Dr. Elmendorf’s contributions to science included identification of insulin-dependent and insulin-independent signaling mechanisms regulating GLUT4-mediated glucose transport in tissues and cultured cells. Several of his early studies implicated that proximal insulin signaling defects did not account for the loss of GLUT4 regulation in insulin-resistant fat and muscle, suggesting that distal and/or separate defects may exist.
1997. Elmendorf JS, Damrau-Abney A, Smith TR, David TS, Turinsky J: Phosphatidylinositol 3-kinase and dynamics of insulin resistance in denervated slow and fast muscles in vivo. Am J Physiol272 (Endocriol. Metab. 35):E661-E670, 1997. PMID: 9142889
1997. Turinsky J, Damrau-Abney A, Elmendorf JS, Smith TR: Effect of monensin on 2-deoxyglucose uptake, on insulin receptor, and phosphatidylinositol 3-kinase activity in rat muscle.Journal of Endocrinology154:85-93, 1997. PMID: 9246941
1998. Elmendorf JS, Chen D, Pessin JE: Guanosine 5'-O(3-Thiotriphosphate) (GTPγS) stimulation of GLUT4 translocation is tyrosine kinase-dependent. J Biol Chem273:13289-13296, 1998. PMID: 9582374
1999. Elmendorf JS, Boeglin D, Pessin JE: Temporal separation of insulin-stimulated GLUT4/IRAP vesicle plasma membrane docking and fusion in 3T3L1 adipocytes. J Biol Chem274:37357-37361, 1999. PMID: 10601305
A recurring finding in his predoctoral and postdoctoral work was that membrane lipids seemed to be critically involved in the physiology and pathophysiology of insulin action. Dr. Elmendorf’s 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 resistanceincrease 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.
2004. 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 Physiol286:C317-C329, 2004. PMID: 14522816
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 Chem279:39705-39709, 2004. PMID: 15277534
2005. Strawbridge AB, Elmendorf JS: Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance. Diabetes54(6):1698-1705, 2005. PMID: 15919791
2006. 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 Physiol291:C860-C868, 2006. PMID: 16774991
Prompted by the above-described findings, Dr. Elmendorf’s group began testing whether known antidiabetic agents protected against membrane/cytoskeletal insulin resistance. A significant discovery made was that trivalent chromium (Cr3+), a micronutrient recognized to improve glucose tolerance, protects against PM cholesterol accumulation, F-actin loss, and GLUT4 dysregulation. His research team 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. His group’s 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 this 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. Dr. Elmendorf’s group’s studies demonstrating that Cr3+enhances glucose and cholesterol metabolism has significant implications for metabolic health and targeting cardiovascular disease risk in diabetics.
2006. 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 Endocrinology20(4):857-870, 2006. PMID: 16339278
2011. Sealls W, Penque B, Elmendorf JS: Evidence that chromium modulates cellular cholesterol homeostasis and ABCA1 functionality impaired by hyperinsulinemia.Arterioscler Thromb Vasc Biol31(5):1139-1140, 2011. PMID: 21311039
2012. Habegger KM, Hoffman NJ, Ridenour CM, Brozinick JT, Elmendorf JS: AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol. Endocrinology153(5):2130-2141, 2012. PMID: 22434076
2014. Hoffman NJ, Penque BA, Habegger KM, Sealls W, Tackett L, Elmendorf JS: Chromium enhances insulin responsiveness via AMPK. The Journal of Nutritional Biochemistry25(5):565-572, 2014. PMID: 24725432
Ongoing studies from his group are investigating the mechanism by which increased hexosamine biosynthesis pathway (HBP) activity causes insulin resistance. A key finding from their molecular investigations revealed that increased glucose flux through the 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. They found that the HBP-induced cholesterolgenic transcriptional response culminated in increased PM cholesterol content that perturbed F-actin structure and insulin sensitivity. Moreover, his team found that inhibiting the HBP, or Sp1 binding to DNA, blocked hyperinsulinemia-induced membrane cholesterol accumulation, F-actin loss, and insulin resistance. Their 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 Dr. Elmendorf’s earlier findings and recent data of others that have questioned the role of proximal insulin signaling defects in the development of insulin resistance.The group’s in vitrodata support a novel hypothesis that the breakdown of glucose homeostasis, characteristic of obesity/T2D is secondary to increased HBP-mediated cholesterol biosynthesis.
2002. Kralik SF, Liu P, Leffler BJ, Elmendorf JS: Ceramide and glucosamine antagonism of alternate signaling pathways regulating insulin- and osmotic shock-induced glucose transporter 4 translocation. Endocrinology143(1)37-46. 2002. PMID: 11751589
2003. Chen G, Liu P, Thurmond DC, Elmendorf, JS: Glucosamine-induced insulin resistance is coupled to O-linked glycosylation of Munc18c. FEBS Lett534(1-3):54-60. 2003. PMID: 12527361
2011. 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. Endocrinology152(9):3373-3384, 2011. PMID: 21712361
2013. Penque BA, Tackett L, Hoggatt AM, Herring BP, Elmendorf JS: Hexosamine biosynthesis impairs insulin action via a cholesterolgenic response. Molecular Endocrinology27(3):536-547, 2013. PMID: 23315940
Translational studies Dr. Elmendorf and his team have pursued and continue to pursue demonstrate that increased skeletal muscle plasma membrane cholesterol is highly correlated with diminished glucose disposal rates in mice, rats, swine, and humans. A key research focus is to test whether the development of glucose intolerance in vivoinvolves an HBP-induced cholesterolgenic Sp1-mediated transcriptional response that impairs one or more distal membrane-based mechanisms of GLUT4 regulation. Advancement of this understanding will reshape understanding of insulin resistance development and identify new therapeutic targets for its prevention and/or treatment.
2004. 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 Chem279: 40699-40706, 2004. PMID: 15247264
2012. 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. Diabetologia55:457-467, 2012. PMID: 22002007
2014. Ambery AG, Tackett L, Penque BA, Hickman DL, Elmendorf JS: Effect of Corncob bedding on feed conversion efficiency in a high-fat diet-induced prediabetic model in C57Bl/6J mice. J Am Assoc Lab Anim Sci53(5):449-451, 2014. PMID: 25255066
2017. Ambery AG, Tackett L, Penque BA, Brozinick JT, Elmendorf JS: Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet.Physiological Reports5(16), 2017. PMID: 28811359