Cited by 175Adrenal Hormones and DisordersPancreatic function and diabetesStress Responses and Cortisol

The DOI matches its Crossref record; 71 of the 71 references it cites were found in a registry or an index; none of the 51 sources its claims cite is checked for support yet.

Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans.

Open access
Dinneen, S, Alzaid, A, Miles, J, Rizza, R·1993·Journal of Clinical Investigation

Abstract

Glucocorticoid concentrations vary throughout the day. To determine whether an increase in cortisol similar to that present during sleep is of physiologic significance in humans, we studied the disposition of a mixed meal when the nocturnal rise in cortisol was mimicked or prevented using metyrapone plus either a variable or constant hydrocortisone infusion. When glucose concentrations were matched with a glucose infusion, hepatic glucose release (2.6 +/- 0.2 vs. 1.5 +/- 0.4 nmol/kg per 6 h) was higher (P < 0.05) while glucose disappearance (5.9 +/- 0.3 vs. 7.3 +/- 0.9 mmol/kg per 6 h) and forearm arteriovenous glucose difference (64 +/- 24 vs. 231 +/- 62 mmol/dl per 6 h) were lower (P < 0.05) during the variable than basal infusion. The greater hepatic response during the variable cortisol infusion was mediated (at least in part) by inhibition of insulin and stimulation of glucagon secretion as reflected by lower (P < 0.05) C-peptide (0.29 +/- 0.01 vs. 0.38 +/- 0.04 mmol/liter per 6 h) and higher (P < 0.05) glucagon (42.7 +/- 2.0 vs. 39.3 +/- 1.8 ng/ml per 6 h) concentrations. In contrast, the decreased rates of glucose uptake appeared to result from a state of "physiologic" insulin resistance. The variable cortisol infusion also increased (P < 0.05) postprandial palmitate appearance as well as palmitate, beta-hydroxybutyrate, and alanine concentrations, suggesting stimulation of lipolysis, ketogenesis, and proteolysis. We conclude that the circadian variation in cortisol concentration is of physiologic significance in normal humans.

Overview

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Written from the paper’s full text.

TL;DR

In healthy humans, mimicking the nocturnal rise in cortisol with a variable hydrocortisone infusion raised fasting and postprandial glucose and altered postprandial carbohydrate, fat, and protein metabolism compared with a basal infusion. The effects were largely offset by compensatory hyperglycemia, except for increased palmitate appearance, suggesting the circadian cortisol rise is physiologically significant.

Key findings

  • The variable cortisol infusion increased fasting glucose (95±2 vs. 88±2 mg/dl, P < 0.005) and postprandial glucose response (8.2±1.0 vs. 5.1±0.9 g/dl per 6 h), peak glucose (182±5 vs. 158±7 mg/dl), and nadir (90±2 vs. 77±4 mg/dl) versus basal cortisol (P < 0.01).
  • When postprandial glucose concentrations were matched, hepatic glucose release was higher (2.6±0.2 vs. 1.5±0.4 nmol/kg per 6 h) while glucose disappearance (5.9±0.3 vs. 7.3±0.9 mmol/kg per 6 h) and forearm arteriovenous glucose difference (64±24 vs. 231±62 mmol/dl per 6 h) were lower during variable versus basal-plus-glucose infusion (P < 0.05).
  • Matched-glucose studies showed lower C-peptide (0.29±0.01 vs. 0.38±0.04 mmol/liter per 6 h) and higher glucagon (42.7±2.0 vs. 39.3±1.8 ng/ml per 6 h) during variable cortisol, suggesting inhibited insulin and stimulated glucagon secretion.
  • Variable cortisol also increased postprandial palmitate appearance and palmitate, β-hydroxybutyrate, and alanine concentrations, consistent with stimulated lipolysis, ketogenesis, and proteolysis.

Methods

  • Ten healthy volunteers (5 males, 5 females; mean age 34±4 yr; mean BMI 22.7±0.8 kg/m²) were studied in random order on two occasions separated by at least 2 wk; endogenous cortisol secretion was blocked with metyrapone, and hydrocortisone was infused either at a constant basal rate or variably to mimic the nocturnal cortisol rise.
  • A mixed meal (472 kcal; 45% carbohydrate, 40% fat, 15% protein) was given at 1000 with [2-³H]glucose and D-xylose; glucose turnover was measured with [6-³H]glucose and NaH¹⁴CO₃, and palmitate kinetics were measured in 5 volunteers.
  • Six volunteers underwent a third study with basal hydrocortisone plus intravenous glucose to match postprandial glucose to the variable-cortisol study; postprandial responses were calculated as area above zero by trapezoidal rule, and paired t tests were used with P < 0.05 considered significant.

Limitations

  • Stated: ¹⁴CO₂ incorporation into glucose provides only an index of gluconeogenesis because intramitochondrial specific activity is unknown, and precursor dilution may underestimate gluconeogenesis.
  • Stated: alanine concentration changes could reflect altered de novo synthesis, utilization, or proteolytic release; palmitate appearance may only qualitatively estimate lipolysis and may miss fatty acids oxidized before systemic mixing.
  • Stated and evident: the variable infusion peak cortisol (~20 µg/dl) was slightly higher than reported nocturnal values (~15–18 µg/dl), while the basal infusion rose to ~9 µg/dl, potentially over- and underestimating effects respectively; complete matched-glucose forearm and isotopic data were available in only five volunteers, and the study was acute and in normal humans only.

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Integrity signals

Registry

Crossref · 10.1172/jci116832

Cites

71 of 71 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

49 Own result · 34 Own interpretation · 27 Not checked yet · 6 Own method · 2 No basis given

Verify all 51 references — free account
  • The quote only partly states this claim. 3
  • Probably not a substantial claim. 18
  • It may state two separate claims as one. 11
29 of 29
  • The paper relies on this without support.

    It is unknown whether the normal variations in cortisol are of physiologic significance in normal humans.

    “It is currently unknown whether these variations in cortisol are of physiologic significance in normal humans.”
  • The paper relies on this without support.

    The basal hydrocortisone infusion (0.3 μg/kg/min) is an adequate control for the absence of the nocturnal rise in cortisol.

    “On the other hand, the basal infusion was accompanied by a slight but consistent increase in cortisol to -9 jug/dl.”
  • The paper relies on this without support.

    Matching postprandial glucose concentrations with a glucose infusion isolates the direct effects of cortisol from those due to compensatory increases in glucose concentration.

    “These latter studies permitted us to differentiate the direct effects of cortisol from those due to compensa- tory increases in glucose concentration.”
  • The paper relies on this without support.

    The forearm arteriovenous glucose difference reflects muscle glucose uptake.

    “The decrease in extraction ofglucose across the forearm implies that skeletal muscle participates in this response.”
  • The paper relies on this without support.

    D-xylose concentration is a valid marker of carbohydrate absorption.

    “Plasma D-xylose concentration, a marker of carbohydrate absorption, did not differ amongst studies (data not shown).”
  • The authors state this as an assumption.

    C-peptide and glucagon clearance remained constant on the two study days.

    “Assuming that C- peptide and glucagon clearance remained constant on the two study days”
6 of 6

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Citations

Cites

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Research works printed but not linked: 1

  1. Faloona, G., and R. Unger. 1974. Glucagon. In Methods of Hormone Radioimmunoassay. B. Jaffe and H. Behrman, editors. Academic Press, Inc., New York. 317-330.

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Metadata

Authors
Dinneen, S., Alzaid, A., Miles, J., & Rizza, R.
Affiliations
Mayo Clinic (US)
Venue
Journal of Clinical Investigation
Published
1993-11-01
Volume
92
Issue
5
Pages
2283-2290
ISSN
0021-9738 (ISSN-L)
OpenAlex
W1969547717
Cited by
175
References
71
Citations by year
2026: 4 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 9 · 2019: 6 · 2018: 4 · 2017: 10 · 2016: 7 · 2015: 8 · 2014: 12 · 2013: 4 · 2012: 9
FWCI
2.71
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Mayo Foundation for Medical Education and Research
  • National Institutes of Health (7r01dk038092-09, RR-00585)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK38092, DK 29953)
  • National Center for Research Resources (RR-00585, M01RR000585)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
diurnal cortisol rhythm, glucocorticoids, carbohydrate metabolism, hepatic glucose production, glucose disposal, insulin resistance, insulin inhibition, glucagon secretion, C-peptide, mixed meal, metyrapone, lipolysis, ketogenesis, proteolysis, postprandial lipemia
MeSH terms
Adult, Blood Glucose, C-Peptide, Female, Glucagon, Humans, Hydrocortisone, Infusions, Intravenous, Insulin, Male, Metyrapone, Palmitates, Periodicity, Sleep, Carbohydrate Metabolism

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