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Acute effects of insulin on circulating natriuretic peptide levels in humans

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      Abstract

      Background

      The natriuretic peptide hormones play an important role in salt and blood pressure regulation. In observational studies, obesity and insulin resistance have been consistently associated with lower concentrations of natriuretic peptides. It has been proposed that insulin influences natriuretic peptide production.

      Objective

      We sought to determine the acute effects of insulin administration on natriuretic peptide concentrations.

      Methods

      31 men and women (11 lean, 10 overweight, and 10 obese), ages 30–70 years, without cardiovascular disease or overt diabetes underwent a hyperinsulinemic-euglycemic insulin clamp. Plasma concentrations of N-terminal pro atrial natriuretic peptide (NT-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured at baseline and steady-state (the final 30 minutes of the clamp protocol).

      Results

      From baseline to steady-state, insulin levels increased from a mean level of 9.5 to 176.7 μU/ml ( p<0.001). Over this period, circulating NT-proANP concentrations decreased by 9% (-1933 ng/L, p = 0.01). The changes in NT-proANP did not differ between lean, overweight, and obese individuals. Steady-state NT-proANP levels, adjusted for baseline, were lower in individuals with greater insulin resistance, independent of BMI. In contrast to NT-proANP, NT-proBNP levels did not change significantly during the clamp (p = 0.41).

      Conclusion

      Insulin administration was associated with a moderate decrease in circulating NT-proANP, but not NT-proBNP. The lowest NT-proANP concentrations were found in insulin-resistant individuals. Further investigations are warranted to elucidate potential mechanisms underlying the effects of insulin on the cardiac hormonal axis.

      Related collections

      Most cited references 46

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      Insulin signalling and the regulation of glucose and lipid metabolism.

      The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.
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        Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.

        The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C(-/-) mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.
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          Impact of obesity on plasma natriuretic peptide levels.

          The mechanisms linking obesity to hypertension have not been established, but sodium retention and excessive sympathetic tone are key contributors. The natriuretic peptides are important regulators of sodium homeostasis and neurohormonal activation, raising the possibility that obese individuals have an impaired natriuretic peptide response. We examined the relations of plasma B-type natriuretic peptide (BNP) and N-terminal proatrial natriuretic peptide (N-ANP) to body mass index in 3389 Framingham Study participants (1803 women) without heart failure. Multivariable regression analyses were performed, adjusting for clinical and echocardiographic covariates. BNP levels below the assay detection limit and N-ANP levels in the lowest sex-specific quartile were categorized as low. Multivariable-adjusted mean plasma BNP levels in lean ( or =30 kg/m2) men were 21.4, 15.5, and 12.7 pg/mL, respectively (trend P<0.0001). Corresponding values in women were 21.1, 16.3, and 13.1 pg/mL (trend P<0.001). A similar pattern was noted for plasma N-ANP. Obese individuals had higher odds of having low plasma BNP (multivariable-adjusted odds ratios: men, 2.51; 95% CI, 1.71 to 3.68; women, 1.84; 95% CI, 1.32 to 2.58) and low plasma N-ANP (odds ratios: men, 4.81; 95% CI, 2.98 to 7.76; women, 2.85; 95% CI, 2.01 to 4.04) compared with lean individuals. Diabetes also was associated with low plasma natriuretic peptide levels, and the negative effects of obesity and diabetes on natriuretic peptide levels were additive. Obese individuals have low circulating natriuretic peptide levels, which may contribute to their susceptibility to hypertension and hypertension-related disorders.
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            Author and article information

            Affiliations
            [1 ] Veterans Administration Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
            [2 ] Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
            [3 ] Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
            [4 ] Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
            [5 ] Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
            [6 ] Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
            [7 ] Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
            [8 ] Vanderbilt Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
            Ospedale del Cuore G Pasquinucci Fondazione Toscana Gabriele Monasterio di Massa, ITALY
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Contributors
            ORCID: http://orcid.org/0000-0002-6682-4630, Role: Conceptualization, Role: Data curation, Role: Formal analysis, Role: Investigation, Role: Project administration, Role: Writing – original draft, Role: Writing – review & editing
            Role: Funding acquisition, Role: Investigation, Role: Methodology, Role: Project administration, Role: Writing – review & editing
            Role: Investigation, Role: Methodology, Role: Writing – review & editing
            Role: Formal analysis, Role: Writing – review & editing
            Role: Formal analysis, Role: Writing – review & editing
            Role: Writing – review & editing
            Role: Methodology, Role: Writing – review & editing
            Role: Formal analysis, Role: Investigation, Role: Writing – review & editing
            Role: Conceptualization, Role: Formal analysis, Role: Funding acquisition, Role: Investigation, Role: Methodology, Role: Project administration, Role: Resources, Role: Supervision, Role: Writing – review & editing
            Role: Conceptualization, Role: Formal analysis, Role: Investigation, Role: Methodology, Role: Resources, Role: Supervision, Role: Writing – original draft, Role: Writing – review & editing
            Role: Editor
            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, CA USA )
            1932-6203
            14 May 2018
            2018
            : 13
            : 5
            29758041 5951576 10.1371/journal.pone.0196869 PONE-D-17-42749

            This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

            Counts
            Figures: 2, Tables: 1, Pages: 12
            Product
            Funding
            Funded by: funder-id http://dx.doi.org/10.13039/100000968, American Heart Association;
            Award ID: 14SFRN20770008
            Award Recipient :
            Funded by: funder-id http://dx.doi.org/10.13039/100000968, American Heart Association;
            Award ID: 15SDG24890015
            Award Recipient :
            Funded by: funder-id http://dx.doi.org/10.13039/100006108, National Center for Advancing Translational Sciences;
            Award ID: UL1TR000445
            Award Recipient : Talat Alp Ikizler
            Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
            Award ID: T32DK007061
            Award Recipient : ORCID: http://orcid.org/0000-0002-6682-4630
            Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
            Award ID: R01 HL102780
            Award Recipient :
            Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
            Award ID: P30 DK020593
            Award Recipient :
            Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
            Award ID: K24 DK62849
            Award Recipient : Talat Alp Ikizler
            Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
            Award ID: P30 DK079341
            Award Recipient : Talat Alp Ikizler
            Funded by: funder-id http://dx.doi.org/10.13039/100006538, Vanderbilt University School of Medicine;
            Award ID: Vanderbilt University Medical Center Faculty Research Scholars award
            Award Recipient : ORCID: http://orcid.org/0000-0002-6682-4630
            Funded by: funder-id http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;
            Award ID: 1I01CX000414
            Award Recipient : Talat Alp Ikizler
            Funded by: American Heart Association (US)
            Award ID: 14SFRN20770008
            Award Recipient : Talat Alp Ikizler
            Research reported in this publication was supported by the American Heart Association awards ( https://research.americanheart.org) 14SFRN20770008 (S.M.D., T.A.I.) and 15SDG24890015 (J.F.F.); the National Institutes of Health ( https://www.nih.gov) Clinical Translational Science Award UL1TR000445 (T.A.I.) from the National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases awards T32DK007061 (K.N.B.), P30 DK020593 (K.D.N.), K24 DK62849 (T.A.I.), and Vanderbilt O’Brien Mouse Kidney Center Grant P30 DK079341 (T.A.I.); National Heart, Lung, and Blood Institute award R01 HL102780 (T.J.W.); Vanderbilt University Medical Center Faculty Research Scholars award ( http://my.vanderbilt.edu/vfrs) (K.N.B.), and U.S. Department of Veterans Affairs ( https://www.research.va.gov/funding/) under Award Number 1I01CX000414 (T.A.I.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Medicine and Health Sciences
            Endocrinology
            Diabetic Endocrinology
            Insulin
            Biology and Life Sciences
            Biochemistry
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            Insulin
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            Natriuretic Peptide
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