Jeffrey Elmendorf, Ph.D.
Department of Cellular & Integrative Physiology
Indiana University School of Medicine
635 Barnhill Drive, Room 307
Indianapolis, Indiana 46202-5120
Education / Training
- 1991, B.S., State University of New York at Oneonta, New York
- 1995, M.S., Albany Medical College, Albany, New York
- 1996, Ph.D., Albany Medical College, Albany, New York
- 1996-1999, Postdoctoral Fellowship, University of Iowa, Iowa City, Iowa
Research Biography Summary
Solving how insulin resistance develops and eventually progresses and worsens resulting in type 2 diabetes remains a fundamental challenge in biology and a significant issue in medicine. During my Ph.D. training with Dr. Jiri Turinsky at Albany Medical College and postdoctoral training with Dr. Jeffrey E. Pessin at the University of Iowa, I developed expertise in the field of insulin action and glucose transport.
Contribution to Science
A recurring finding in all of my predoctoral and postdoctoral work was that membrane lipids seemed to be critically involved in the physiology and pathophysiology of insulin action. My laboratory’s efforts in this area found that several key derangements (e.g., hyperlipidemia, hyperinsulinemia, hyperglycemia) known to impair insulin sensitivity and contribute significantly to the progression/worsening of insulin resistance increase plasma membrane (PM) cholesterol content in adipose tissue and skeletal muscle. This PM cholesterol accumulation was observed concomitant with a loss of cortical filamentous-actin (F-actin) necessary for proper incorporation of the insulin sensitive glucose transporter GLUT4 into the PM.
- Liu P, Leffler BJ, Weeks LK, Bouchard CM, Chen G, Strawbridge AB, Elmendorf JS: Sphingomyelinase activates GLUT4 translocation via a cholesterol dependent mechanism. Am J Physiol Cell Physiol 286:C317-C329, 2004.
- Chen G, Raman P, Bhonagiri P, Strawbridge AB, Pattar G, Elmendorf JS: Protective effect of phosphatidylinositol 4,5-bisphosphate against cortical filamentous actin loss and insulin resistance induced by sustained exposure of 3T3-L1 adipocytes to insulin. J Biol Chem 279:39705-39709, 2004.
- Strawbridge AB, Elmendorf JS: Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance. Diabetes 54(6):1698-1705, 2005.
- McCarthy AM, Spisak KO, Brozinick JT, Elmendorf JS: Actin cytoskeletal defects as a basis for insulin-induced insulin resistance in skeletal muscle. Am J Physiol Cell Physiol 291:C860-C868, 2006.
Our translational studies strongly demonstrate that increased skeletal muscle PM cholesterol is highly correlated with diminished glucose disposal rates in mice, rats, swine, and humans. Mechanistically, our molecular investigations revealed that increased glucose flux through the hexosamine biosynthesis pathway (HBP) promotes elevated O-linked N-acetylglucosamine (O-GlcNAc) modification of specificity protein 1 (Sp1), leading to transcriptional activation of HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis. We found that the HBP-induced cholesterolgenic transcriptional response culminated in increased PM cholesterol content that perturbed F-actin structure and insulin sensitivity. Moreover, we found that inhibiting the HBP, or Sp1 binding to DNA, blocked hyperinsulinemia-induced membrane cholesterol accumulation, F-actin loss, and insulin resistance. Our studies also demonstrate that key early insulin signaling events (e.g., IR→IRS→PI3K→Akt2→AS160) are sufficiently intact in several models of HBP-induced insulin resistance. This is consistent with recent data of others that have questioned the role of proximal insulin signaling defects in the development of insulin resistance. Our data support a novel hypothesis that the breakdown of glucose homeostasis, characteristic of obesity/T2D is secondary to increased HBP-mediated cholesterol biosynthesis.
- Brozinick JT, Hawkins ED, Strawbridge AB, Elmendorf JS: Disruption of cortical actin in skeletal muscle demonstrates an essential role of the cytoskeleton in GLUT4 translocation in insulin sensitive tissues. J Biol Chem 279: 40699-40706, 2004.
- Bhonagiri P, Pattar GR, Habegger KM, McCarthy AM, Tackett L, Elmendorf JS: Evidence coupling increased hexosamine biosynthesis pathway activity to membrane cholesterol toxicity and cortical filamentous actin derangement contributing to cellular insulin resistance. Endocrinology 152(9):3373-3384, 2011. PMID: 21712361
- Habegger KM, Penque BA, Sealls W, Tackett T, Bell LN, Blue E, Gallagher PJ, Sturek MS, Alloosh MA, Steinberg HO, Considine RV, Elmendorf JS: Fat-induced membrane cholesterol accrual provokes cortical filamentous actin destabilization and glucose transport dysfunction in skeletal muscle. Diabetologia 55:457-467, 2012. PMID: 22002007
- Penque BA, Hoggatt AM, Herring BP, Elmendorf JS: Hexosamine biosynthesis impairs insulin action via a cholesterolgenic response. Molecular Endocrinology 27(3):536-547, 2013. PMID: 23315940
Prompted by the above described findings, we began testing whether known antidiabetic agents protected against membrane/cytoskeletal insulin resistance. A significant discovery we made was that trivalent chromium (Cr3+), a micronutrient recognized to improve glucose tolerance, protects against PM cholesterol accumulation, F-actin loss, and GLUT4 dysregulation. We also found that Cr3+ protected against endosomal membrane cholesterol accumulation that impairs a key mechanism involved in reverse cholesterol transport that forms pre-β-1 high-density lipoprotein cholesterol, a cardioprotective lipoprotein. Our article published in Chen et al., Molecular Endocrinology, was highlighted in Annual Bibliography of Significant Advances in Dietary Supplements Research in 2006. Around 300 papers from 45 peer-reviewed journals were evaluated and our article was among the 25 selected to be presented. Published yearly by the Office of Dietary Supplements at the National Institutes of Health, the bibliography is designed to provide an overall perspective on how research in dietary supplements is advancing. Our studies demonstrating that Cr3+ enhances glucose and cholesterol metabolism has significant implications for metabolic health and targeting cardiovascular disease risk in diabetics. Ongoing and future studies are testing the prediction that membrane cholesterol accumulation represents an early reversible defect and that insight into this pathology will afford new, tailored, time-specific therapy that may ameliorate metabolic and cardiovascular derangements.
- Chen G, Liu P, Pattar GR, Tackett L, Bhonagiri P, Strawbridge AB, Elmendorf JS: Chromium activates GLUT4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism. Molecular Endocrinology 20(4):857-870, 2006.
- Sealls W, Penque B, Elmendorf JS: Evidence that chromium modulates cellular cholesterol homeostasis and ABCA1 functionality impaired by hyperinsulinemia. Arterioscler Thromb Vasc Biol 31(5):1139-1140, 2011. PMID: 21311039
- Hoffman NJ, Penque BA, Habegger KM, Sealls W, Tackett L, Elmendorf JS: Chromium enhances insulin responsiveness via AMPK. The Journal of Nutritional Biochemistry 25(5):565-572, 2014. PMID: 24725432
Complete List of Published Work in MyBibliography:
Dissection of insulin signaling pathways, particularly the pathways regulating glucose transport into skeletal muscle and adipose tissue, and defining their alterations in diabetes, including insulin resistance is my major research interest. In muscle and fat cells, glucose transport is contingent on the ability of insulin to orchestrate the translocation of a glucose transporter protein (GLUT4) from an intracellular membrane compartment to the plasma membrane. Although an enormous research effort has identified many signaling molecules that transmit the signal from the activated insulin receptor to intracellular sequestered GLUT4, we still lack a complete link. Research in my laboratory is aimed at filling the gaps in our understanding of the insulin signaling system and identifying the molecular events responsible for insulin resistance characteristic of type 2 diabetes. Using a combination of biochemical, microscopic, and molecular approaches, studies are underway examining our central hypothesis that the cell surface lipid environment and the actin cytoskeleton has a dramatic influence on insulin action and glucose transport, and disturbances in lipid and cytoskeletal mechanics are involved in the metabolic staging of diabetes. My laboratory is currently funded by an NIH grant, an American Diabetes Association Grant, two American Heart Association grants, and a research grant from the Showalter Trust Foundation. Our research team is currently comprised of a research analyst, a postdoctoral fellow, and four graduate students. The laboratory is affiliated with Department of Biochemistry & Molecular Biology and the Center for Diabetes Research.
Strawbridge AB and Elmendorf JS. Endothelin-1 impairs glucose transporter trafficking via a membrane-based mechanism.
Chen G, Liu P, Pattar GR, Tackett L, Bhonagiri P, Strawbridge AB, and Elmendorf JS. Chromium Activates Glucose Transporter 4 Trafficking and Enhances Insulin-Stimulated Glucose Transport in 3T3-L1 Adipocytes via a Cholesterol-Dependent Mechanism.
Molecular Endochrinology, 20(4):857-870, Apr 2006. PubMed
Strawbridge AB, Elmendorf JS, and Mather KJ. Interactions of endothelin and insulin: expanding parameters of insulin resistance.
Curr Diabetes Rev, 2(3):317-327, Aug 2006. PubMed
McCarthy AM, Spisak KO, Brozinick JT, and Elmendorf JS. Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport.
Am J Physiol Cell Physiol, 291(5):C860-C868, Nov 2006. PubMed
Pattar GR, Tackett L, Liu P, and Elmendorf JS. Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions.
Mutat Res, 610(1-2):93-100, Nov 2006. PubMed
McCarthy AM and Elmendorf JS. GLUT4's itinerary in health & disease.
Indian J Med Res. 125(3):373-388, Mar 2007. PubMed
Brozinick JT, Berkemeier BA, and Elmendorf JS. “Actin”g on GLUT4: Membrane & Cytoskeletal Components of Insulin Action.
Current Diabetes Reviews, Volume 3, Number 2, pp. 111-122(12), May 2007. IngentaConnect, PubMed
Horvath EM, Tackett L, McCarthy AM, Raman P, Brozinick JT, and Elmendorf JS. Antidiabetogenic Effects of Chromium Mitigate Hyperinsulinemia-Induced Cellular Insulin Resistance via Correction of Plasma Membrane Cholesterol Imbalance.
Mol Endocrinol. 22(4):937-950, Apr 2008. PubMed
Horvath EM, Tackett L, Elmendorf JS. A novel membrane-based anti-diabetic action of atorvastatin.
Biochem Biophys Res Commun. 372(4):639-643, Aug 2008. PubMed
Bhonagiri P, Pattar GR, Horvath EM, Habegger KM, McCarthy AM, Elmendorf JS. Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin.
Endocrinology 150(4):1636-1645, Apr 2009. PubMed
Retraction. Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin.
Endocrinology 151(6):2967, Jun 2010. PubMed
Hoffman NJ, Elmendorf JS. Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis.
Trends Endocrinol Metab 22(3):110-116, Mar 2011. PubMed
Jewell JL, Oh E, Ramalingam L, Kalwat MA, Tagliabracci VS, Tackett L, Elmendorf JS, and Thurmond DC. Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis.
The Journal of Cell Biology, The Rockefeller University Press, doi: 10.1083/jcb.201007176, March 28, 2011.
Sealls W, Penque BA, Elmendorf JS. Evidence That Chromium Modulates Cellular Cholesterol Homeostasis and ABCA1 Functionality Impaired by Hyperinsulinemia.
Arterioscler Thromb Vasc Biol. 31(5):1139-1140, May 2011. PubMed
Last update: 04/01/2016