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About Sickkids
About SickKids

Amira Klip, PhD

Research Institute
Director, Research Training
Research Institute

Senior Scientist
Cell Biology

University of Toronto
Professor
Biochemistry, Paediatrics & Physiology

Other Positions
Canada Research Chair
Cell Biology of Insulin Action


Phone: 416-813-6392
Fax: 416-813-5028
Email: amira.klip@sickkids.ca

Brief Biography

Dr. Amira Klip is a Senior Scientist in the Cell Biology Program at the SickKids Research Institute and Professor of Paediatrics, Biochemistry, and Physiology at the University of Toronto. In order to understand the process of insulin resistance, a leading cause of type 2 diabetes, Klip studies insulin action and the cellular and molecular steps involved in this process. She directs a laboratory of six graduate students/postdoctoral fellows, one technician and one research associate, and works with several pharmaceutical companies to screen and identify modes of action of potential anti-diabetic drugs.

Klip received a PhD in Biochemistry (Mexico City, 1976), performed postdoctoral work in Toronto and Zurich, and joined The Hospital for Sick Children (SickKids) in 1979. She was an Associate Chief of Research for 18 years and the founding director of the Research Training Centre. She is an elected fellow of the Royal Society of Canada and the Canadian Academy of Health Sciences and holds the CRC Tier I Chair in Cell Biology of Insulin Action. She has received distinguished international awards and led review panels at several universities world wide. In 2015 she received an Honorary Doctorate from the University of Copenhagen.

Until recently, Klip was a member of the CIHR grant panels on cell physiology, cell biology and mechanisms of disease. She was also the recipient of the MRC/CIHR Scholarship, Scientist Award and Distinguished Scientist Award. She is currently the recipient of CIHR Foundation Grant.

Research Interests

  • insulin action
  • muscle contraction
  • glucose transport
  • insulin delivery across endothelia
  • intracellular vesicle traffic
  • signal transduction
  • diabetes
  • inflammation

Research Activities

Glucose is the major energy substrate for most cells, and it is avidly stored as glycogen in the liver and muscle tissue, as well as processed into fat in adipose tissue. Insulin resistance, a key defect in type 2 diabetes, involves defective responses to insulin in muscle, adipose and hepatic tissues.

Klip’s laboratory studies the regulation of glucose uptake by insulin and muscle contraction, using an array of rat and mouse stable muscle cell lines generated in the lab. The focus is the intracellular traffic of vesicles containing glucose transporters, primarily GLUT4. Current work focuses on how a series of signal transduction pathways activated by insulin within muscle cells impinge on intracellular stores of GLUT4 and how the vesicles move to the cell surface. Results reveal an important bifurcation in insulin signaling downstream of phosphatidylinositol 3-kinase: a) The Akt/PKB arm, a serine/threonine protein kinase leads to the inactivation of the Rab-GAP AS160 (Akt substrate of 160 kDa), which acts through distinct Rab molecules to mobilize and position GLUT4 vesicles. The Klip lab identified Rab8A, Rab13 and Rab14 as important mediators of these steps, with the effector of Rabs 8A (MyoVa, a molecular motor) mobilizing vesicles to the membrane, and the effector of Rab13 (actinin-4, a cortical linker) anchoring vesicles to the membrane. b) The Rac activation arm functions to rapidly remodel actin filaments into a cortical mesh below the cell surface, as shown through a dynamic cycle of actin branching mediated by Arp2/3 and severing mediated by actin-binding proteins known as cofilin. Vesicles mobilized to the cell periphery interact with cortical actin through actinin-4, possibly in preparation for optimal docking and fusion with the membrane. Klip’s team earlier identified the SNARE molecules VAMP2, syntaxin4 and SNAP23 as mediators of this docking/fusion step. Recent work focuses in parallel on the process whereby insulin crosses the microvascular endothelial barrier to reach muscle and adipose cells. This work is done in collaboration with Dr. Warren Lee (St. Michael’s Hospital).

The Klip lab has also established cellular models to study insulin resistance:

  1. Exposure of muscle cell cultures to high glucose and high insulin, emulating the environment in type 2 diabetes;
  2. Exposure to high saturated fats or their derivative ceramides and reactive oxygen species, emulating the lipotoxic component of the metabolic syndrome; and
  3. Exposure to conditioned media from palmitate-treated macrophages, emulating the inflammation component of insulin resistance.

In each case, GLUT4 translocation in response to insulin was dampened, but interestingly through distinct signaling defects, respectively: reduction in IRS-1 phosphorylation, in Rac activation and in Akt and AS160 phosphorylation. These findings suggest that insulin resistance in vivo must be analyzed at each signaling level and may require distinct and specific interventional therapies.

External Funding

Recent External Funding

  • Cell biology and physiology of muscle insulin delivery, action ad resistance leading to diabetes. CIHR Foundation Grant (2015-22)
  • The GLUT4 interactomes and their metabolic implications. Canadian Institutes of Health Research (2007-12)
  • Regulation of muscle glucose transporters by Rac and Rabs during insulin action and lipotoxicity. Canadian Institutes of Health Research (2010-15)
  • Interplay between fatty acids and macrophages in the genesis and relief of muscle cell insulin resistance. Canadian Diabetes Association (2009-12)

Publications

Pillon NJ, Chan KL, Zhang S, Mejdani M, Jacobson MR, Ducos A, Bilan PJ, Niu W, Klip A (2016) Saturated fatty acids activate caspase-4/-5 in human monocytes, triggering IL-1β and IL-18 release.  Am. J. Physiol. Endocrinol. Metab. 311: E825-35.

Miyatake S, Bilan PJ, Pillon NJ, Klip A (2016) Contracting C2C12 myotubes release CCL2 in an NF-κB-dependent manner to induce monocyte chemoattraction.  Am. J. Physiol. Endocrinol. Metab. 310: E160-70.

Sun Y, Jaldin-Fincati J, Liu Z, Bilan PJ, Klip A (2016) A complex of Rab13 with MICAL-L2 and α-actinin-4 is essential for insulin-dependent GLUT4 exocytosis.  Mol. Biol. Cell 27: 75-89.

Chang Y-J, Pownall S, Jensen TE, Mouaaz S, Foltz W, Zhou L, Liadis N, Woo M, Hao Z, Dutt P, Bilan PJ, Klip A, Mak T, Stambolic V.  (2015) The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes.  eLife 4: e06011: 1-24.

Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D, Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji RR, Zhang J, Salter MW, Mogil JS (2015) Different immune cells mediate mechanical pain hyper-sensitivity in male and female mice. Nat. Neurosci. 18: 1081-5.

Chan KL, Pillon NJ, Sivaloganathan DM, Costford SR, Liu Z, Théret M, Chazaud B, Klip A (2015) Palmitoleate Reverses High Fat-induced Proinflammatory Macrophage Polarization via AMP-activated Protein Kinase (AMPK).  J. Biol. Chem. 290: 16979-88.

Osorio-Fuentealba C, Klip A (2015) Commentary. Dissecting signalling by individual Akt/PKB isoforms, three steps at once.  Biochem. J. 470: 2: e13-16.

Pillon NJ, Azizi PM, Li YE, Liu J, Wang C, Chan KL, Hopperton KE, Bazinet RP, Heit B, Bilan PJ, Lee WL, Klip A.  (2015) Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promotes monocyte adhesion and impair insulin transcytosis.  Am. J. Physiol. Endocrinol. Metab. 309: E35-44.

Azizi PM, Zyla RE, Guan S, Wang C, Liu J, Bolz S-S, Heit B, Klip A, Lee W  (2015) Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells.  Mol. Biol. Cell 26: 740-50.
Metab. 307: 2: E209-24.

Pillon NJ, Li YE, Fink LN, Brozinick JT, Nikolayev A, Kuo MS, Bilan PJ, Klip A (2014) Nucleotides Released from Palmitate-Challenged Muscle Cells Through Pannexin-3 Attract Monocytes.  Diabetes 63: 3815-26.

Li Q, Zhu X, Ishikura S, Zhang D, Gao J, Sun Y, Contreras-Ferrat A, Foley KP, Lavandero S, Yao Z, Bilan PJ, Klip A, Niu W (2014) Ca2+ signals promote GLUT4 exocytosis and reduce its endocytosis in muscle cells.  Am. J. Physiol. Endocrinol. Metab. 307: E209-24.

Costford SR, Castro-Alves J, Chan KL, Bailey LJ, Woo M, Belsham DD, Brumell JH, Klip A.  (2014) Mice lacking NOX2 are hyperphagic and store fat preferentially in the liver. Am. J. Physiol. Endocrinol. Metab. 306: E1341-53.

Foley KP, Klip A (2014) Dynamic GLUT4 sorting through a syntaxin-6 compartment in muscle cells is derailed by insulin resistance-causing ceramide.  Biol. Open 3: 314-25.

Sun Y, Chiu TT, Foley KP, Bilan PJ, Klip A (2014) Myosin Va mediates Rab8A-regulated GLUT4 vesicle exocytosis in insulin-stimulated muscle cells.  Mol. Biol. Cell 25: 1159-70.

Fink LN, Costford SR, Lee YS, Jensen TE, Bilan PB, Oberbach A, Bluher M, Olefsky JM, Sams A, Klip A (2014) Pro-inflammatory macrophages increase in skeletal muscle of high fat-fed mice and correlate with metabolic risk markers in humans. Obesity 22: 747-57.

Chiu TT, Sun Y, Koshkina A, Klip A (2013) Rac-1 Superactivation Triggers Insulin-independent Glucose Transporter 4 (GLUT4) Translocation That Bypasses Signaling Defects Exerted by c-Jun N-terminal kinase (JNK)- and Ceramide-induced Insulin Resistance.  J. Biol. Chem. 288: 17520-31.

Fink LN, Oberbach A, Costford SR, Chan KL, Sams A, Blüher M, Klip A (2013) Expression of anti-inflammatory macrophage genes within skeletal muscle correlates with insulin sensitivity in human obesity and type 2 diabetes.  Diabetologia 561623-8.

Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, Espinosa A, Li Q, Niu W, Lavandero S, Klip A, Jaimovich E.  (2013) Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells.  Diabetes 62:  1519-26.

Rudich A, Klip A (2013) Putting Rac1 on the path to glucose uptake. Invited Commentary. Diabetes 62: 1831-2.

Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, Espinosa A, Li Q, Niu W, Lavandero S, Klip A, Jaimovich E (2013) Electrical Stimuli Release ATP to Increase Glucose Uptake and GLUT4 Translocation via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells.  Diabetes, 62: 1519-26.

Sylow L, Jensen TE, Kleinert M, Mouatt JR, Maarbjerg SJ, Jeppesen J, Prats C, Chiu TT, Boguslavsky S, Klip A, Schjerling P, Richter EA (2013) Rac1 Is a Novel Regulator of Contraction-Stimulated Glucose Uptake in Skeletal Muscle.  Diabetes, 62: 4: 1139-51

Boguslavsky S, Chiu T, Foley KP, Osorio-Fuentealba C, Antonescu CN, Bayer KU, Bilan PJ, Klip A (2012) Myo1c binding to submembranous actin mediates insulin-induced tethering of GLUT4 vesicles.  Mol. Biol. Cell 23: 4065-78.

Hussey SE, Liang H, Costford SR, Klip A, DeFronzo RA, Sanchez-Avila A, Ely B, Musi N (2012) TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signaling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells.  Biosci. Rep. 33: 37-47.

Pillon N, Arane K, Bilan PJ, Chiu TT, Klip A (2012) Muscle cells challenged with saturated fatty acids mount an autonomous inflammatory response that activates macrophages.  Cell Commun. Signal. 10: 1: 30.

Niu W, Bilan PJ, Yu J, Gao J, Boguslavsky S, Schertzer JD, Chu G, Yao Z, Klip A (2011) PKCε Regulates Contraction-Stimulated GLUT4 Traffic in Skeletal Muscle Cells.  J. Cell. Physiol. 226: 173-80.

Schertzer JD, Tamrakar AK, Magalhães JG, Pereira S, Bilan PJ, Fullerton MD, Liu Z, Steinberg GR, Giacca A, Philpott DJ, Klip A (2011) NOD1 Activators Link Innate Immunity to Insulin Resistance.  Diabetes 60: 2206-15.

Yu J, Shi L, Wang H, Bilan PJ, Yao Z, Samaan MC, He Q, Klip A, Niu W (2011) Conditioned medium from hypoxia-treated adipocytes renders muscle cells insulin resistant.  Eur. J. Cell Biol. 90: 1000-15.

Kewalramani G, Fink LN, Asadi F, Klip A (2011) Palmitate-Activated Macrophages Confer Insulin Resistance to Muscle Cells by a Mechanism Involving Protein Kinase C θ and ε.  PLoS One 6: e26947.

Tamrakar AK, Schertzer JD, Chiu TT, Foley KP, Bilan PJ, Philpott DJ, Klip A (2010) NOD2 Activation Induces Muscle Cell-Autonomous Innate Immune Responses and Insulin Resistance.  Endocrinol. 151: 5624-37.

Sun Y, Bilan PJ, Liu Z, Klip A (2010) Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells.  Proc. Natl. Acad. Sci. USA 107: 46: 19909-14.

Tamrakar AK, Schertzer JD, Chiu TT, Foley KP, Bilan PJ, Philpott DJ, Klip A (2010) NOD2 Activation Induces Muscle Cell-Autonomous Innate Immune Responses and Insulin Resistance.  Endocrinol. 151: 5624-37.

Chiu TT, Patel N, Shaw AE, Bamburg JR, Klip A (2010) Arp2/3- and cofilin-coordinated actin dynamics is required for insulin-mediated GLUT4 translocation to the surface of muscle cells. Mol. Biol. Cell 21: 3529-39.

Niu W, Bilan PJ, Ishikura S, Schertzer J, Contreras-Ferrat A, Fu Z, Liu J, Boguslavsky S, Foley K, Liu Z, Li J, Chu G, Panakkezhum T, Lopaschuk G, Lavandero S,Yao Z, Klip A (2010) Contraction-related stimuli regulate GLUT4 traffic in C2C12-GLUT4myc skeletal muscle cells.  Am. J. Physiol. Endocrinol. Metab. 298: E1058-71.

Review Articles

Klip A (2016) Homeostasis – the Walter B. Cannon’s Legacy – Applied to the Metabolic Syndrome and the Scientific Enterprise. (Editorial) Physiology 31: 246-7.

Lee WL, Klip A (2016) Endothelial Transcytosis of Insulin: Does It Contribute to Insulin Resistance? (Review) Physiology 31: 336-45.

Klip A, Sun Y, Chiu TT, Foley KP.  (2014) Signal Transduction meets Vesicle Traffic: The Software and Hardware of GLUT4 Translocation.  Am. J. Physiol. Cell Physiol. 306: 10: C879-86.

Antonescu CN, McGraw TE, Klip A (2014) Reciprocal Regulation of Endocytosis and Metabolism.  Cold Spring Harb. Perspect. Biol.; Schmid SL, Sorkin A, Zerial M (Editors), Woodbury, NY, 6: 7: 1-20.

Contreras-Ferrat A, Lavandero S, Jaimovich E, Klip A (2014) Calcium signaling in insulin action on striated muscle.  Cell Calcium 56: 390-6.

Pillon NJ, Bilan PJ, Fink LN, Klip A (2013) Cross-talk between skeletal muscle and immune cells: muscle-derived mediators and metabolic implications.  Am. J. Physiol. Endocrinol. Metab. 304: E453-65.

Lee WL, Klip A (2012) Shuttling glucose across brain microvessels, with a little help from GLUT1 and AMP Kinase. Focus on “AMP kinase regulation of sugar transport in brain capillary endothelial cells during acute metabolic stress”.  Am. J. Physiol. Cell Physiol. 303: C803-5.

Foley K, Boguslavsky S, Klip A (2011) Endocytosis, Recycling, and Regulated Exocytosis of Glucose Transporter 4.  Biochemistry 50: 3048-61.

Chiu TT, Jensen TE, Sylow L, Richter EA, Klip A (2011) Rac1 signalling towards GLUT4/glucose uptake in skeletal muscle.  Cell. Signal. 23: 1546-54.

Schertzer JD, Klip A.  (2011) Give a NOD to Insulin Resistance.  Am. J. Physiol. Endocrinol. Metab. 301: E585-6.

Badawi A, Klip A, Haddad P, Cole DEC, Bailo BG, El-Sohemy A, Karmali M (2010) Type 2 diabetes mellitus and inflammation: Prospects for biomarkers of risk and nutritional intervention.  Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Dove Medical Press Ltd., 3: 173-86.

Kewalramani G, Bilan PJ, Klip A (2010) Muscle insulin resistance: assault by lipids, cytokines and local macrophages.  Curr. Opin. Clin. Nutr. Metab. Care 13: 382-90.

Ishikura S, Antonescu CN, Klip A (2010) Documenting GLUT4 exocytosis and endocytosis in muscle cell monolayers.  Curr. Protoc. Cell Biol. 46: Unit 15.15: 1-9.

Intellectual Property

Use of R-(+)-.alpha.-lipoic acid, R-(-)dihydrolipoic acid and metabolites for the treatment of Diabetes Mellitus (US patent # 5,693,664; European Patent # EP 0 958 816 A2; German Patent #  42 18 572 A1)

Licensing Opportunity # 687 – Transgenic Mouse Model to Study Glucose Transporter 4myc Regulation in Skeletal Muscle
Licensing Opportunity # 437 - Immortalized Rat Skeletal Muscle Cells (L6) Expressing GLUT4myc Glucose Transporter
Licensing Opportunity # 429 –Immortalized L6 Rat Skeletal Muscle Cells of High Fusion Capacity and Insulin-Responsive Glucose Uptake