Arterial Norepinephrine Concentration is Inversely and Independently Associated With Insulin Clearance in Obese Individuals With Metabolic Syndrome
Open accessAbstract
CONTEXT: Impaired insulin clearance contributes to the hyperinsulinemia of obesity, yet relatively little is known concerning the pathophysiological determinants of insulin clearance in obese populations. OBJECTIVE: To examine the cross-sectional relationship between insulin clearance and resting sympathetic nervous system activity in a cohort of obese subjects with metabolic syndrome. PARTICIPANTS AND METHODS: Unmedicated, nonsmoking subjects (31 male, 27 female; aged 56 ± 1 year; body mass index 33.7 ± 0.6 kg/m(2)) underwent euglycemic hyperinsulinemic clamp to determine insulin sensitivity (M) and insulin clearance, assessment of norepinephrine kinetics, peripheral arterial tonometry, Doppler echocardiography, and oral glucose tolerance test. RESULTS: Univariate correlation analyses showed inverse associations between insulin clearance and arterial norepinephrine concentration (r = -0.44, P = .0006), calculated norepinephrine spillover rate (r = -0.33, P = .01), augmentation index (AI, r = -0.37, P = .005), and positive associations with M (r = 0.30, P = .02), Matsuda insulin sensitivity index (r = 0.27, P = .04), and cardiac output (r = 0.27, P = .04). Insulin clearance and sensitivity did not differ between genders, however females had higher AI compared to males (35 ± 3% versus 14 ± 2%, P < .001). In age and gender adjusted stepwise regression analyses, arterial norepinephrine concentration alone explained 19% of the variance in insulin clearance. When all significant variables were entered into the regression model, arterial norepinephrine, AI, gender, and M were independent predictors of insulin clearance, together explaining 41% of the variance. CONCLUSIONS: Arterial norepinephrine concentration is inversely and independently associated with whole-body insulin clearance rate in obese individuals with metabolic syndrome. Prospective studies are needed to determine the direction of causality and the chronology of interactions between insulin clearance and sympathetic neural activity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The difference in insulin clearance was similar and significant regardless of adjustment for endogenous insulin secretion.
“This difference was similar and significant regardless of adjustment for endogenous insulin secretion (15), and the adjusted value is presented.”
From Primary aldosteronism decreases insulin secretion and increases insulin clearance in humans (2020) · cites this paper as [15]
The Glucose metabolism and insulin clearance section (page unavailable) describes calculating insulin clearance with a correction for residual endogenous insulin secretion. The Discussion (page unavailable) reports a significant association involving insulin clearance, but the paper does not compare adjusted and unadjusted results or establish that a difference remained similar and significant under both calculations. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Alberti, K. G. M. M., Eckel, R. H., Grundy, S. M., Zimmet, P. Z., Cleeman, J. I., Donato, K. A., Fruchart, J.-C., James, W. P. T., Loria, C. M., & Smith, S. C. (2009) · Circulation · doi:10.1161/circulationaha.109.192644 · Cited by 14,860 · see citing works
Matsuda, M., & DeFronzo, R. A. (1999) · Diabetes Care · doi:10.2337/diacare.22.9.1462 · Cited by 5,621 · see citing works
Kim, J.-A., Montagnani, M., Koh, K. K., & Quon, M. J. (2006) · Circulation · doi:10.1161/circulationaha.105.563213 · Cited by 1,652 · see citing works
Alberti, K. G. M. M., Eckel, R. H., Grundy, S. M., Zimmet, P. Z., Cleeman, J. I., Donato, K. A., Fruchart, J., James, W. P. T., Loria, C. M., & Smith, S. C. (2009) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · Cited by 852 · see citing works
Hamburg, N. M., Keyes, M. J., Larson, M. G., Vasan, R. S., Schnabel, R. B., Pryde, M. M., Mitchell, G. F., Sheffy, J., Vita, J. A., & Benjamin, E. J. (2008) · Circulation · doi:10.1161/circulationaha.107.748574 · Cited by 692 · see citing works
Kolterman, O., Gray, R. S., Griffin, J., BURSTEIN, P. J., Insel, J. R., Scarlett, J. A., & Olefsky, J. M. (1981) · Journal of Clinical Investigation · doi:10.1172/jci110350 · Cited by 629 · see citing works
Splanchnic insulin metabolism in obesity. Influence of body fat distribution.
Peiris, A. N., Mueller, R. A., Smith, G. A., Struve, M. F., & Kissebah, A. H. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112758 · Cited by 346 · see citing works
Determination of norepinephrine apparent release rate and clearance in humans
Esler, M., Jackman, G. P., Bobik, A., Kelleher, D., Jennings, G., Leonard, P., Skews, H., & Korner, P. I. (1979) · Life Sciences · doi:10.1016/0024-3205(79)90371-0 · Cited by 340 · see citing works
Reflex sympathetic activation induces acute insulin resistance in the human forearm.
Jamerson, K. A., Julius, S., Gudbrandsson, T., Andersson, O., & Brant, D. O. (1993) · Hypertension · doi:10.1161/01.hyp.21.5.618 · Cited by 311 · see citing works
Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome
Grassi, G., Dell’Oro, R., Quarti-Trevano, F., Scopelliti, F., Seravalle, G., Paleari, F., Gamba, P. L., & Mancia, G. (2005) · Diabetologia · doi:10.1007/s00125-005-1798-z · Cited by 294 · see citing works
Splanchnic and renal metabolism of insulin in human subjects: a dose-response study
Ferrannini, E., Wahren, J., FABER, O. K., Felig, P., Binder, C., & DeFronzo, R. A. (1983) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1983.244.6.e517 · Cited by 214 · see citing works
Effect of liver fat on insulin clearance
Kotronen, A., Vehkavaara, S., Seppälä-Lindroos, A., Bergholm, R., & Yki-Järvinen, H. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00444.2007 · Cited by 202 · see citing works
Mittelman, S. D., Citters, G. W. V., Kim, S. P., Davis, D. A., Dea, M. K., Hamilton-Wessler, M., & Bergman, R. N. (2000) · Diabetes · doi:10.2337/diabetes.49.12.2116 · Cited by 200 · see citing works
Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin
Rahmouni, K., Morgan, D. A., Morgan, G. M., Liu, X., Sigmund, C. D., Mark, A. L., & Haynes, W. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21737 · Cited by 187 · see citing works
Free fatty acids impair hepatic insulin extraction in vivo.
Wiesenthal, S. R., Sandhu, H., McCall, R. H., Tchipashvili, V., Yoshii, H., Polonsky, K. S., Shi, Z. Q., Lewis, G. F., Mari, A., & Giacca, A. (1999) · Diabetes · doi:10.2337/diabetes.48.4.766 · Cited by 167 · see citing works
Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study
Flaa, A., Aksnes, T. A., Kjeldsen, S. E., Eide, I. A., & Rostrup, M. (2008) · Metabolism · doi:10.1016/j.metabol.2008.05.012 · Cited by 150 · see citing works
Mora, M. V., Scarfone, A., Calvani, M., Greco, A. V., & Mingrone, G. (2003) · Journal of the American College of Nutrition · doi:10.1080/07315724.2003.10719326 · Cited by 148 · see citing works
Long-term mild jogging increases insulin action despite no influence on body mass index or VO2 max
Oshida, Y., Yamanouchi, K., Hayamizu, S., & Sato, Y. (1989) · Journal of Applied Physiology · doi:10.1152/jappl.1989.66.5.2206 · Cited by 132 · see citing works
Fatty Acids Enhance Vascular α-Adrenergic Sensitivity
Stepniakowski, K. T., Goodfriend, T. L., & Egan, B. M. (1995) · Hypertension · doi:10.1161/01.hyp.25.4.774 · Cited by 130 · see citing works
Mediators of sympathetic activation in metabolic syndrome obesity
Straznicky, N. E., Eikelis, N., Lambert, É., & Esler, M. (2008) · Current Hypertension Reports · doi:10.1007/s11906-008-0083-1 · Cited by 126 · see citing works
Self-citationRoles of insulin resistance and obesity in regulation of plasma insulin concentrations
Jones, C. N. O., Abbasi, F., Carantoni, M., Polonsky, K. S., & Reaven, G. M. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.3.e501 · Cited by 113 · see citing works
Insulin Clearance and the Incidence of Type 2 Diabetes in Hispanics and African Americans
Lee, C. C., Haffner, S. M., Wagenknecht, L. E., Lorenzo, C., Norris, J. M., Bergman, R. N., Stefanovski, D., Anderson, A., Rotter, J. I., Goodarzi, M. O., et al. (2012) · Diabetes Care · doi:10.2337/dc12-1316 · Cited by 103 · see citing works
Casey, D. P., Curry, T. B., Joyner, M. J., Charkoudian, N., & Hart, E. C. (2011) · Hypertension · doi:10.1161/hypertensionaha.110.164517 · Cited by 83 · see citing works
Xun, P., Wu, Y., He, Q., & He, K. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.065565 · Cited by 80 · see citing works
Renal and Ocular Hemodynamic Effects of Insulin
Schmetterer, L. F., Müller, M., Fasching, P., Diepolder, C., Gallenkamp, A., Zanaschka, G., Findl, O., Strenn, K., Mensik, C., Tschernko, E., et al. (1997) · Diabetes · doi:10.2337/diab.46.11.1868 · Cited by 79 · see citing works
Bonora, E., Zavaroni, I., Bruschi, F., Alpi, O., Pezzarossa, A., GUERRA, L., Dall’Aglio, E., Coscelli, C., & BUTTURINI, U. (1984) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-59-6-1121 · Cited by 68 · see citing works
Fasting insulin reflects heterogeneous physiological processes: role of insulin clearance
Goodarzi, M. O., Cui, J., Chen, Y. I., Hsueh, W. A., Guo, X., & Rotter, J. I. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00013.2011 · Cited by 61 · see citing works
Non-esterified fatty acids increase arterial pressure via central sympathetic activation in humans
Florian, J. P., & Pawelczyk, J. A. (2009) · Clinical Science · doi:10.1042/cs20090063 · Cited by 57 · see citing works
Essential Hypertension Is Associated With Decreased Insulin Clearance and Insulin Resistance
Lender, D., Arauz-Pacheco, C., ADAMS-HUET, B. A., & Raskin, P. (1997) · Hypertension · doi:10.1161/01.hyp.29.1.111 · Cited by 55 · see citing works
Differences in insulin clearance between metabolically healthy and unhealthy obese subjects
Marini, M. A., Frontoni, S., Succurro, E., Arturi, F., Fiorentino, T. V., Sciacqua, A., Perticone, F., & Sesti, G. (2013) · Acta Diabetologica · doi:10.1007/s00592-013-0511-9 · Cited by 51 · see citing works
Lindgren, K., Hagelin, E., Hansén, N., & Lind, L. (2005) · Journal of Hypertension · doi:10.1097/01.hjh.0000198024.91976.c2 · Cited by 50 · see citing works
Goodarzi, M. O., Taylor, K. D., Guo, X., Quiñones, M. J., Cui, J., Li, X., Hang, T., Yang, H., Holmes, E. W., Hsueh, W. A., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.4.1222 · Cited by 48 · see citing works
RICHARDSON, P. D. I., & Withrington, P. G. (1977) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1977.tb07746.x · Cited by 45 · see citing works
Kim, S. H., Abbasi, F., Chu, J. W., McLaughlin, T., Lamendola, C. A., Polonsky, K. S., & Reaven, G. M. (2005) · Diabetes · doi:10.2337/diabetes.54.8.2447 · Cited by 43 · see citing works
Klein, H. H., Matthaei, S., Drenkhan, M., Ries, W., & Scriba, P. C. (1991) · Biochemical Journal · doi:10.1042/bj2740787 · Cited by 33 · see citing works
Bm, E. (1991) · PubMed · Cited by 31 · see citing works
Rothe, C. F., & Maass‐Moreno, R. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.279.3.h1147 · Cited by 28 · see citing works
Renal and ocular hemodynamic effects of insulin
Schmetterer, L. F., Muller, M., Fasching, P., et al. (1997) · Diabetes · doi:10.2337/diabetes.46.11.1868 · Cited by 19 · see citing works
Sugawara, J., Brothers, R. M., Raven, P. B., Okazaki, K., & Ogoh, S. (2013) · The Journal of Physiological Sciences · doi:10.1007/s12576-013-0272-9 · Cited by 12 · see citing works
Acute Effects of Blood Pressure Elevation on Insulin Clearance in Normotensive Healthy Subjects
O'Callaghan, C. J., Komersova, K., & Louis, W. J. (1998) · Hypertension · doi:10.1161/01.hyp.31.1.104 · Cited by 12 · see citing works
Klein, H., Matthaei, S., Drenkhan, M., Ries, W. L., & Scriba, P. C. (1991) · Open access LMU (Ludwid Maxmilian's Universitat Munchen) · Cited by 8 · see citing works
Lee, C. C., Haffner, S. M., Wagenknecht, L. E., Lorenzo, C., Norris, J. M., Bergman, R. N., Stefanovski, D., Anderson, A. M., Rotter, J. I., Goodarzi, M. O., et al. (2013) · eScholarship (California Digital Library) · Cited by 6 · see citing works
He, K., Xun, P., Wu, Y., & He, Q. (2020) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/tzzf-yp68 · Cited by 5 · see citing works
Desoyé, G., Ertl-Stockinger, U., & Porta, S. (1991) · Life Sciences · doi:10.1016/0024-3205(91)90340-h · Cited by 4 · see citing works
Joost, H., & Quentin, S. H. (1984) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)21984-x · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Climie, R. E., van Sloten, T. T., Bruno, R. M., Taddei, S., Empana, J. P., Stehouwer, C. D. A., Sharman, J. E., Boutouyrie, P., & Laurent, S. (2019) · Hypertension · doi:10.1161/hypertensionaha.118.11769 · Cited by 184 · see citing works
Should the sympathetic nervous system be a target to improve cardiometabolic risk in obesity?
Lambert, É., Straznicky, N. E., Dixon, J. B., & Lambert, G. W. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00096.2015 · Cited by 115 · see citing works
Self-citationPrimary aldosteronism decreases insulin secretion and increases insulin clearance in humans
Adler, G. K., Murray, G. R., Turcu, A. F., Nian, H., Yu, C., Solorzano, C. C., Manning, R., Peng, D., & Luther, J. M. (2020) · Hypertension · doi:10.1161/hypertensionaha.119.13922 · Cited by 71 · see citing works
“Insulin clearance was calculated as the insulin infusion rate divided by average insulin concentration during the last 30 minutes of each insulin infusion period, adjusted for C-peptide to account for endogenous insulin secretion.(15)”
MethodAgaty, S. M. E., Kirmani, A., & Labban, E. (2016) · Annals of Noninvasive Electrocardiology · doi:10.1111/anec.12427 · Cited by 25 · see citing works
Vaganova, A. N., Shemiakova, T. S., Ленская, К. В., Rodionov, R. N., Steenblock, C., & Gainetdinov, R. R. (2023) · Biomolecules · doi:10.3390/biom13111618 · Cited by 14 · see citing works
Labadzhyan, A., Cui, J., Péterfy, M., Guo, X., Chen, Y. I., Hsueh, W. A., Rotter, J. I., & Goodarzi, M. O. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166263 · Cited by 14 · see citing works
Straznicky, N. E., Grima, M. T., Sari, C. I., Lambert, É., Phillips, S. E., Eikelis, N., Kobayashi, D., Hering, D., Mariani, J. A., Dixon, J. B., et al. (2015) · Cardiovascular Diabetology · doi:10.1186/s12933-015-0276-2 · Cited by 16 · see citing works
Self-citationTura, A., Bizzotto, R., Yamada, Y., Seino, Y., Pacini, G., & Åhrén, B. (2018) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00181.2017 · Cited by 13 · see citing works
Nestel, P. J., Khan, A. A., Straznicky, N. E., Mellett, N. A., Jayawardana, K. S., Mundra, P. A., Lambert, G. W., & Meikle, P. J. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.11.032 · Cited by 13 · see citing works
Self-citationMetabolic syndrome and the hepatorenal reflex
Wider, M. D. (2016) · Surgical Neurology International · doi:10.4103/2152-7806.190438 · Cited by 9 · see citing works
Parasiliti‐Caprino, M., Obert, C., Lopez, C., Bollati, M., Bioletto, F., Bima, C., Egalini, F., Berton, A. M., Prencipe, N., Settanni, F., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10091967 · Cited by 8 · see citing works
Metabolic syndrome and the hepatorenal reflex
Wider, M. D. (2016) · Surgical Neurology International · doi:10.4103/2152-7806.194147 · Cited by 8 · see citing works
Schweighofer, N., Genser, B., Maerz, W., Kleber, M. E., Trummer, O., Pieber, T. R., & Obermayer-Pietsch, B. M. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s235663 · Cited by 4 · see citing works
Milanovic, S. M., Lew, R., Xiong, K., Casavant, E., Galluppi, G. R., Chen, Y., Lai, Y., Chakravarthy, M. V., Dehn, C., Koblan, K. S., et al. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70136 · Cited by 3 · see citing works
Renklint, R., Liv, P., Katsoularis, I., Olsson, T., & Otten, J. (2025) · Journal of Diabetes · doi:10.1111/1753-0407.70161 · Cited by 1 · see citing works
Tao, W., Bao, J., Wang, Q., Xie, Y., Li, S., Wang, Z., Zhu, S., Huang, L., Yang, Y., Xu, X., et al. (2026) · European journal of medical research · doi:10.1186/s40001-025-03761-3 · Cited by 1 · see citing works
Autonomic Nervous System: Metabolic Function☆
Straznicky, N. E., Lambert, É., Lambert, G. W., & Esler, M. D. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.01819-8 · Cited by 1 · see citing works
Self-citationHEART RATE VARIABILITY AS A MARKER OF MAXIMUM PHYSICAL LOAD IN PEOPLE WITH OBESITY
LISUN, Y. B., Yevsieieva, V. V., & Polyukhovich, L. M. (2023) · Pain anesthesia and intensive care · doi:10.25284/2519-2078.2(103).2023.284627 · Cited by 1 · see citing works
Kryzhevskyi, Y., Bilyayeva, O. O., Rykov, S. О., Shargorodska, I. V., Osadchaya, O., Barinov, Y. V., & Petrovsky, M. (2021) · Journal of Education Health and Sport · doi:10.12775/jehs.2021.11.04.024 · Cited by 1 · see citing works
Zhang, K., Cao, H., Ji, H., Yu, G., Wu, L., Shen, Q., Qian, W., & Tao, W. (2026) · BMJ Open · doi:10.1136/bmjopen-2025-110949
- Authors
- Straznicky, N. E., Grima, M. T., Lambert, E. A., Sari, C. I., Eikelis, N., Nestel, P. J., Phillips, S. E., Hering, D., Karapanagiotidis, S., Dixon, J. B., Schlaich, M. P., & Lambert, G. W.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- Corresponding author
- Straznicky, Nora E.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2015-04
- Volume
- 100
- Issue
- 4
- Pages
- 1544-1550
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2036894778
- Cited by
- 20
- References
- 44
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 1 · 2016: 6 · 2015: 2
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Funders
- Pfizer
- Diabetes Australia
- Monash University
- State Government of Victoria
- Servier
- Allergan
- Merck Sharp and Dohme
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin clearance, insulin sensitivity, metabolic syndrome, obesity, sympathetic activity, norepinephrine spillover, augmentation index, cardiac output, sex differences
- MeSH terms
- Arteries, Blood Glucose, Cross-Sectional Studies, Female, Glucose Tolerance Test, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Norepinephrine, Obesity, Glucose Clamp Technique, Cohort Studies, Metabolic Syndrome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
