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Cited by 252Blood Pressure and Hypertension StudiesDiabetes, Cardiovascular Risks, and LipoproteinsNitric Oxide and Endothelin Effects

Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension.

Open access
Lembo, G, Napoli, R, Capaldo, B, Rendina, V, Iaccarino, G, Volpe, M, Trimarco, B, Saccà, L·1992·Journal of Clinical Investigation
DOI 10.1172/jci115842PMC PMC443058
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Abstract

The reason why hyperinsulinemia is associated with essential hypertension is not known. To test the hypothesis of a pathophysiologic link mediated by the sympathetic nervous system, we measured the changes in forearm norepinephrine release, by using the forearm perfusion technique in conjunction with the infusion of tritiated NE, in patients with essential hypertension and in normal subjects receiving insulin intravenously (1 mU/kg per min) while maintaining euglycemia. Hyperinsulinemia (50-60 microU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects. However, the response of hypertensives was threefold greater compared to that of normotensives (2.28 +/- 45 ng.liter-1.min-1 in hypertensives and 0.80 +/- 0.27 ng.liter-1 in normals; P less than 0.01). Forearm glucose uptake rose to 5.1 +/- .7 mg.liter-1.min-1 in response to insulin in hypertensives and to 7.9 +/- 1.3 mg.liter-1.min-1 in normotensives (P less than 0.05). To clarify whether insulin action was due to a direct effect on muscle NE metabolism, in another set of experiments insulin was infused locally into the brachial artery to expose only the forearm tissues to the same insulin levels as in the systemic studies. During local hyperinsulinemia, forearm NE release remained virtually unchanged both in hypertensive and in normal subjects. Furthermore, forearm glucose disposal was activated to a similar extent in both groups (5.0 +/- 0.6 and 5.2 +/- 1.1 mg.liter-1.min-1 in hypertensives and in normals, respectively). These data demonstrate that: (a) insulin evokes an abnormal muscle sympathetic overactivity in essential hypertension which is mediated by mechanisms involving the central nervous system; and (b) insulin resistance associated with hypertension is demonstrable in the skeletal muscle tissue only with systemic insulin administration which produces muscle sympathetic overactivity. The data fit the hypothesis that the sympathetic system mediates the pathophysiologic link between hyperinsulinemia and essential hypertension.

AI snapshot

Written from the paper’s full text.

TL;DR

In patients with essential hypertension, systemic euglycemic hyperinsulinemia evoked a threefold greater increase in forearm skeletal muscle norepinephrine release than in normotensive controls. Local intra-arterial insulin did not change norepinephrine release in either group, suggesting the abnormal sympathetic response is centrally mediated rather than a direct muscle effect.

Key findings

  • Systemic insulin infusion increased forearm NE release in both groups, but the absolute rise was threefold higher in hypertensives (2.28±0.45 vs. 0.80±0.27 ng·liter⁻¹·min⁻¹; P < 0.01); percent increases were 140% in hypertensives (P < 0.001) and 35% in normotensives (P < 0.05).
  • During systemic insulin, forearm glucose uptake was lower in hypertensives than normotensives (5.1±0.7 vs. 7.9±1.3 mg·liter⁻¹·min⁻¹; P < 0.05), and whole-body glucose utilization was also lower (4.6±0.3 vs. 5.8±0.5 mg/kg per min; P < 0.05).
  • During local intrabrachial insulin, forearm NE release remained virtually unchanged in both groups, while forearm glucose disposal was similar in hypertensives and normals (5.0±0.6 and 5.2±1.1 mg·liter⁻¹·min⁻¹, respectively).
  • Forearm NE balance increased fourfold in hypertensives during systemic hyperinsulinemia (P < 0.05), whereas it was statistically indistinguishable from zero in normals.

Methods

  • Forearm perfusion technique with tritiated norepinephrine tracer was used in 45 subjects: 21 normotensives and 24 patients with mild to moderate essential hypertension.
  • Two protocols: systemic insulin infusion at 1 mU/kg per min for 120 min with euglycemia (12 normals, 14 hypertensives), or local intrabrachial insulin at 0.05 mU/kg per min (9 normals, 10 hypertensives); tracer subgroups received [³H]norepinephrine.
  • Forearm NE kinetics were calculated from arterial–venous balance, fractional extraction, clearance, uptake, and release; comparisons used paired and unpaired t tests, with values reported as mean±SE.

Limitations

  • The paper states that it cannot answer whether hyperinsulinemia is the primary defect leading to hypertension via sympathetic overactivity, and that an alternative primary sympathetic overactivity causing both hypertension and insulin resistance would be equally compatible with the data.
  • The paper states that the mechanism of insulin-evoked muscle sympathetic overactivity is unknown and that a peripheral reflex such as a venous baroreflex or chemoreflex cannot be excluded.
  • Evident from the text: sample sizes are small, especially for tracer subgroups (e.g., 8 normals and 7 hypertensives for systemic tracer studies; 5 and 5 for local tracer studies), and the local infusion model relies on adequate mixing, which was assessed in only 16 tested cases.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci115842

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Systemic insulin infusion (1 mU/kg per min, euglycemic) evoked a significant increase in forearm norepinephrine release in both normotensive and hypertensive subjects.

    “Hyperinsulinemia (50-60 jsU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects.”
    Quote in the paperSubstantial claim
  • Findingown data

    Forearm glucose uptake increased in response to intraarterial insulin infusion to a comparable extent in both groups.

    “Forearm glucose uptake increased in response to intraarterial insulin infusion to a comparable ex- tent in both groups.”
    Quote in the paperSubstantial claim
  • Findingown data

    The mean absolute change in forearm NE release during hyperinsulinemia was threefold higher in hypertensive (2.28±0.45 ng·liter−1·min−1) than in normotensive subjects (0.80±0.27 ng·liter−1·min−1) (P < 0.01).

    “The mean absolute change in forearm NE release during hyperinsulinemia was threefold higher in hypertensive (2.28±0.45ng.liter-' * min') than in normotensive subjects (0.80±0.27 ng liter-' * min-') (P < 0.01) (Fig. 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Arterial plasma FFA levels were not affected by local insulin (from 0.42±0.05 to 0.39±0.04 mmol in normal subjects and from 0.36±0.05 to 0.39±0.05 mmol in hypertensives).

    “Arterial plasma FFA levels were not affected by local insulin (from 0.42±0.05 to 0.39±0.04mmol in normal sub- jects and from 0.36±0.05 to 0.39±0.05mmol in hypertensives).”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Blood pressure remained unchanged throughout insulin infusion.

    “since blood pressure remained unchanged throughout insulin infusion.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    Heart rate was comparable in the two groups in basal conditions and increased slightly during hyperinsulinemia only in hypertensive patients (P < 0.05).

    “Heart rate was comparable in the two groups in basal conditions and increased slightly during hyperinsulinemia only in hypertensive patients (P < 0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In normal subjects, forearm norepinephrine balance was statistically indistinguishable from zero both in the basal state and during systemic insulin infusion.

    “In normal subjects, forearm NE balance was statistically indistinguishable from zero both in the basal state and during insulin infusion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Systolic and diastolic blood pressures were significantly higher in hypertensive patients than in normotensive subjects.

    “As expected, systolic and diastolic blood pressures were significantly higher in hypertensives than in normotensives”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both forearm NE uptake and NE release were totally unaffected by local forearm insulinization.

    “Both forearm NE uptake and NE release were totally unaffected by local forearm insulinization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plasma insulin concentration in the deep forearm vein was similar in the basal state in the two groups and increased to a comparable extent during systemic insulin infusion.

    “Plasma insulin concentration in the deep forearm vein was similar in the basal state in the two groups and increased to a comparable extent during systemic insulin infusion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Forearm NE uptake was similar in the basal state and increased comparably in the two groups during insulin infusion (P < 0.05).

    “Accordingly, forearm NE uptake was similar in the basal state and increased comparably in the two groups during insulin infusion (P < 0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During systemic insulin infusion, forearm glucose uptake increased in both groups, but the level attained was significantly lower in hypertensive patients than in normotensive subjects (5.1±0.7 vs 7.9±1.3 mg/L/min; P < 0.05).

    “Forearm glucose uptake rose to 5.1±.7 mg * liter-' * min-in response to insulin in hypertensives and to 7.9±1.3mg.liter' -min' in normotensives (P < 0.05).”
    • Also stated in: § Downers Grove, IL). · plain
      “Forearm glucose uptake in the basal state was not statistically different in normal and hypertensive subjects and increased considerably in response to insulin infusion in both groups.However, the levels attained in hypertensive patients were significantly lower than those ob- served in control subjects (P < 0.05) (Table III).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Venous plasma insulin levels increased to the same extent after insulin whereas systemic insulin concentration remained stable at its basal level.

    “Ve- nous plasma insulin levels increased to the same extent after insulin whereas systemic insulin concentration remained stable at its basal level.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Basal arterial blood glucose concentrations were similar in normal and hypertensive subjects and remained virtually unchanged during systemic insulin infusion in both groups.

    “As shown in Table III, basal arterial blood glucose concen- trations were similar in normal and hypertensive subjects, and remained virtually unchanged during insulin infusion in both groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Estimated forearm blood flow was similar in the two groups in the basal state and increased slightly but not significantly after systemic insulin administration.

    “Estimated forearm blood flow was similar in the two groups in the basal state and increased slightly but not signifi- cantly after insulin administration (Table III).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Insulin evokes an abnormal muscle sympathetic overactivity in essential hypertension that is mediated by mechanisms involving the central nervous system.

    “These data demonstrate that: (a) insulin evokes an ab- normal muscle sympathetic overactivity in essential hyperten- sion which is mediated by mechanisms involving the central nervous system;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the fructose-fed rat model, insulin resistance, hyperinsulinemia, and hypertension develop.

    “In this model, insu- lin resistance, hyperinsulinemia, and hypertension develop”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5]

      Not checked in the free run.

    • cites [6]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A program of physical activity or body weight control leads to a parallel reduction of hyperinsulinemia and blood pressure levels.

    “Particularly relevant is the observation that a program of physical activity or body weight control leads to a parallel reduction of hyperinsulinemia and blood pressure levels (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    All of the insulin effect on muscle NE metabolism seen with systemic insulinization is mediated either by central mechanisms involving the hypothalamic nuclei or by a peripheral reflex.

    “This leads to the conclu- sion that all of the insulin effect on muscle NE metabolism, seen with systemic insulinization, is mediated either by central mechanisms involving the hypothalamic nuclei or by a periph- eral reflex.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Forearm norepinephrine release measured by the [3H]norepinephrine infusion technique reflects skeletal muscle sympathetic nerve activity.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the offspring of essential hypertensive parents, insulin resistance and hyperinsulinemia are demonstrable before the development of high blood pressure.

    “Of interest is also the recent observation that in the offspring of essential hyperten- sive parents insulin resistance and hyperinsulinemia are de- monstrable before the development of high blood pressure (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Sympathetic overactivity may be potentially responsible for elevated blood pressure.

    “(d) sympathetic overactivity may be potentially responsible for elevated blood pressure (15)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In vitro insulin affects NE uptake by atrial strips.

    “Evi- dence to support this last hypothesis comes from the observa- tion that in vitro insulin affects NE uptake by the atrial strips (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Insulin resistance associated with hypertension is demonstrable in skeletal muscle tissue only with systemic insulin administration, which produces muscle sympathetic overactivity.

    “and (b) insulin resistance associated with hypertension is demonstrable in the skeletal muscle tissue only with systemic insulin administration which produces muscle sympathetic overactivity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    NE can induce vascular smooth muscle cell polyploidy independent of blood pressure elevation.

    “and that NE can in- duce vascular smooth muscle cell polyploidy independent of blood pressure elevation (47).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The exaggerated sympathetic activation induced by systemic insulinization in hypertensives may play a causal role in the impaired glucose uptake by the muscle tissue.

    “Alternatively, the data may indicate that the exaggerated sympathetic activation induced by systemic insulinization in hypertensives may play a causal role in the impaired glucose uptake by the muscle tissue.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    These are potential factors that may lead to structural alterations in the arterial vessels, thus reducing the lumen area, amplifying the vasoconstrictor response to contractile agents, and limiting vasodilation.

    “These are potential factors that may lead to structural alterations in the arterial vessels, thus reducing the lumen area, amplifying the vasoconstrictor re- sponse to contractile agents, and limiting vasodilation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The abnormal sympathetic response to insulin may further aggravate insulin resistance and hyperinsulinemia, thus acting as a self-perpetuating mechanism in essential hypertension.

    “Whatever the initial event, our data also point out the possibility that the abnormal sympathetic response to insulin may further aggravate insulin resistance and hypennsu- linemia, thus acting as a self-perpetuating mechanism in essen- tial hypertension.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    Muscle insulin resistance in hypertension is entirely mediated by the indirect component of insulin action.

    “The different response of muscle glucose uptake to local or systemic insulin may suggest that muscle insulin resistance in hypertension is entirely mediated by the indirect component of insulin action (28).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The sympathetic nervous system promotes the growth of vascular muscle fibers and myocardium.

    “In this context, it is pertinent to recall that the sympa- thetic nervous system promotes the growth of vascular muscle fibers (43, 44) and myocardium (45,46)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [43]

      Not checked in the free run.

    • cites [44]

      Not checked in the free run.

    • cites [45]

      Not checked in the free run.

24 of 24

  • The paper relies on this without support.

    The reason why hyperinsulinemia is associated with essential hypertension is not known.

    “The reason why hyperinsulinemia is associated with essential hypertension is not known.”

  • The paper relies on this without support.

    The available clinical data support the concept that insulin and human hypertension must be linked by pathophysiologic mechanisms.

    “The available clinical data, however, tend to support the concept that the two factors must be linked by pathophysiologic mechanisms.”

  • The paper relies on this without support.

    The effluent venous blood from the deep antecubital vein drains predominantly muscle tissue.

    “Under these conditions, the effluent venous blood drained predominantly muscle tissue.”

  • The paper relies on this without support.

    Forearm norepinephrine release measured by the [3H]norepinephrine infusion technique reflects skeletal muscle sympathetic nerve activity.

    “In conclusion, the current study provides evidence for an abnormal muscle sympathetic activity reflexly evoked by insu- lin in essential hypertension.”
4 of 4

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?

  • In humans, acute euglycemic hyperinsulinemia stimulates both sympathetic efferent activity and blood flow in skeletal muscle.

    “Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown.”

    From Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans (1993) · cites this paper as [8]

    The Introduction reports that intravenous insulin during euglycemia increased forearm norepinephrine release in both normal and hypertensive subjects. In the systemic-insulinization results (Table III), forearm blood flow increased only slightly and not significantly, so the paper does not establish the claimed vasodilation under those conditions. The Discussion says the mechanism of insulin-evoked muscle sympathetic overactivity is not known. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A central neural action of insulin may also contribute to stimulation of sympathetic outflow in this setting.

    “Alternatively, a central neural action of insulin may also contribute to stimulation of sympathetic outflow in this setting (8, 40-43).”

    From Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans (1993) · cites this paper as [8]

  • In humans, local intraarterial insulin infusion, in contrast to systemic intravenous infusion, did not have any stimulatory effect on sympathetic activity in skeletal muscle.

    “findings in humans, showing that local intraarterial insulin infusion, in contrast to systemic intravenous infusion, did not have any stimulatory effect on sympathetic activity in skeletal muscle (15).”

    From Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. (1994) · cites this paper as [15]

  • In hypertensive insulin-resistant humans, insulin augments stimulation of norepinephrine release into forearm tissue.

    “in hypertensive insulin-resistant humans, Lembo et al. (15) recently provided evidence for augmented stimulation of norepinephrine release into forearm tissue by insulin.”

    From Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. (1994) · cites this paper as Lembo et al. (15)

  • Insulin-induced increases in sympathetic activity and norepinephrine release in skeletal muscle are substantially exaggerated in hypertensive patients.

    “In contrast, Lembo et al84 demonstrated that insulin-induced increases in sympathetic activity and norepinephrine release in skeletal muscle are substantially exaggerated in hypertensive patients (Figure 3, right panel).”

    From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [84]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • NE-release calculation has its subtraction reversed

    Minor

    Under the paper's stated sign convention, net NE balance is uptake minus release. Release therefore equals uptake minus net balance, not net balance minus uptake as the calculation describes.

1 of 1

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Related

Authors
Lembo, G., Napoli, R., Capaldo, B., Rendina, V, Iaccarino, G., Volpe, M., Trimarco, B., & Saccà, L.
Affiliations
Federico II University Hospital (IT)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1992-07-01
Volume
90
Issue
1
Pages
24-29
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci115842
PMC
PMC443058
OpenAlex
W2159417090
Semantic Scholar
8fe2d8db2d3c3ab4a67dd67a612135319f91815b
Cited by
252
References
47
Citations by year
2026: 1 · 2025: 10 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 9 · 2017: 3 · 2016: 9 · 2015: 5 · 2014: 6 · 2013: 4 · 2012: 8
FWCI
12.48
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Funders
Società Italiana dell'Ipertensione Arteriosa
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
essential hypertension, hyperinsulinemia, insulin resistance, skeletal muscle, sympathetic nervous system, noradrenaline release, glucose uptake
MeSH terms
Adult, Female, Humans, Hypertension, Insulin, Male, Muscles, Norepinephrine, Sympathetic Nervous System

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