CoChat
Sign Up
Cited by 74Adrenal Hormones and DisordersStress Responses and CortisolHormonal Regulation and Hypertension

The postprandial rise in plasma cortisol in men is mediated by macronutrient-specific stimulation of adrenal and extra-adrenal cortisol production

Open access
Stimson, Roland H., Mohd-Shukri, Nor A., Bolton, Jennifer L., Andrew, Ruth, Reynolds, Rebecca M., Walker, Brian R.·2014·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2013-2307PMC PMC4392802
Open this paper in CoChat — free account

Abstract

CONTEXT: Circadian variation is a fundamental characteristic of plasma glucocorticoids, with a postprandial rise in cortisol an important feature. The diurnal rhythm is presumed to reflect alterations in hypothalamic-pituitary-adrenal axis activity; however, cortisol is produced not only by the adrenal glands but also by regeneration from cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 1, mainly in liver and adipose tissue. OBJECTIVE: We tested the contribution of peripheral cortisol regeneration to macronutrient-induced circadian variation of plasma cortisol in humans. DESIGN: This was a randomized, single-blinded, crossover study. SETTING: The study was conducted at a hospital research facility. PARTICIPANTS: Eight normal-weight healthy men participated in the study. INTERVENTIONS: Subjects were given isocaloric energy isodense flavor-matched liquid meals composed of carbohydrate, protein, fat, or low-calorie placebo during infusion of the stable isotope tracer 9,11,12,12-[2H]4-cortisol. OUTCOME MEASURES AND RESULTS: Plasma cortisol increased similarly after all macronutrient meals (by ∼90 nmol/L) compared with placebo. Carbohydrate stimulated adrenal secretion and extra-adrenal regeneration of cortisol to a similar degree. Protein and fat meals stimulated adrenal cortisol secretion to a greater degree than extra-adrenal cortisol regeneration. The increase in cortisol production by 11β-hydroxysteroid dehydrogenase type 1 was in proportion to the increase in insulin. The postprandial cortisol rise was not accounted for by decreased cortisol clearance. CONCLUSIONS: Food-induced circadian variation in plasma cortisol is mediated by adrenal secretion and extra-adrenal regeneration of cortisol. Given that the latter has the more potent effect on tissue cortisol concentrations and that effects on adrenal and extra-adrenal cortisol production are macronutrient specific, this novel mechanism may contribute to the physiological interplay between insulin and glucocorticoids and the contrasting effects of certain diets on postprandial metabolism.

AI snapshot

Written from the paper’s full text.

TL;DR

In eight normal-weight healthy men, isocaloric carbohydrate, protein, and fat liquid meals each raised plasma cortisol by ~90 nmol/L versus placebo, but through macronutrient-specific adrenal and extra-adrenal production. Carbohydrate increased 11β-HSD1 regeneration and adrenal secretion similarly, whereas protein and fat mainly increased adrenal secretion, with 11β-HSD1 rise proportional to insulin.

Key findings

  • Plasma cortisol rose similarly after all macronutrient meals compared with placebo: carbohydrate peak change +98 ± 44 nmol/L at 75 minutes, protein +97 ± 41 nmol/L at 45 minutes, and fat +87 ± 33 nmol/L at 45 minutes.
  • Carbohydrate stimulated adrenal secretion and extra-adrenal regeneration to a similar degree: rise in Ra cortisol attributable to 11β-HSD1 was 11.9 ± 2.4 nmol/min, and attributable to adrenal secretion was 15.9 ± 9.5 nmol/min (P = .06). Protein and fat stimulated adrenal secretion more than 11β-HSD1: protein 29.4 ± 16.2 vs 7.4 ± 2.7 nmol/min; fat 12.9 ± 9.8 vs 5.1 ± 2.6 nmol/min. Adrenal secretion accounted for 70%–80% of the cortisol rise after protein and fat.
  • Ra d3-cortisol, a specific measure of 11β-HSD1 production, increased after carbohydrate (peak +5.5 ± 1.2 nmol/min vs placebo, P < .001 vs all other meals) and protein (+5.1 ± 1.2 nmol/min, P < .01) but not after fat (+0.8 ± 1.0 nmol/min). The increase in 11β-HSD1 production was in proportion to the increase in insulin.
  • The postprandial cortisol rise was not accounted for by decreased cortisol clearance: d4-cortisol clearance was unchanged after carbohydrate and fat, and increased after protein (peak +0.08 ± 0.05 L/min, P < .05).

Methods

  • Randomized, single-blinded, crossover study in 8 healthy normal-weight men (aged 23.5 ± 2.3 years; BMI 22.4 ± 0.4 kg/m²) at a hospital research facility. Subjects attended four visits separated by 1 week and received isocaloric energy isodense flavor-matched liquid meals (561 kcal in 500 mL) of high carbohydrate, high protein, high fat, or low-calorie placebo during infusion of 9,11,12,12-[2H]4-cortisol.
  • The d4-cortisol infusion was 0.35 mg/h for 390 minutes after a 0.7 mg priming bolus, with frequent blood sampling and urine collection. Plasma and urine steroids were measured by liquid chromatography-tandem mass spectrometry and gas chromatography triple quadrupole mass spectrometry; kinetic calculations estimated Ra cortisol, Ra d3-cortisol, and d4-cortisol clearance.
  • Statistical analysis used R version 2.14.0 with linear mixed-effects models, subject as grouping factor and placebo as dummy variable; P < .05 was considered significant. The high-protein meal was not pure protein: protein accounted for 73% of energy, with carbohydrate 14% and fat 13%.

Limitations

  • Stated by the paper: the study included only 8 lean healthy men; the high-protein meal was not 100% protein because a pure protein meal was unpalatable; the type of carbohydrate was not explored; the mediator of the adrenal cortisol rise is unclear; and urinary deuterated metabolites did not establish whether increased protein-meal clearance was due to 11β-dehydrogenase, 5α-reductase, and/or 5β-reductase activity.
  • Evident from the text: the study was single-blinded, acute, and used liquid meals rather than mixed whole-food meals representative of normal living conditions; it did not include women, overweight/obese participants, or longer-term feeding, so generalizability and chronic effects remain untested.

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

Integrity signals

Registry

Crossref · 10.1210/jc.2013-2307

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    After carbohydrate, Ra d3-cortisol increased substantially, with a peak of +5.5 ± 1.2 nmol/min versus placebo (P < .001 versus all other meals).

    “In addition, the Ra d3-cortisol was substantially increased after carbohydrate (peak +5.5 ± 1.2 nmol/min vs placebo, P < .001 vs all other meals) (Figure 3B).”
    Quote in the paperSubstantial claim
  • Findingown data

    After carbohydrate, Ra cortisol increased by +27.8 ± 10.4 nmol/min compared with placebo (P < .05).

    “Similarly, Ra cortisol (a measure of cortisol production from any source) was increased after carbohydrate (change from placebo +27.8 ± 10.4 nmol/min, P < .05) (Figure 3A).”
    Quote in the paperSubstantial claim
  • Findingown data

    After carbohydrate, d4-cortisol clearance was unchanged compared with placebo.

    “d4-Cortisol clearance was unchanged compared with placebo (Figure 3C).”
    Quote in the paperSubstantial claim
  • Findingown data

    After placebo, plasma cortisol continued to fall in line with normal diurnal variation.

    “After the placebo meal, plasma cortisol continued to fall, following normal diurnal variation (Figure 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Carbohydrate did not have the largest effect on adrenal cortisol secretion.

    “and yet in our study carbohydrate did not have the largest effect on adrenal cortisol secretion.”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    After carbohydrate, plasma cortisol rose compared with placebo, peaked 75 minutes after the meal at a placebo-corrected change of +98 ± 44 nmol/L, and remained elevated for the rest of the protocol.

    “After the carbohydrate meal, plasma cortisol rose compared with placebo (P < .05). Cortisol concentrations peaked 75 minutes after the meal (change from placebo +98 ± 44 nmol/L) and remained increased for the remainder of the study protocol (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After placebo, Ra d3-cortisol and d4-cortisol clearance were unchanged.

    “Ra d3-cortisol (a specific measure of cortisol production by 11β-HSD1) and d4-cortisol clearance were both unchanged after placebo (Figure 3, B and C).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Plasma insulin rose significantly after carbohydrate and to a lesser extent after protein.

    “Plasma insulin concentrations rose significantly after carbohydrate (P < .001 vs other meals) and to a lesser extent after protein (P < .05 vs placebo and fat).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Plasma glucose rose significantly after the carbohydrate meal but not after protein, fat, or placebo.

    “Plasma glucose levels rose significantly after the carbohydrate meal (P < .001 vs other meals) but not after protein, fat, or placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After the high-protein meal, plasma cortisol rose compared with placebo and similarly to carbohydrate, peaking 45 minutes after the meal at a placebo-corrected change of +97 ± 41 nmol/L.

    “After the high-protein meal, plasma cortisol rose compared with placebo (P < .05) and similarly to the rise after carbohydrate (Figure 2). Cortisol concentrations peaked 45 minutes after the meal (change from placebo +97 ± 41 nmol/L)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Carbohydrate increased cortisol regeneration by 11β-HSD1 for a given d3-cortisone substrate concentration more than the other meals, while protein had a smaller effect.

    “Carbohydrate substantially increased cortisol regeneration by 11β-HSD1 for a given d3-cortisone substrate concentration compared with the other three meals, while protein had a lesser effect.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Cortisol production by 11β-HSD1 is linearly correlated with cortisone substrate availability, and d3-cortisone has an affinity for 11β-HSD1 similar to that of endogenous cortisone.

  • May combine two claims.

    Findingown data

    After the fat meal, circulating cortisol rose compared with placebo and similarly to carbohydrate and protein, peaking 45 minutes after the meal at a placebo-corrected change of +87 ± 33 nmol/L.

    “After the fat meal, circulating cortisol rose compared with placebo (P < .05) and similarly to the rise after the carbohydrate and protein meals (Figure 2). Cortisol levels peaked 45 minutes after the meal (change from placebo +87 ± 33 nmol/L)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The rise in Ra cortisol attributable to adrenal secretion was 15.9 ± 9.5 nmol/min after carbohydrate (P = .06), 29.4 ± 16.2 nmol/min after protein (P < .05), and 12.9 ± 9.8 nmol/min after fat (P = .27).

    “Correspondingly, the rise in Ra cortisol attributable to adrenal secretion was 15.9 ± 9.5 nmol/min after carbohydrate (P = .06), 29.4 ± 16.2 nmol/min after protein (P < .05), and 12.9 ± 9.8 nmol/min after fat (P = .27).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cortisol clearance was not decreased by any meal and therefore does not contribute to the postprandial rise in plasma cortisol.

    “Cortisol clearance, calculated using the d4-cortisol tracer, was not decreased by any of the meals and so does not contribute to postprandial elevations in plasma cortisol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The steady-state ratio of cortisone to d3-cortisone was about 1.2 and did not vary significantly between visits.

    “The ratio of cortisone to d3-cortisone during steady state was approximately 1.2 and did not significantly vary between visits (Supplemental Figure 1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increase in 11β-HSD1 cortisol production paralleled the change in circulating insulin, which was greatest after carbohydrate and smaller after protein.

    “First, the increase in cortisol production by 11β-HSD1 paralleled the change in circulating insulin concentrations, which was greatest after carbohydrate with a smaller rise after protein (Figures 2C and 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After the high-protein meal, Ra d3-cortisol increased but less than after carbohydrate, peaking 175 minutes after the meal at +5.1 ± 1.2 nmol/min versus placebo (P < .01).

    “Ra d3-cortisol was increased but to a lesser extent than after carbohydrate and peaked 175 minutes after the meal (peak +5.1 ± 1.2 nmol/min vs placebo, P < .01) (Figure 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Circulating cortisol increased substantially (about 90 nmol/L) and remained elevated versus placebo for at least 3 hours after carbohydrate and protein and for 2 hours after fat.

    “Circulating cortisol levels increased substantially (~90 nmol/L) and remained elevated compared with placebo for at least 3 hours after both the carbohydrate and protein meals and for 2 hours after the fat meal.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Urinary deuterated metabolite analysis did not determine whether the increased clearance after protein was due to increased 11β-dehydrogenase, 5α-reductase, and/or 5β-reductase activity.

    “Analysis of urinary deuterated metabolite excretion did not establish whether this is due to increased 11β-dehydrogenase, 5α-reductase, and/or 5β-reductase activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    After carbohydrate, the adrenal glands and 11β-HSD1 each accounted for about 50% of the postprandial cortisol rise, although the adrenal increase was not statistically significant.

    “The adrenal glands and 11β-HSD1 each accounted for approximately 50% of the postprandial cortisol rise after carbohydrate”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Cortisol production by 11β-HSD1 is linearly correlated with cortisone substrate availability, and d3-cortisone has an affinity for 11β-HSD1 similar to that of endogenous cortisone.

  • May combine two claims.

    Findingown data

    The rise in Ra cortisol attributable to extra-adrenal 11β-HSD1 production was 11.9 ± 2.4 nmol/min after carbohydrate (P < .01 versus placebo/fat, P < .05 versus protein), 7.4 ± 2.7 nmol/min after protein (P < .05 versus placebo), and 5.1 ± 2.6 nmol/min after fat (P < .05 versus placebo).

    “The rise in Ra cortisol attributable to extra-adrenal production by 11β-HSD1 was 11.9 ± 2.4 nmol/min after carbohydrate (P < .01 vs placebo/fat, P < .05 vs protein), 7.4 ± 2.7 nmol/min after protein (P < .05 vs placebo), and 5.1 ± 2.6 nmol/min after fat (P < .05 vs placebo).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Cortisol production by 11β-HSD1 is linearly correlated with cortisone substrate availability, and d3-cortisone has an affinity for 11β-HSD1 similar to that of endogenous cortisone.

  • May combine two claims.

    Findingown data

    After adjustment for the change in cortisone, cortisol regeneration by 11β-HSD1 was significantly increased after the fat meal and similar to that after protein.

    “After accounting for the change in cortisone, cortisol regeneration by 11β-HSD1 was significantly increased after the fat meal and similar to that observed after protein.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Cortisol production by 11β-HSD1 is linearly correlated with cortisone substrate availability, and d3-cortisone has an affinity for 11β-HSD1 similar to that of endogenous cortisone.

  • May combine two claims.

    Findingown data

    The ratio of cortisone to d3-cortisone rose after all three meals from about 1.2 to about 1.5, while it fell after placebo.

    “The ratio of cortisone to d3-cortisone increased after all three meals from approximately 1.2 to approximately 1.5, whereas it fell, following normal diurnal variation after placebo (Supplemental Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All three meals substantially increased adrenal cortisol secretion, which accounted for most (70%-80%) of the cortisol rise after protein and fat.

    “All three meals also substantially increased cortisol secretion from the adrenal glands, which accounted for the majority (70%– 80%) of the cortisol rise after both protein and fat.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Using nonsteady-state equations did not significantly change the results.

    “Results obtained using nonsteady state equations did not significantly alter the results.”
    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

    Body weight, fat mass, fasting glucose, and lipid profile did not change between study visits.

    “Body weight, fat mass, fasting glucose, and lipid profile were unaltered between visits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    11β-HSD1 is expressed mainly in liver, adipose tissue, and brain, where it regenerates cortisol from cortisone and amplifies local tissue glucocorticoid levels.

    “the type 1 isozyme (11β-HSD1) is present mainly in the liver, adipose tissue, and brain and regenerates cortisol from cortisone, amplifying local tissue glucocorticoid levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Seckl JR Walker BR 11β-Hydroxysteroid dehydrogenase type 1—a tissue-specific amplifier of glucocorticoid action Endocrinology 2001 142 1371 1376 11250914

      Not checked in the free run.

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

    Study design and conductown data

    The participants could not distinguish between the test meals.

    “none of the subjects was able to discriminate between the test meals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Before each meal, cortisol concentrations, Ra cortisol, Ra d3-cortisol, and d4-cortisol clearance did not differ between visits.

    “Prior to each meal, cortisol concentrations (Figure 2), Ra cortisol, Ra d3-cortisol (Table 2), and d4-cortisol clearance (Figure 3) did not differ between visits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cortisol production by 11β-HSD1 increases acutely after a mixed meal and after intravenous insulin/glucose infusion.

    “cortisol production by 11β-HSD1 acutely increases after a mixed meal (16) and after iv insulin/glucose infusion (17).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Basu R Singh R Basu A Johnson CM Rizza RA Effect of nutrient ingestion on total-body and splanchnic cortisol production in humans Diabetes 2006 55 667 674 16505229

      Not checked in the free run.

    • cites [17] Wake DJ Homer NZ Andrew R Walker BR Acute in vivo regulation of 11β-hydroxysteroid dehydrogenase type 1 activity by insulin and Intralipid infusions in humans J Clin Endocrinol Metab 2006 91 4682 4688 16954164

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortisol regenerated by 11β-HSD1 enters the bloodstream and therefore affects circulating as well as tissue cortisol concentrations.

    “Cortisol regenerated by 11β-HSD1 is released into the bloodstream and so impacts on circulating in addition to tissue concentrations (Figure 1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Basu R Singh RJ Basu A Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-β hydroxysteroid dehydrogenase (11β-hsd) type 1 pathway Diabetes 2004 53 2051 2059 15277385

      Not checked in the free run.

    • cites [11] Andrew R Westerbacka J Wahren J Yki-Jarvinen H Walker BR The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans Diabetes 2005 54 1364 1370 15855321

      Not checked in the free run.

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

    Study design and conductown data

    The study was a randomized, single-blind, crossover trial in eight healthy men.

    “Eight healthy men were recruited to a randomized, single-blind, crossover study.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Circulating cortisol concentrations rise after each meal.

    “it is well known that circulating cortisol concentrations rise following each meal (3, 4).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Quigley ME Yen SS A mid-day surge in cortisol levels J Clin Endocrinol Metab 1979 49 945 947 511983

      Not checked in the free run.

    • cites [4] Follenius M Brandenberger G Hietter B Diurnal cortisol peaks and their relationships to meals J Clin Endocrinol Metab 1982 55 757 761 7202017

      Not checked in the free run.

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

    Study design and conductcitation

    The study had more than 90% power to detect a 10% difference in Ra cortisol and d3-cortisol, based on previous measurements.

    “The study had greater than 90% power to detect a 10% difference in the Ra cortisol and d3-cortisol, based on previous measurements (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Stimson RH Johnstone AM Homer NZ Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men J Clin Endocrinol Metab 2007 92 4480 4484 17785367

      Not checked in the free run.

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

    Premisecitation

    Cortisol production by 11β-HSD1 and cortisol metabolism by 5α- and 5β-reductases change during weight-loss diets, with effects differing by dietary macronutrient content.

    “Cortisol production by 11β-HSD1 and metabolism by 5α- and 5β-reductases are altered during weight-loss diets, with differential effects according to dietary macronutrient content (12–15).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [12] Stimson RH Johnstone AM Homer NZ Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men J Clin Endocrinol Metab 2007 92 4480 4484 17785367

      Not checked in the free run.

    • cites [13] Johnstone AM Faber P Andrew R Influence of short-term dietary weight loss on cortisol secretion and metabolism in obese men Eur J Endocrinol 2004 150 185 194 14763916

      Not checked in the free run.

    • cites [14] Engeli S Bohnke J Feldpausch M Regulation of 11β-HSD genes in human adipose tissue: influence of central obesity and weight loss Obes Res 2004 12 9 17 14742837

      Not checked in the free run.

    • cites [15] Tomlinson JW Moore JS Clark PM Holder G Shakespeare L Stewart PM Weight loss increases 11β-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue J Clin Endocrinol Metab 2004 89 2711 2716 15181046 PMC7611657

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Steady-state enrichment of d4-cortisol with cortisol and d3-cortisol was reached by 180 minutes of infusion.

    “Steady-state enrichments of d4-cortisol with cortisol and d3-cortisol were achieved by 180 minutes of the d4-cortisol infusion.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Cortisol is produced by the adrenal glands and also regenerated from cortisone by 11β-hydroxysteroid dehydrogenase type 1, mainly in liver and adipose tissue.

    “cortisol is produced not only by the adrenal glands but also by regeneration from cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 1, mainly in liver and adipose tissue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Seckl JR Walker BR 11β-Hydroxysteroid dehydrogenase type 1—a tissue-specific amplifier of glucocorticoid action Endocrinology 2001 142 1371 1376 11250914

      Not checked in the free run.

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

    Interpretationown data

    The data suggest that the poorly understood increase in hepatic insulin resistance caused by high-GI foods might be due to increased intrahepatic postprandial cortisol levels.

    “a poorly understood effect that our data suggest might be due to increased intrahepatic postprandial cortisol levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Haus JM Solomon TP Lu L Intramyocellular lipid content and insulin sensitivity are increased following a short-term lowglycemic index diet and exercise intervention Am J Physiol Endocrinol Metab 2011 301 E511 E516 21712533 PMC3174532

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The carbohydrate content of the high-protein meal could have contributed to increased 11β-HSD1 activity, but it is unlikely to be solely responsible because Ra d3-cortisol after the high-protein meal reached that after carbohydrate by the end of the protocol.

    “The high-protein meal contained some carbohydrate, which could have contributed to elevated 11β-HSD1 activity but is unlikely to be solely responsible because the Ra d3-cortisol after the high protein meal rose to that of the carbohydrate meal by the end of the study protocol (Figure 3B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Subcutaneous adipose tissue and skeletal muscle might contribute to extra-adrenal cortisol regeneration, but they are unlikely to explain the full rise in Ra d3-cortisol because that rise is much larger than their baseline d3-cortisol generation.

    “Subcutaneous adipose tissue (19) and skeletal muscle (22) might also contribute but are unlikely to account in full for the rise in Ra d3-cortisol (~6 nmol/min) because this is far greater in magnitude than the baseline d3-cortisol generation in these tissues.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Stimson RH Andersson J Andrew R Cortisol release from adipose tissue by 11β-hydroxysteroid dehydrogenase type 1 in humans Diabetes 2009 58 46 53 18852329 PMC2606892

      Not checked in the free run.

    • cites [22] Hughes KA Manolopoulos KN Iqbal J Recycling between cortisol and cortisone in human splanchnic, subcutaneous adipose, and skeletal muscle tissues in vivo Diabetes 2012 61 1357 1364 22511204 PMC3357308

      Not checked in the free run.

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

    Premisecitation

    Studies that found a cortisol rise after carbohydrate used high-GI foods, whereas some studies that did not find a rise used lower-GI carbohydrate.

    “Other studies showing a cortisol rise after carbohydrate have used similarly high GI foods (7, 31), whereas some studies that did not demonstrate a cortisol rise have used carbohydrate with a lower GI (5).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Martens MJ Rutters F Lemmens SG Born JM Westerterp-Plant-enga MS Effects of single macronutrients on serum cortisol concentrations in normal weight men Physiol Behav 2010 101 563 567 20849868

      Not checked in the free run.

    • cites [31] Iranmanesh A Lawson D Dunn B Veldhuis JD Glucose ingestion selectively amplifies ACTH and cortisol secretory-burst mass and enhances their joint synchrony in healthy men J Clin Endocrinol Metab 2011 96 2882 2888 21752898 PMC3167666

      Not checked in the free run.

    • cites [5] Slag MF Ahmad M Gannon MC Nuttall FQ Meal stimulation of cortisol secretion: a protein induced effect Metabolism 1981 30 1104 1108 6270500

      Not checked in the free run.

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

    Premisecitation

    High-GI foods increase hepatic insulin resistance.

    “Intriguingly, high-GI foods increase hepatic insulin resistance (32),”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Haus JM Solomon TP Lu L Intramyocellular lipid content and insulin sensitivity are increased following a short-term lowglycemic index diet and exercise intervention Am J Physiol Endocrinol Metab 2011 301 E511 E516 21712533 PMC3174532

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Adrenal release was nonsignificantly greater after protein, which may explain why some earlier studies concluded that the effect was specific to protein.

    “although adrenal release was (nonsignificantly) greater after protein, which may explain why some previous studies concluded this was a specific protein-mediated mechanism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Meals that intermittently raise cortisol could potentially lead to adverse cardiometabolic outcomes, although meals at times other than midday may cause a smaller cortisol rise.

    “therefore, meals that raise cortisol levels intermittently could potentially lead to adverse cardiometabolic outcomes, although meals at times other than midday may induce a lesser rise in cortisol (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Follenius M Brandenberger G Hietter B Diurnal cortisol peaks and their relationships to meals J Clin Endocrinol Metab 1982 55 757 761 7202017

      Not checked in the free run.

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

    Premisecitation

    Increased liver 11β-HSD1 may contribute to metabolic adaptation to a carbohydrate load, for example by increasing recycling between glucose-6-phosphate and glycogen.

    “may contribute to metabolic adaptation to a carbohydrate load, for example, by increasing recycling between glucose-6-phosphate and glycogen (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Andrews RC Walker BR Glucocorticoids and insulin resistance: old hormones, new targets Clin Sci (Lond) 1999 96 513 523 10209084

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Placebo-corrected values were used for comparisons so that diurnal variation in cortisol would not influence the results.

    “therefore, placebo corrected values were used for the comparisons rather than absolute values to ensure that diurnal variation of cortisol did not influence the results.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    It is unlikely that individual macronutrients act directly on the adrenal cortex to stimulate cortisol production, because intravenous lipid or amino acid infusion does not demonstrably raise circulating cortisol.

    “It seems unlikely that particular macronutrients act directly on the adrenal cortex to stimulate cortisol production, given that iv infusion of lipids (17) or amino acids (6) do not produce a demonstrable rise in circulating cortisol.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Wake DJ Homer NZ Andrew R Walker BR Acute in vivo regulation of 11β-hydroxysteroid dehydrogenase type 1 activity by insulin and Intralipid infusions in humans J Clin Endocrinol Metab 2006 91 4682 4688 16954164

      Not checked in the free run.

    • cites [6] Benedict C Hallschmid M Scheibner J Gut protein uptake and mechanisms of meal-induced cortisol release J Clin Endocrinol Metab 2005 90 1692 1696 15585568

      Not checked in the free run.

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

    Premisecitation

    Meals eaten at times other than midday may produce a smaller rise in cortisol.

    “although meals at times other than midday may induce a lesser rise in cortisol (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Follenius M Brandenberger G Hietter B Diurnal cortisol peaks and their relationships to meals J Clin Endocrinol Metab 1982 55 757 761 7202017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    The gut cells that sense carbohydrate are more distal than those that sense protein and fat.

    “An alternative explanation is that the cells in the gut responsible for sensing carbohydrate are more distal than those sensing protein and fat (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Sjolund K Sanden G Hakanson R Sundler F Endocrine cells in human intestine: an immunocytochemical study Gastroenterology 1983 85 1120 1130 6194039

      Not checked in the free run.

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

    Premisecitation

    Protein ingestion increases insulin levels.

    “Protein ingestion also increases insulin levels (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Nuttall FQ Mooradian AD Gannon MC Billington C Krezowski P Effect of protein ingestion on the glucose and insulin response to a standardized oral glucose load Diabetes Care 1984 7 465 470 6389060

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Chronic excess glucocorticoid exposure causes adverse metabolic effects.

    “Chronic excess glucocorticoid exposure causes adverse metabolic effects (33);”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Walker BR Glucocorticoids and cardiovascular disease Eur J Endocrinol 2007 157 545 559 17984234

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This novel mechanism may contribute to the physiological interplay between insulin and glucocorticoids and to the contrasting effects of certain diets on postprandial metabolism.

    “this novel mechanism may contribute to the physiological interplay between insulin and glucocorticoids and the contrasting effects of certain diets on postprandial metabolism.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: No prior study had examined the relative contributions of adrenal secretion, extra-adrenal regeneration, and clearance to the postprandial cortisol rise or tested whether these effects differ by macronutrient.

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

    Premisecitation

    Higher cortisol levels after glucose tolerance testing and after a standardized meal in men with dysregulated HPA axis activity have been associated with features of the metabolic syndrome.

    “In addition, higher cortisol levels after glucose tolerance testing (35, 36) and after a standardized meal in men exhibiting dysregulated hypothalamic-pituitary-adrenal axis activity have been associated with features of the metabolic syndrome (37).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Walker BR Soderberg S Lindahl B Olsson T Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women J Intern Med 2000 247 198 204 10692082

      Not checked in the free run.

    • cites [36] Reynolds RM Walker BR Syddall HE Whorwood CB Wood PJ Phillips DI Elevated plasma cortisol in glucose-intolerant men: differences in responses to glucose and habituation to venepuncture J Clin Endocrinol Metab 2001 86 1149 1153 11238500

      Not checked in the free run.

    • cites [37] Rosmond R Holm G Bjorntorp P Food-induced cortisol secretion in relation to anthropometric, metabolic and haemodynamic variables in men Int J Obes Relat Metab Disord 2000 24 416 422 10805497

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    No prior study had examined the relative contributions of adrenal secretion, extra-adrenal regeneration, and clearance to the postprandial cortisol rise or tested whether these effects differ by macronutrient.

    “However, no previous studies have examined the relative contribution of adrenal secretion, extra-adrenal regeneration, and clearance to the rise in circulating cortisol after a meal or tested whether the effects differ between dietary constituents.”

  • The authors state this as an assumption.

    Cortisol production by 11β-HSD1 is linearly correlated with cortisone substrate availability, and d3-cortisone has an affinity for 11β-HSD1 similar to that of endogenous cortisone.

    “Assuming that cortisol production by 11β-HSD1 is linearly correlated with cortisone substrate availability and that d3-cortisone has a similar affinity for 11β-HSD1 as endogenous cortisone”
2 of 2

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 source of cortisol increases appears to be via both adrenal and extra-adrenal production.

    “The source of cortisol increases appears to be via both adrenal and extra-adrenal production”

    From Role of addiction and stress neurobiology on food intake and obesity (2018) · cites this paper as Stimson et al., 2014

  • Laboratory chow and specific macronutrients such as carbohydrates, fats, and proteins stimulate autonomic and cortisol responses in animals and humans.

    “laboratory chow and specific macronutrients such as carbohydrates, fats and proteins stimulate autonomic and cortisol responses in animals and humans”

    From Role of addiction and stress neurobiology on food intake and obesity (2018) · cites this paper as Stimson et al., 2014

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Stimson, R. H., Mohd-Shukri, N. A., Bolton, J. L., Andrew, R., Reynolds, R. M., & Walker, B. R.
Affiliations
British Heart Foundation Centre for Cardiovascular Science (GB)
Corresponding author
Stimson, Roland H.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2014-01
Volume
99
Issue
1
Pages
160-168
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2013-2307
PMC
PMC4392802
OpenAlex
W2088475925
Semantic Scholar
2eed3351e227046e841639f8625d6390e958c5f1
Cited by
74
References
41
Citations by year
2026: 7 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 9
FWCI
5.78
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Wellcome Trust
  • British Heart Foundation (RG/11/4/28734)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
plasma cortisol, 11β-hydroxysteroid dehydrogenase type 1, cortisone, carbohydrate meal, protein meal, fatty meal, insulin, hypothalamic-pituitary-adrenal axis, circadian rhythm, cortisol clearance, stable isotope tracers
MeSH terms
Adipose Tissue, Adrenal Glands, Adult, Eating, Food, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Liver, Male, Pituitary-Adrenal System, Placebos, Single-Blind Method, Cross-Over Studies, Postprandial Period, Young Adult

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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