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Cited by 72Hormonal Regulation and HypertensionPancreatic function and diabetesAdrenal Hormones and Disorders

Primary aldosteronism decreases insulin secretion and increases insulin clearance in humans

Open access
Adler, Gail K., Murray, Gillian R., Turcu, Adina F., Nian, Hui, Yu, Chang, Solorzano, Carmen C., Manning, Robert, Peng, Dungeng +1 more·2020·Hypertension
DOI 10.1161/hypertensionaha.119.13922PMC PMC7155918
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Abstract

Primary aldosteronism is a frequent cause of resistant hypertension and is associated with an increased risk of developing diabetes mellitus. Aldosterone impairs insulin secretion in isolated islets, and insulin secretion is increased in aldosterone synthase–deficient mice. We hypothesized that treatment for primary aldosteronism increases insulin secretion and insulin sensitivity in humans. We conducted a prospective cohort study in patients with primary aldosteronism, with assessment of glucose metabolism before and 3 to 12 months after treatment. Participants underwent treatment for primary aldosteronism with adrenalectomy or a mineralocorticoid receptor antagonist at the discretion of their treating physician. We assessed insulin secretion and insulin sensitivity by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively, on 2 study days after a 5-day standardized diet. After treatment, the C-peptide and insulin response during the hyperglycemic clamp increased compared with pretreatment (ΔC-peptide at 90–120 minutes +530.5±384.1 pmol/L, P =0.004; Δinsulin 90–120 minutes +183.0±122.6, P =0.004). During hyperinsulinemic-euglycemic clamps, insulin sensitivity decreased after treatment (insulin sensitivity index 30.7±6.2 versus 18.5±4.7 nmol·kg −1 ·min −1 ·pmol −1 ·L; P =0.02). Insulin clearance decreased after treatment (872.8±207.6 versus 632.3±178.6 mL/min; P =0.03), and disposition index was unchanged. We conclude that the insulin response to glucose increases and insulin clearance decreases after treatment for primary aldosteronism, and these effects were not due to alterations in creatinine clearance or plasma cortisol. These studies may provide further insight into the mechanism of increased diabetes mellitus risk in primary aldosteronism.

Integrity signals

Registry

Crossref · 10.1161/hypertensionaha.119.13922

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

11 of 16 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Short-term stimulation of the renin-angiotensin-aldosterone system during sodium restriction impairs insulin secretion in humans.

    “short-term stimulation of the renin-angiotensin-aldosterone system during sodium restriction impairs insulin secretion in humans (8)”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Premisecitation

    Genetic aldosterone deficiency markedly increases insulin secretion in mice.

    “genetic aldosterone deficiency markedly increases insulin secretion in mice (6, 7)”
    Quote in the paperSubstantial claim2 of 2 sources checked
  • Premisecitation

    Aldosterone directly reduces insulin secretion in isolated murine pancreatic islets.

    “We recently demonstrated that aldosterone directly impairs insulin secretion in isolated murine pancreatic islets”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [6] source
    • cites [7] source

      The Introduction and Discussion state that aldosterone directly impairs insulin secretion in isolated murine islets. However, the Discussion identifies this as a previously demonstrated finding and cites an earlier study [18]; this paper’s own insulin-secretion measurements were made in vivo. Thus it supports the finding, but not its attribution to this paper as the original islet experiment. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingown data

    Achieved insulin concentration was significantly higher post-treatment during both low-dose and high-dose insulin infusion.

    “The achieved insulin concentration was significantly higher post-treatment during both low-dose (Figure 2C, average 188.9 ± 39.3 vs 304.1 ± 115.9 pmol/L for pre- vs post-treatment; p=0.023) and high-dose insulin infusion (average 1770.5 ± 272.9 vs 2452.6 ± 360.9 pmol/L for pre- vs post-treatment; p=0.031).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The average achieved glucose at 90-120 minutes during hyperglycemic clamps was similar before and after treatment.

    “the average achieved glucose at 90–120 minutes was similar (10.8±0.2 vs 10.9±0.3 mmol/L before vs after treatment, p=0.20)”
    Quote in the paperSubstantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Premisecitation

    Primary aldosteronism is linked to impaired glucose tolerance and a higher risk of type 2 diabetes.

    “Primary aldosteronism is also associated with glucose intolerance and an increased risk of type 2 diabetes (2–4)”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [2] source

      The Results section (page not available in our copy) reports a significantly higher risk of incident diabetes in patients with primary aldosteronism treated with mineralocorticoid receptor antagonists than in patients with essential hypertension. It does not report impaired glucose tolerance or specify that the incident diabetes was type 2. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [3] source

      The Discussion reports greater insulin resistance and impaired insulin secretion in people with primary hyperaldosteronism. It also reports an association between higher aldosterone and incident diabetes in the Jackson Heart Study, but that finding is not specific to people with primary aldosteronism. The paper does not establish the claimed increased type 2 diabetes risk for that group or directly report glucose intolerance in it. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [4] source
    • Rests on an assumption: The mechanisms linking primary aldosteronism to increased diabetes risk are unclear.

  • May combine two claims.

    Findingcitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] source

      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

  • May combine two claims.

    Premisecitation

    Aldosterone deficient mice developed increased adiposity during high fat diet, accompanied by increased insulin response to hyperglycemia.

    “We previously demonstrated that aldosterone deficient mice developed increased adiposity during high fat diet, which accompanied their markedly increased insulin response to hyperglycemia (7).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Aldosterone deficiency in mice increases insulin secretion in vivo without altering insulin sensitivity.

    “aldosterone deficiency in mice increases insulin secretion in vivo without altering insulin sensitivity (6).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Aldosterone impairs insulin secretion in isolated rodent islets and insulinoma cell lines.

    “Aldosterone impairs insulin secretion in isolated rodent islets and insulinoma cell lines”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

    Findingnone given

    Insulin clearance was higher in pre-treated than in treated participants.

    “Insulin clearance was higher in pre-treated than in treated participants (872.8±207.6 vs 632.3±178.6 mL/m2/min; p=0.031).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Serum potassium did not markedly change after treatment.

    “serum potassium (3.67 ± 0.24 vs 4.12 ± 0.35 mEq/L; p=0.063)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Creatinine did not markedly change after treatment.

    “creatinine (1.09 ± 0.16 vs 1.21 ± 0.38 mg/dL; p=0.35) did not markedly change after treatment.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Mean daily potassium chloride supplementation decreased after treatment.

    “the mean daily potassium chloride supplementation decreased accordingly (80.0 ± 64.0 vs 2.2 ± 6.7 mEq/d after treatment; p=0.02)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The C-peptide response increased after treatment similarly to the insulin response.

    “we measured the C-peptide response which was similarly increased after treatment as compared with before treatment (Figure 1C–D and Table 3)”
    Quote in the paperSubstantial claim

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

    Findingown data

    Plasma glucose concentrations during low-dose and high-dose hyperinsulinemic clamps were equivalent before and after treatment.

    “Plasma glucose concentrations maintained during the clamps were equivalent before and after treatment during both the low-dose insulin (Figure 2A, 5.3±0.1 vs 5.3±0.1 mmol/L; p=0.89) and high-dose insulin (5.3±0.1 vs 5.2±0.1; p=0.38).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The decrease in insulin secretion is observed in both the acute insulin response and the steady-state insulin response.

    “This decrease in insulin secretion is observed both in the acute insulin response and the steady-state insulin response.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Gynoid fat percentage did not increase after treatment.

    “but not gynoid fat percentage increased significantly after treatment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    8AM cortisol and ACTH were unchanged after treatment.

    “In the present study, 8AM cortisol and ACTH were unchanged after treatment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the overall data, insulin sensitivity correlated with android fat percentage, body mass index, and plasma aldosterone.

    “insulin sensitivity correlated with android fat percentage (rho=−0.62, p=0.013), body mass index (rho=−0.60, p=0.013), and plasma aldosterone (rho=−0.60, p=0.019).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The reduced insulin secretion in primary aldosteronism pre-treatment was accompanied by an opposing increase in insulin sensitivity.

    “the reduced insulin secretion in primary aldosteronism pre-treatment was accompanied by an opposing increase in insulin sensitivity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Body weight, lean body percentage, and total fat percentage were unchanged after treatment.

    “Body weight, lean body percentage, and total fat percentage were unchanged after treatment.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Resting energy expenditure and respiratory quotient were unchanged after treatment.

    “The resting energy expenditure and respiratory quotient were unchanged.”
    Quote in the paperNot a substantial claim

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

    Findingreasoning

    Increased total and gynoid fat mass after treatment was an unexpected finding.

    “increased total and gynoid fat mass after treatment of primary aldosteronism was an unexpected finding”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Ten patients consented, and one dropped out before any metabolic assessment.

    “Ten patients consented to the study procedures, and 1 participant dropped out due to scheduling difficulty before any metabolic assessment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The duration between assessment periods was similar between treatment groups.

    “The duration between assessment periods was similar (6.8±2.8 and 5.0±0.8 months in adrenalectomy and medically-treated participants, respectively; p=0.58).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    One participant completed only the hyperglycemic clamp assessments.

    “One participant consented for and completed only the hyperglycemic clamp assessments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Controls were well-matched for age, gender, race, BMI, and blood pressure.

    “Controls were well-matched for age, gender, race, BMI, and blood pressure.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    There were no clear differences in screening measurements based on treatment choice.

    “There were no clear differences in screening measurements based on treatment choice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In patients with aldosterone-producing adenomas, insulin secretion and disposition index increase after adrenalectomy.

    “In patients with aldosterone-producing adenomas, insulin secretion and disposition index assessed with intravenous glucose tolerance tests increase after adrenalectomy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] source

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

    Study design and conductown data

    The study was registered at clinicaltrials.gov before the first participant was enrolled.

    “This study was registered at clinicaltrials.gov prior to the enrollment of the first participant (NCT02362308).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The effects of treatment on insulin response and clearance were not due to changes in creatinine clearance or plasma cortisol.

    “these effects were not due to alterations in creatinine clearance or plasma cortisol”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Impaired glucose metabolism in primary aldosteronism is due to reductions in insulin secretion accompanied by increased insulin clearance.

    “the present study suggests that impaired glucose metabolism in primary aldosteronism is due to reductions in insulin secretion (i.e., impaired beta cell function) accompanied by increased insulin clearance.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Insulin secretion and insulin sensitivity are key factors governing glycemic control.

  • May combine two claims.

    Interpretationreasoning

    Insulin levels in primary aldosteronism are reduced due to reduced beta cell function and increased insulin clearance.

    “this paper suggests that insulin levels in primary aldosteronism are reduced due to reduced beta cell function and increased insulin clearance.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Aldosterone increases pre-adipocyte differentiation tissue in vivo.

    “Aldosterone increases pre-adipocyte differentiation tissue in vivo (39)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] source

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

    Study design and conductreasoning

    The present study was observational, and proving causation is difficult.

    “The present study was an observational study, because it was not deemed feasible to perform a randomized trial, and so proving causation is difficult.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The within-subject correlation of insulin secretion is very high in prior studies utilizing hyperglycemic clamps.

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

    Premisecitation

    Increased adipocyte-specific MR expression exacerbates diet-induced weight gain and insulin resistance in mice.

    “increased adipocyte-specific MR expression exacerbates diet-induced weight gain and insulin resistance in mice (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] source

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

    Interpretationreasoning

    The decrease in insulin could lead to glucose intolerance unless patients with hyperaldosteronism can adapt by improving insulin sensitivity.

    “This decrease in insulin could lead to glucose intolerance unless patients with hyperaldosteronism can adapt by improving insulin sensitivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Other potentially confounding characteristics of primary aldosteronism and control subjects were similar, including blood pressure, body mass index, age, and insulin sensitivity.

    “Other potentially confounding characteristics of primary aldosteronism and control subjects were similar, including blood pressure, body mass index, age, and insulin sensitivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Treatment of primary aldosteronism led to improved insulin secretion, reduced insulin clearance, and reduced insulin sensitivity accompanied by increased adiposity.

    “Treatment of primary aldosteronism led to improved insulin secretion, reduced insulin clearance and reduced insulin sensitivity accompanied by increased adiposity.”
    Quote in the paperSubstantial claim
35 of 35

  • The paper relies on this without support.

    The mechanisms linking primary aldosteronism to increased diabetes risk are unclear.

    “The mechanisms responsible for this association remains unclear.”

  • The paper relies on this without support.

    Insulin secretion and insulin sensitivity are key factors governing glycemic control.

    “Since insulin secretion and sensitivity are key factors governing glycemic control”

  • The paper relies on this without support.

    The within-subject correlation of insulin secretion is very high in prior studies utilizing hyperglycemic clamps.

    “we have found that the within-subject correlation is very high in prior studies utilizing hyperglycemic clamps.”
3 of 3

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?

  • A recently published study found that patients with primary aldosteronism had reduced insulin secretion, increased insulin clearance and insulin sensitivity, and unchanged disposition index using hyperglycemic and euglycemic-hyperinsulinemic clamps.

    “In a recently published study, patients with PA had reduced insulin secretion, increased insulin clearance and insulin sensitivity, and unchanged DI using hyperglycemic and euglycemic-hyperinsulinemic clamps [52].”

    From Insulin sensitivity and pancreatic β-cell function in patients with primary aldosteronism (2021) · cites this paper as [52]

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.

  • Insulin-clearance values have conflicting units

    Minor

    The same pre- and post-treatment clearance values are reported per square meter of body surface area in the results but without that normalization in the abstract.

  • Two different formulas are given for disposition index

    Minor

    The methods define disposition index using the acute insulin-response AUC, while the results define it using the C-peptide-response AUC. These are different inputs to the reported unchanged disposition index.

  • Hyperglycemic glucose-infusion duration has two values

    Minor

    The methods describe the continuous glucose infusion as lasting two hours, then say glucose was infused to maintain the target for 150 minutes. The stated durations differ by 30 minutes.

  • Insulin-clearance units differ between the abstract and results

    Minor

    The same pre- and post-treatment clearance values are reported in mL/min in the abstract but in mL/m2/min in the results. These units describe different quantities.

4 of 4

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Authors
Adler, G. K., Murray, G. R., Turcu, A. F., Nian, H., Yu, C., Solorzano, C. C., Manning, R., Peng, D., & Luther, J. M.
Affiliations
  • Brigham and Women's Hospital (US)
  • University of Michigan (US)
  • Vanderbilt University (US)
  • Department of Surgery (C.C.S.), Vanderbilt University Medical Center, Nashville, TN.
  • Vanderbilt University Medical Center (US)
Corresponding author
Luther, James M.
ORCID
Venue
Hypertension
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2020-05
Volume
75
Issue
5
Pages
1251-1259
ISSN
  • 0194-911X (ISSN-L)
  • 1524-4563
DOI
10.1161/hypertensionaha.119.13922
PMC
PMC7155918
OpenAlex
W3011848118
Cited by
71
References
40
Citations by year
2026: 11 · 2025: 10 · 2024: 13 · 2023: 8 · 2022: 17 · 2021: 8 · 2020: 3 · 2019: 1
FWCI
6.98
Type
journal article
Language
en
Open access
Locations
  • Hypertension (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Doris Duke Charitable Foundation (2019087)
  • National Institutes of Health (UL1TR002541, UL1TR000445, 5p60dk020593-31)
  • National Heart, Lung, and Blood Institute (T32HL007609, K24HL103845)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K23DK081662, P60-DK020593, K08DK109116, R01DK096994, P30DK020593)
  • National Center for Research Resources (TL1RR024978, UL1RR024975)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
primary aldosteronism, insulin secretion, insulin clearance, insulin sensitivity, hyperinsulinemic-euglycemic clamp, hyperglycemic clamp, adrenalectomy, mineralocorticoid receptor antagonists, diabetes risk, resistant hypertension, aldosterone, disposition index
MeSH terms
Insulin Secretion, Adolescent, Adrenalectomy, Adult, Aged, Mineralocorticoid Receptor Antagonists, Blood Glucose, Body Composition, C-Peptide, Diet, Energy Metabolism, Female, Glucose, Humans, Hydrocortisone, Hyperaldosteronism, Hyperglycemia, Insulin, Insulin Resistance, Male, Middle Aged, Potassium, Prospective Studies, Sodium, Dietary, Glucose Clamp Technique, Young Adult

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