Thirty-eight years after the landmark discovery of insulin, chromium was identified to be a separate factor required to maintain normal glucose tolerance. Unlike the intensive research in pursuit of understanding the molecular mechanisms of insulin signaling and resistance to its biological action associated most significantly with obesity and type 2 diabetes, the molecular basis of chromium action has been intermittently studied over the years. Recent data is consistent with the theory that chromium enhances insulin action during the insulin resistant state by amplifying the activity of the insulin receptor. However, given that the etiology of impaired insulin action results from one or more factors that target multiple post-receptor signaling steps, the molecular basis of signal enhancement by chromium most likely extends beyond the insulin receptor. Careful selection of most relevant insulin signal transduction data in terms of plasma membrane and insulin resistance prompted us to ask if membrane changes largely represent a common denominator explaining chromium action. In preliminary studies on the 3T3L1 adipocyte cell culture system, chromium increased the basal and insulin-stimulated level of plasma membrane GLUT4, an intracellular localized glucose transporter. Chromium also was found to concomitantly diminish cholesterol from the plasma membrane. Replenishment of the lost plasma membrane cholesterol reversed the potentiating action of chromium on GLUT4 mobilization to the cell surface. This proposal will extend upon these findings and use an integrated approach to study several (not mutually exclusive) means by which chromium could exert its GLUT4 regulatory action at the cell membrane. First, we will define plasma membrane architectural changes mediating the chromium enhanced glucose transport process; a subset of that work will test if the cholesterol-dependent actin mesh beneath the cell surface is affected by chromium. Second, we will assess if chromium engages a specific subset of GL UT4 signaling molecules. Evidence supports the idea that several insulin and insulin mimetic signaling components reside or accumulate at cholesterol-dependent regions of the plasma membrane. Our postulate is that key GLUT4 effectors intricately rely upon the activity of membrane lipids and/or actin cytoskeleton at the cell surface. Finally, we will test if chromium corrects signal transduction mechanisms disturbed by insulin resistant conditions that target proximal or distal components of the insulin signaling network. These results will be significant, because they are expected to provide new targets for the preventative and therapeutic interventions that will be particularly important to the growing numbers of insulin resistant individuals in this country who display different biochemical signatures but a shared loss in insulin sensitivity.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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Metabolism Study Section (MET)
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Moen, Laura K
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Hoffman, Nolan J; Penque, Brent A; Habegger, Kirk M et al. (2014) Chromium enhances insulin responsiveness via AMPK. J Nutr Biochem 25:565-72
Habegger, K M; Penque, B A; Sealls, W et al. (2012) Fat-induced membrane cholesterol accrual provokes cortical filamentous actin destabilisation and glucose transport dysfunction in skeletal muscle. Diabetologia 55:457-67
Habegger, Kirk M; Hoffman, Nolan J; Ridenour, Colin M et al. (2012) AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol. Endocrinology 153:2130-41
Jewell, Jenna L; Oh, Eunjin; Ramalingam, Latha et al. (2011) Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis. J Cell Biol 193:185-99
Bhonagiri, Padma; Pattar, Guruprasad R; Habegger, Kirk M et al. (2011) Evidence coupling increased hexosamine biosynthesis pathway activity to membrane cholesterol toxicity and cortical filamentous actin derangement contributing to cellular insulin resistance. Endocrinology 152:3373-84
Hoffman, Nolan J; Elmendorf, Jeffrey S (2011) Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis. Trends Endocrinol Metab 22:110-6
Sealls, Whitney; Penque, Brent A; Elmendorf, Jeffrey S (2011) Evidence that chromium modulates cellular cholesterol homeostasis and ABCA1 functionality impaired by hyperinsulinemia--brief report. Arterioscler Thromb Vasc Biol 31:1139-40
(2010) RETRACTED: A novel membrane-based anti-diabetic action of atorvastatin. Biochem Biophys Res Commun 401:319
Bhonagiri, Padma; Pattar, Guruprasad R; Horvath, Emily M et al. (2009) Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin. Endocrinology 150:1636-45
Horvath, Emily M; Tackett, Lixuan; McCarthy, Alicia M et al. (2008) Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance. Mol Endocrinol 22:937-50

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