Mice, Mice, Knockout, Mice, Transgenic, Osteoblasts, Osteogenesis, Phenotype, Receptor, Insulin
Show Abstract · Added July 28, 2014
Type 1 diabetes mellitus (T1D) is associated with decreased bone mineral density, a deficit in bone structure, and subsequently an increased risk of fragility fracture. These clinical observations, paralleled by animal models of T1D, suggest that the insulinopenia of T1D has a deleterious effect on bone. To further examine the action of insulin signaling on bone development, we generated mice with an osteoprogenitor-selective (osterix-Cre) ablation of the insulin receptor (IR), designated OIRKO. OIRKO mice exhibited an 80% decrease in IR in osteoblasts. Prenatal elimination of IR did not affect fetal survival or gross morphology. However, loss of IR in mouse osteoblasts resulted in a postnatal growth-constricted phenotype. By 10-12 weeks of age, femurs of OIRKO mice were more slender, with a thinner diaphyseal cortex and, consequently, a decrease in whole bone strength when subjected to bending. In male mice alone, decreased metaphyseal trabecular bone, with thinner and more rodlike trabeculae, was also observed. OIRKO mice did not, however, exhibit abnormal glucose tolerance. The skeletal phenotype of the OIRKO mouse appeared more severe than that of previously reported bone-specific IR knockdown models, and confirms that insulin receptor expression in osteoblasts is critically important for proper bone development and maintenance of structural integrity.
1 Communities
2 Members
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16 MeSH Terms
Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation.
Fox EM, Kuba MG, Miller TW, Davies BR, Arteaga CL
(2013) Breast Cancer Res 15: R55
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Membrane, Cell Proliferation, Disease Models, Animal, Drug Resistance, Neoplasm, Estrogen Receptor Modulators, Female, Humans, Insulin-Like Growth Factor I, Ligands, MCF-7 Cells, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase Inhibitors, Protein Transport, Proto-Oncogene Proteins c-akt, Pyrimidines, Pyrroles, Receptor Protein-Tyrosine Kinases, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Estrogen, Tumor Burden, Up-Regulation, Xenograft Model Antitumor Assays
Show Abstract · Added September 3, 2013
INTRODUCTION - Estrogen receptor α-positive (ER+) breast cancers adapt to hormone deprivation and acquire resistance to antiestrogen therapies. Upon acquisition of hormone independence, ER+ breast cancer cells increase their dependence on the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We examined the effects of AKT inhibition and its compensatory upregulation of insulin-like growth factor (IGF)-I/InsR signaling in ER+ breast cancer cells with acquired resistance to estrogen deprivation.
METHODS - Inhibition of AKT using the catalytic inhibitor AZD5363 was examined in four ER+ breast cancer cell lines resistant to long-term estrogen deprivation (LTED) by western blotting and proliferation assays. Feedback upregulation and activation of receptor tyrosine kinases (RTKs) was examined by western blotting, real-time qPCR, ELISAs, membrane localization of AKT PH-GFP by immunofluorescence and phospho-RTK arrays. For studies in vivo, athymic mice with MCF-7 xenografts were treated with AZD5363 and fulvestrant with either the ATP-competitive IGF-IR/InsR inhibitor AZD9362 or the fibroblast growth factor receptor (FGFR) inhibitor AZD4547.
RESULTS - Treatment with AZD5363 reduced phosphorylation of the AKT/mTOR substrates PRAS40, GSK3α/β and S6K while inducing hyperphosphorylation of AKT at T308 and S473. Inhibition of AKT with AZD5363 suppressed growth of three of four ER+ LTED lines and prevented emergence of hormone-independent MCF-7, ZR75-1 and MDA-361 cells. AZD5363 suppressed growth of MCF-7 xenografts in ovariectomized mice and a patient-derived luminal B xenograft unresponsive to tamoxifen or fulvestrant. Combined treatment with AZD5363 and fulvestrant suppressed MCF-7 xenograft growth better than either drug alone. Inhibition of AKT with AZD5363 resulted in upregulation and activation of RTKs, including IGF-IR and InsR, upregulation of FoxO3a and ERα mRNAs as well as FoxO- and ER-dependent transcription of IGF-I and IGF-II ligands. Inhibition of IGF-IR/InsR or PI3K abrogated AKT PH-GFP membrane localization and T308 P-AKT following treatment with AZD5363. Treatment with IGFBP-3 blocked AZD5363-induced P-IGF-IR/InsR and T308 P-AKT, suggesting that receptor phosphorylation was dependent on increased autocrine ligands. Finally, treatment with the dual IGF-IR/InsR inhibitor AZD9362 enhanced the anti-tumor effect of AZD5363 in MCF-7/LTED cells and MCF-7 xenografts in ovariectomized mice devoid of estrogen supplementation.
CONCLUSIONS - These data suggest combinations of AKT and IGF-IR/InsR inhibitors would be an effective treatment strategy against hormone-independent ER+ breast cancer.
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27 MeSH Terms
Reversal of type 1 diabetes in mice by brown adipose tissue transplant.
Gunawardana SC, Piston DW
(2012) Diabetes 61: 674-82
MeSH Terms: Adipose Tissue, Brown, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Female, Glucose, Homeostasis, Insulin, Interleukin-6, Ion Channels, Mice, Mice, Inbred C57BL, Mitochondrial Proteins, Receptor, Insulin, Streptozocin, Tumor Necrosis Factor-alpha, Uncoupling Protein 1, Weight Gain
Show Abstract · Added December 5, 2013
Current therapies for type 1 diabetes (T1D) involve insulin replacement or transplantation of insulin-secreting tissue, both of which suffer from numerous limitations and complications. Here, we show that subcutaneous transplants of embryonic brown adipose tissue (BAT) can correct T1D in streptozotocin-treated mice (both immune competent and immune deficient) with severely impaired glucose tolerance and significant loss of adipose tissue. BAT transplants result in euglycemia, normalized glucose tolerance, reduced tissue inflammation, and reversal of clinical diabetes markers such as polyuria, polydipsia, and polyphagia. These effects are independent of insulin but correlate with recovery of the animals' white adipose tissue. BAT transplants lead to significant increases in adiponectin and leptin, but with levels that are static and not responsive to glucose. Pharmacological blockade of the insulin receptor in BAT transplant mice leads to impaired glucose tolerance, similar to what is seen in nondiabetic animals, indicating that insulin receptor activity plays a role in the reversal of diabetes. One possible candidate for activating the insulin receptor is IGF-1, whose levels are also significantly elevated in BAT transplant mice. Thus, we propose that the combined action of multiple adipokines establishes a new equilibrium in the animal that allows for chronic glycemic control without insulin.
2 Communities
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18 MeSH Terms