Effects of insulin on the microvasculature

Summary

Principal Investigator: EUGENE JOSEPH BARRETT
Abstract: DESCRIPTION (provided by applicant): Type 2 diabetes, obesity, and hypertension are highly prevalent in Western society and increasingly prevalent in the developing world. Abundant clinical and basic research suggests that insulin resistance (IR) underlies each of these disorders and emerges in response to the environmental stresses of Western diet and diminished physical activity. However, the precise linkage between these environmental changes and these diverse clinical disorders is only marginally understood. Others have reported that insulin delivery to muscle is the rate limiting step for its metabolic action in vivo. Our laboratory has been testing the hypothesis that vascular IR plays an important pathogenetic role in the development metabolic IR. Specifically, we have provided abundant data (supported by this grant) that skeletal muscle microvasculature is exquisitely sensitive to physiologic concentrations of insulin which act to expand the microvascular pool perfused. We have also reported that insulin is transported across the endothelial cell (EC) by a regulated process which is activated by insulin. In this manner, insulin can facilitate its own delivery and that of glucose and other nutrients to muscle. IR inhibits these vascular actions of insulin. In studies proposed here we will probe the linkage between environmental factors (elevated plasma free fatty acid concentrations, high fat diet, acute and chronic exercise) and vascular and metabolic insulin resistance. We will utilize techniques developed in our laboratory to assess the functional actions of insulin on the microvasculature, its biochemical signaling, and the role of oxidative stress and inflammation within the vasculature on insulin actions. This will be done addressing 3 specific aims : Aim 1-will test whether FFA promote an inflammatory response in the EC, the vascular smooth muscle cell or both in rat vasculature and thereby diminish muscle insulin delivery;Aim 2-will test whether enhancing nitric oxide availability or blocking either the AT1 or endothelin A receptor will diminish/prevent FFA-induced microvascular inflammation and dysfunction, and whether exercise training may have a similar effect;and Aim 3- will test whether different dietary lipids [saturated, omega-3, and omega-6 polyunsaturated fatty acids (PUFA)] will differentially affect muscle microvascular insulin responsiveness, delivery of 125I-insulin to skeletal muscle, muscle insulin sensitivity, and vascular inflammation. By addressing the origins of muscle microvascular dysfunction in IR should allow us to develop strategies to limit or reverse vascular IR and thereby improve metabolic IR. PUBLIC HEALTH RELEVANCE: Insulin resistance (IR) underlies multiple, prevalent, serious diseases. Muscle is a major insulin target tissue and insulin movement from the plasma to muscle interstitium is rate limiting for insulin's metabolic action and IR slows this. Using novel methods developed in our laboratory we will test whether vascular inflammation and increased production of reactive oxygen species induced by pro- inflammatory lipids play a critical role in producing skeletal muscle vascular and consequent metabolic IR and if this can be reversed.
Funding Period: 2000-04-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. ncbi The vascular endothelial cell mediates insulin transport into skeletal muscle
    Hong Wang
    Division of Endocrinology and Metabolism, Departmetn of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 291:E323-32. 2006
  2. pmc Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use
    Weidong Chai
    Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
    Hypertension 55:523-30. 2010
  3. ncbi Effects of central administration of insulin or l-NMMA on rat skeletal muscle microvascular perfusion
    E A Bradley
    Menzies Research Institute, University of Tasmania, Hobart, Australia
    Diabetes Obes Metab 12:900-8. 2010
  4. pmc Caveolin-1 is required for vascular endothelial insulin uptake
    Hong Wang
    Division of Endocrinology and Metablism, Department of Internal Medicine, University of Virginia Health System, P O Box 801410, 450 Ray C Hunt Dr, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 300:E134-44. 2011
  5. pmc Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFα
    Nasui Wang
    Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 300:E195-201. 2011
  6. pmc Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans
    Jia Liu
    Division of Endocrinology and Metabolism, Department of Internal Medicine and General Clinical Research Center, University of Virginia Health System, P O Box 801410, Charlottesville, Virginia 22908, USA
    J Clin Endocrinol Metab 96:438-46. 2011
  7. ncbi Hemodynamic systems analysis of capillary network remodeling during the progression of type 2 diabetes
    Kelly F Benedict
    Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
    Microcirculation 18:63-73. 2011
  8. pmc Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature
    Eugene J Barrett
    Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 301:E252-63. 2011
  9. pmc Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans
    Weidong Chai
    Department of Internal Medicine, Division of Endocrinology and Metabolism, and the GeneralClinical Research Center, University of Virginia Health System, Charlottesville, Virginia, USA
    Diabetes Care 34:1634-8. 2011
  10. pmc Insulin entry into muscle involves a saturable process in the vascular endothelium
    S Majumdar
    University of Virginia Health System, PO Box 801410, 450 Ray C Hunt Drive, Charlottesville, VA 22908, USA
    Diabetologia 55:450-6. 2012

Detail Information

Publications32

  1. ncbi The vascular endothelial cell mediates insulin transport into skeletal muscle
    Hong Wang
    Division of Endocrinology and Metabolism, Departmetn of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 291:E323-32. 2006
    ....
  2. pmc Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use
    Weidong Chai
    Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
    Hypertension 55:523-30. 2010
    ..Pharmacological manipulation of the balance of AT(1)R and AT(2)R activity affords the potential to improve glucose metabolism...
  3. ncbi Effects of central administration of insulin or l-NMMA on rat skeletal muscle microvascular perfusion
    E A Bradley
    Menzies Research Institute, University of Tasmania, Hobart, Australia
    Diabetes Obes Metab 12:900-8. 2010
    ..Herein we test whether ICV insulin has peripheral haemodynamic and metabolic effects and whether peripheral effects of systemic insulin are affected by the ICV administration of the NOS inhibitor N(G) -methyl-l-arginine (l-NMMA)...
  4. pmc Caveolin-1 is required for vascular endothelial insulin uptake
    Hong Wang
    Division of Endocrinology and Metablism, Department of Internal Medicine, University of Virginia Health System, P O Box 801410, 450 Ray C Hunt Dr, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 300:E134-44. 2011
    ..Proinflammatory cytokines may inhibit insulin uptake, at least in part, by inhibiting caveolin-1 expression...
  5. pmc Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFα
    Nasui Wang
    Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 300:E195-201. 2011
    ..Thus, chronic inflammation, as seen in type 2 diabetes, may limit resveratrol's vasodilatory actions on muscle microvasculature...
  6. pmc Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans
    Jia Liu
    Division of Endocrinology and Metabolism, Department of Internal Medicine and General Clinical Research Center, University of Virginia Health System, P O Box 801410, Charlottesville, Virginia 22908, USA
    J Clin Endocrinol Metab 96:438-46. 2011
    ..Plasma concentrations of free fatty acids (FFAs) are elevated in patients with diabetes, which impairs insulin-mediated skeletal muscle microvascular recruitment...
  7. ncbi Hemodynamic systems analysis of capillary network remodeling during the progression of type 2 diabetes
    Kelly F Benedict
    Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
    Microcirculation 18:63-73. 2011
    ..In this work, we tested the hypothesis that the onset of diabetes would influence microvascular architecture in a manner that would significantly increase capillary network resistance and reduce blood flow...
  8. pmc Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature
    Eugene J Barrett
    Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
    Am J Physiol Endocrinol Metab 301:E252-63. 2011
    ....
  9. pmc Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans
    Weidong Chai
    Department of Internal Medicine, Division of Endocrinology and Metabolism, and the GeneralClinical Research Center, University of Virginia Health System, Charlottesville, Virginia, USA
    Diabetes Care 34:1634-8. 2011
    ..Elevating plasma FFAs impairs insulin's microvascular and metabolic actions in vivo. Whether salsalate, an anti-inflammatory agent, prevents FFA-induced microvascular and/or metabolic insulin resistance in humans is unknown...
  10. pmc Insulin entry into muscle involves a saturable process in the vascular endothelium
    S Majumdar
    University of Virginia Health System, PO Box 801410, 450 Ray C Hunt Drive, Charlottesville, VA 22908, USA
    Diabetologia 55:450-6. 2012
    ..Despite its obvious importance, uncertainty remains as to whether the transport of insulin from plasma to muscle interstitium is a passive diffusional process or a saturable transport process regulated by the insulin receptor...
  11. pmc Insulin-induced endothelial cell cortical actin filament remodeling: a requirement for trans-endothelial insulin transport
    Hong Wang
    Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA
    Mol Endocrinol 26:1327-38. 2012
    ....
  12. pmc The endothelial cell: an "early responder" in the development of insulin resistance
    Eugene J Barrett
    Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
    Rev Endocr Metab Disord 14:21-7. 2013
    ..In the current review, we examined the evidence that supports the general concept of vascular endothelium as a target of insulin action and discussed the biochemical and physiological consequences of vascular insulin resistance...
  13. pmc Endothelial cells actively concentrate insulin during its transendothelial transport
    Amanda J Genders
    Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA
    Microcirculation 20:434-9. 2013
    ....
  14. pmc Muscle contraction, but not insulin, increases microvascular blood volume in the presence of free fatty acid-induced insulin resistance
    April C Inyard
    University of Virginia, Charlottesville, Virginia, USA
    Diabetes 58:2457-63. 2009
    ....
  15. pmc The trafficking/interaction of eNOS and caveolin-1 induced by insulin modulates endothelial nitric oxide production
    Hong Wang
    Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
    Mol Endocrinol 23:1613-23. 2009
    ..These data show that insulin acutely regulates eNOS and CAV-1 trafficking to PM of vascular endothelial cells where their interaction can regulate eNOS activity...
  16. ncbi Graded occlusion of perfused rat muscle vasculature decreases insulin action
    Georgie C Vollus
    Department of Biochemistry, University of Tasmania Medical School, Private Bag 58, 7001, Hobart, Tasmania, Australia
    Clin Sci (Lond) 112:457-66. 2007
    ....
  17. ncbi Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway
    Guolian Li
    Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, P O Box 801410, Charlottesville, Virginia 22908 1410, USA
    Endocrinology 148:3356-63. 2007
    ....
  18. ncbi Contraction stimulates nitric oxide independent microvascular recruitment and increases muscle insulin uptake
    April C Inyard
    Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
    Diabetes 56:2194-200. 2007
    ..This microvascular response may, in part, explain enhanced insulin action in exercising skeletal muscle...
  19. ncbi Hyperinsulinemia does not acutely enhance adrenal androgen production in women or men
    K D Helm
    The Center for Research in Reproduction, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA
    Horm Metab Res 39:617-9. 2007
  20. ncbi Hyperinsulinemia rapidly increases human muscle microvascular perfusion but fails to increase muscle insulin clearance: evidence that a saturable process mediates muscle insulin uptake
    Emma M Eggleston
    University of Virginia Health System, P O Box 801410, 450 Ray C Hunt Dr, Charlottesville, VA 22908, USA
    Diabetes 56:2958-63. 2007
    ..We further hypothesized that expansion of the microvascular volume of muscle would enhance muscle insulin clearance...
  21. ncbi Insulin signaling stimulates insulin transport by bovine aortic endothelial cells
    Hong Wang
    Department of Medicine, University of Virginia, Box 801410, Charlottesville, VA 22908, USA
    Diabetes 57:540-7. 2008
    ..Here, we addressed whether insulin signaling within the endothelial cell is required for the first step of transendothelial insulin transport: its uptake by the endothelial cell...
  22. pmc Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle
    Michael G Clark
    Menzies Research Institute, University of Tasmania, Private Bag 58, Hobart 7001, Australia
    Am J Physiol Endocrinol Metab 295:E732-50. 2008
    ..Regular exercise may prevent and ameliorate insulin resistance by increasing "vascular fitness" and thereby recovering insulin-mediated capillary recruitment...
  23. pmc The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action
    E J Barrett
    University of Virginia Health System, Charlottesville, VA 22908, USA
    Diabetologia 52:752-64. 2009
    ..These findings highlight the need to further understand the role of the vascular actions of insulin in metabolic regulation...
  24. pmc Limb stress-rest perfusion imaging with contrast ultrasound for the assessment of peripheral arterial disease severity
    Jonathan R Lindner
    Cardiovascular Division, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
    JACC Cardiovasc Imaging 1:343-50. 2008
    ..We hypothesized that stress-rest perfusion imaging of skeletal muscle in the lower extremity with contrast-enhanced ultrasound (CEU) could evaluate the severity of peripheral arterial disease (PAD)...
  25. pmc Insulin and insulin-like growth factor-I receptors differentially mediate insulin-stimulated adhesion molecule production by endothelial cells
    Guolian Li
    Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908 1410, USA
    Endocrinology 150:3475-82. 2009
    ..Dual-receptor activation may most effectively contribute to the pathogenesis of atherosclerotic disease in diabetes...
  26. pmc Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal
    Michelle A Keske
    Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA
    Diabetes Care 32:1672-7. 2009
    ..Ingestion of a mixed meal recruits flow to muscle capillaries and increases total forearm blood flow in healthy young lean people. We examined whether these vascular responses are blunted by obesity...
  27. pmc Abnormal skeletal muscle capillary recruitment during exercise in patients with type 2 diabetes mellitus and microvascular complications
    Lisa Womack
    General Clinical Research Center, University of Virginia, Charlottesville, USA
    J Am Coll Cardiol 53:2175-83. 2009
    ..We sought to determine whether skeletal muscle capillary recruitment is impaired in type 2 diabetes mellitus (DM) with and without microvascular complications (MC)...
  28. pmc Endothelial markers may link kidney function to cardiovascular events in type 2 diabetes
    Christina Maier
    Department of Endocrinology, Medical University Hospital Vienna, Vienna, Austria
    Diabetes Care 32:1890-5. 2009
    ..The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes...
  29. pmc Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature
    Zhenqi Liu
    Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, P O Box 801410, Charlottesville, Virginia 22908, USA
    J Clin Endocrinol Metab 94:3543-9. 2009
    ..Insulin recruits muscle microvasculature, which increases the endothelial exchange surface area to facilitate substrate delivery. Elevated plasma concentrations of free fatty acids (FFAs) cause insulin resistance...
  30. pmc Nitric oxide directly promotes vascular endothelial insulin transport
    Hong Wang
    Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia
    Diabetes 62:4030-42. 2013
    ..We conclude that NO directly promotes EC insulin transport by enhancing protein S-nitrosylation. NO also inhibits PTP1B activity, thereby enhancing insulin signaling...

Research Grants30

  1. AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)
    Neil B Ruderman; Fiscal Year: 2013
    ..The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention...
  2. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  3. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  4. Selective Insulin Resistance- Diabetic Cardiovascular Diseases
    George L King; Fiscal Year: 2013
    ....
  5. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  6. Ang II and Overnutrition and Insulin resistance in Cardiovascular Tissue
    JAMES RUSSELL SOWERS; Fiscal Year: 2013
    ..A better understanding of factors involved in insulin resistance should help in the development of therapeutic targets to help prevent diabetes and cardiovascular disease. ..
  7. Interactions of the RAAS and a Western Diet on Insulin Metabolic Actions
    JAMES RUSSELL SOWERS; Fiscal Year: 2013
    ..tyrosine (p) and the resultant downstream IRS-1/PI3-K/Akt signaling. ..