Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans.
Open accessAbstract
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.
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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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- Findingown data
Premeal palmitate concentrations did not differ during the variable and basal cortisol infusions (134±23 vs. 114±23 μmol/liter, P = 0.4-0.8).
“Pre- meal palmitate concentrations (134±23 vs. 114±23 ,umol/ liter) and palmitate appearance (2.3±0.4 vs. 2.2±0.5 gmol/kg per min) did not differ (P = 0.4-0.8)during the variable and basal cortisol infusions (Fig. 6).”
Quote in the paperNot a substantial claim - Findingown data
The C-peptide response to meal ingestion was similar during the variable and basal cortisol infusions when glucose concentrations were allowed to vary (0.30±0.02 vs. 0.28±0.02 mmol/liter per 6 h).
“The C-peptide response to meal ingestion was similar (0.30±0.02 vs. 0.28±0.02mmol/liter per 6 h) during the variable and basal cortisol infusions when glucose concen- trations were allowed to vary.”
Quote in the paperNot a substantial claim - Findingown data
The postprandial insulin response was slightly greater during the variable than during the basal cortisol infusion (P < 0.05).
“Although premeal insulin concentrations did not differ amongst studies, the postprandial insulin response was slightly greater (P < 0.05) during the variable than during the basal cortisol infusion (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
Peak glucose concentrations were higher during the variable than during the basal cortisol infusion (182±5 vs. 158±7 mg/dl, P < 0.01).
“Upon meal ingestion, total postprandial response (8.2±1.0 vs. 5.1±0.9g/dl per 6 h), peak glucose concentrations (182±5 vs. 158±7 mg/dl), and postprandial glucose nadir (90±2 vs. 77±4 mg/dl) also were higher (P < 0.01 ) during the variable than during the basal cortisol infusion.”
Quote in the paperSubstantial claim - Findingown data
When glucose concentrations were matched, β-OHB concentrations were higher during the variable than during the basal cortisol plus glucose study (30±4 vs. 6±1 mmol/liter per 6 h, P < 0.05).
“However when glucose concentrations were matched, both plasma alanine (126±9 vs. 101±6 mol/liter per 6 h) and fl-OHB (30±4 vs. 6±1 mmol/liter per 6 h) concentrations were higher (P < 0.05) during the variable than during the basal cortisol plus glucose study (Fig. 5).”
Quote in the paperSubstantial claim
- Findingown data
There was no detectable difference in hepatic glucose release during the variable and basal cortisol infusions when glucose concentrations were allowed to vary.
“However when the individual components of glucose appearance were compared, there was no detectable difference in the appearance ofingested glucose, hepatic glucose release or carbon dioxide incorporation into glucose during the variable and basal cortisol infusions (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Premeal palmitate appearance did not differ during the variable and basal cortisol infusions (2.3±0.4 vs. 2.2±0.5 μmol/kg per min, P = 0.4-0.8).
“Pre- meal palmitate concentrations (134±23 vs. 114±23 ,umol/ liter) and palmitate appearance (2.3±0.4 vs. 2.2±0.5 gmol/kg per min) did not differ (P = 0.4-0.8)during the variable and basal cortisol infusions (Fig. 6).”
Quote in the paperNot a substantial claim - Findingown data
The postprandial glucagon concentrations were similar during the variable and basal cortisol infusions when glucose concentrations were allowed to vary (41.1±1.9 vs. 41.8±2.5 ng/ml per 6 h).
“The postprandial glucagon concentrations were similar during the variable and basal cortisol infusions (41.1±1.9 vs. 41.8±2.5 ng/ml per 6 h) when glucose concentrations were allowed to vary.”
Quote in the paperSubstantial claim - Findingown data
There was no detectable difference in carbon dioxide incorporation into glucose during the variable and basal cortisol infusions when glucose concentrations were allowed to vary.
“However when the individual components of glucose appearance were compared, there was no detectable difference in the appearance ofingested glucose, hepatic glucose release or carbon dioxide incorporation into glucose during the variable and basal cortisol infusions (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Fasting glucose concentrations were higher during the variable than during the basal cortisol infusion (95±2 vs. 88±2 mg/dl, P < 0.005).
“As shown in Fig. 1, fasting glucose concentrations were higher (P < 0.005) during the variable than during the basal cortisol infusion (95±2 vs. 88±2 mg/dl).”
Quote in the paperSubstantial claim - Findingown data
When glucose concentrations were matched, glucagon concentrations were higher during the variable than basal cortisol plus glucose infusions (P < 0.05).
“On the other hand when glucose concentra- tions were matched, glucagon concentrations were higher (P < 0.05) during the variable than basal cortisol plus glucose infusions.”
Quote in the paperSubstantial claim - Findingown data
The magnitude of the change in lactate concentration did not differ amongst studies.
“The magnitude ofthe change in lactate concentration did not differ amongst studies (Fig. 5).”
Quote in the paperNot a substantial claim - Findingown data
Premeal insulin concentrations did not differ amongst studies.
“Although premeal insulin concentrations did not differ amongst studies, the postprandial insulin response was slightly greater (P < 0.05) during the variable than during the basal cortisol infusion (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
The systemic rate of appearance of ingested glucose was slightly but not significantly greater during the variable than the basal plus glucose study.
“The systemic rate of appearance of ingested glucose was slightly but not significantly greater during the variable than the basal plus glucose study (Fig. 3).”
Quote in the paperNot a substantial claim - Findingown data
Postprandial suppression of lipolysis as reflected by the decrement in palmitate appearance was not impaired.
“Furthermore, postprandial suppression oflipolysis as reflected by the decrement in palmitate appearance was not impaired.”
Quote in the paperSubstantial claim - Findingown data
The variable hydrocortisone infusion resulted in an increase in cortisol concentrations from -2±1 μg/dl at 0100 to a peak of 20±1 μg/dl at 0930 falling to -9±1 μg/dl by study end.
“The variable hy- drocortisone infusion resulted in an increase in cortisol con- centrations from -2±1 jig/dl at 0100 to a peak of 20±1 jig/dl at 0930 falling to -9±1 Aig/dl by study end (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
Total postprandial glucose response was higher during the variable than during the basal cortisol infusion (8.2±1.0 vs. 5.1±0.9 g/dl per 6 h, P < 0.01).
“Upon meal ingestion, total postprandial response (8.2±1.0 vs. 5.1±0.9g/dl per 6 h), peak glucose concentrations (182±5 vs. 158±7 mg/dl), and postprandial glucose nadir (90±2 vs. 77±4 mg/dl) also were higher (P < 0.01 ) during the variable than during the basal cortisol infusion.”
Quote in the paperSubstantial claim - Findingreasoning
Free fatty acid concentrations were falling in both groups at the time when differences in glucose disposal were most marked.
“Therefore free fatty acid concentrations were falling in both groups at the time when differences in glucose disposal were most marked.”
Quote in the paperSubstantial claim - Findingown data
Lactate concentration increased after meal ingestion.
“Lactate and alanine concentration increased and 13-OHB concentrations decreased after meal ingestion.”
Quote in the paperNot a substantial claim - Findingown data
The initial postprandial rise in plasma glucose was greater during the variable than the basal cortisol infusion.
“Since the initial postprandial rise in plasma glucose was greater during the variable than the basal cortisol infusion, it follows that the difference between glucose appearance and glucose disappearance must have been greater during the former than the latter ( 330±44 vs. 209±51 ,mol/kg per 2 h; P < 0.02).”
Quote in the paperSubstantial claim - Findingown data
Overnight insulin concentrations did not differ during the variable and basal cortisol infusions.
“Since overnight insulin concentrations did not differ during the vari- able and basal cortisol infusions, it is unlikely that hyperinsu- linemia had important metabolic effects in the present experi- ments.”
Quote in the paperSubstantial claim - Findingown data
The two basal hydrocortisone infusions resulted in an increase in cortisol from -3±1 μg/dl at 0100 to values of -10 μg/dl from 1000 to 1200.
“In contrast, the two basal hydrocortisone infusions resulted in an increase in cortisol from -3±1 gg/dl at 0100 to values of -10 jgg/dl from 1000 to 1200.”
Quote in the paperNot a substantial claim - Findingown data
Alanine concentration increased after meal ingestion.
“Lactate and alanine concentration increased and 13-OHB concentrations decreased after meal ingestion.”
Quote in the paperNot a substantial claim - Findingown data
When glucose concentrations were matched, plasma alanine concentrations were higher during the variable than during the basal cortisol plus glucose study (126±9 vs. 101±6 μmol/liter per 6 h, P < 0.05).
“However when glucose concentrations were matched, both plasma alanine (126±9 vs. 101±6 mol/liter per 6 h) and fl-OHB (30±4 vs. 6±1 mmol/liter per 6 h) concentrations were higher (P < 0.05) during the variable than during the basal cortisol plus glucose study (Fig. 5).”
Quote in the paperSubstantial claim - Findingown data
When postprandial glucose concentrations were matched, the insulin response did not differ during the variable and basal cortisol plus glucose infusions.
“When postprandial glucose concentrations were matched, the insulin response did not differ during the variable and basal cortisol plus glucose infu- sions (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
There was no detectable difference in the appearance of ingested glucose during the variable and basal cortisol infusions when glucose concentrations were allowed to vary.
“However when the individual components of glucose appearance were compared, there was no detectable difference in the appearance ofingested glucose, hepatic glucose release or carbon dioxide incorporation into glucose during the variable and basal cortisol infusions (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Blood flow did not differ between the basal and variable cortisol studies (3.5±0.5 vs. 2.9±0.3 ml/dl forearm per minute, P = 0.22).
“Since blood flow did not differ between the basal and variable corti- sol studies (3.5±0.5 vs. 2.9±0.3 ml/dl forearm per minute, P = 0.22) and since the variation in blood flow introduced considerable noise into the measurement of forearm glucose uptake, we have elected to present the forearm data as the arteriovenous differences.”
Quote in the paperSubstantial claim - Findingown data
Postprandial glucose nadir was higher during the variable than during the basal cortisol infusion (90±2 vs. 77±4 mg/dl, P < 0.01).
“Upon meal ingestion, total postprandial response (8.2±1.0 vs. 5.1±0.9g/dl per 6 h), peak glucose concentrations (182±5 vs. 158±7 mg/dl), and postprandial glucose nadir (90±2 vs. 77±4 mg/dl) also were higher (P < 0.01 ) during the variable than during the basal cortisol infusion.”
Quote in the paperSubstantial claim - Findingown data
When postprandial glucose concentrations were matched, C-peptide levels were lower during the variable than basal cortisol plus glucose infusions (0.29±0.01 vs. 0.38±0.04 mmol/liter per 6 h, P < 0.05).
“lower (P < 0.05) C-peptide (0.29±0.01 vs. 0.38±0.04mmol/ liter per 6 h)”
Quote in the paperSubstantial claim - Findingreasoning
The difference between glucose appearance and glucose disappearance was greater during the variable than the basal cortisol infusion (330±44 vs. 209±51 μmol/kg per 2 h, P < 0.02).
“Since the initial postprandial rise in plasma glucose was greater during the variable than the basal cortisol infusion, it follows that the difference between glucose appearance and glucose disappearance must have been greater during the former than the latter ( 330±44 vs. 209±51 ,mol/kg per 2 h; P < 0.02).”
Quote in the paperSubstantial claim - Findingown data
The increase in palmitate appearance indicates that more free fatty acids reached the systemic circulation during the variable than during the basal cortisol infusion.
“Therefore, although the increase in palmitate appearance indi- cates that more free fatty acids reached the systemic circulation during the variable than during the basal cortisol infusion, it does not necessarily reflect the true rate of lipolysis in all tissue compartments.”
Quote in the paperNot a substantial claim - Findingown data
The comparable plasma lactate concentrations and rates of lactate release from the forearm during the variable and basal cortisol infusions argue against substantial differences in de novo synthesis from pyruvate.
“The comparable plasma lactate concen- trations and rates of lactate release from the forearm during the variable and basal cortisol infusions argue against substantial differences in de novo synthesis from pyruvate.”
Quote in the paperSubstantial claim - Findingown data
Postprandial hepatic glucose release was increased by the nocturnal rise in cortisol.
“Both postprandial hepatic glucose release and the rate of incorpora- tion of 14CO2 into glucose (a qualitative indicator of gluconeo- genesis) were increased by the nocturnal rise in cortisol.”
- Also stated in: § Results · plain
“Postprandial hepatic glucose release was higher and postprandial muscle glucose uptake was lower in the presence than in the absence ofa nocturnal rise in corti- sol.”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
Despite comparable glucose concentrations, glucagon concentrations were higher during the variable than the basal plus glucose study.
“Thus despite comparable glucose concentrations, C-peptide concentrations were lower and glucagon concentrations were higher during the variable than the basal plus glucose study (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
Despite comparable glucose concentrations, C-peptide concentrations were lower during the variable than the basal plus glucose study.
“Thus despite comparable glucose concentrations, C-peptide concentrations were lower and glucagon concentrations were higher during the variable than the basal plus glucose study (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
D-xylose concentrations were virtually identical during the variable and basal cortisol infusions.
“The lack ofdifference did not appear to be due to offset- ting changes in gut absorption since D-xylose concentrations were virtually identical during the variable and basal cortisol infusions.”
Quote in the paperSubstantial claim - Findingown data
The rate of incorporation of 14CO2 into glucose, a qualitative indicator of gluconeogenesis, was increased by the nocturnal rise in cortisol.
“Both postprandial hepatic glucose release and the rate of incorpora- tion of 14CO2 into glucose (a qualitative indicator of gluconeo- genesis) were increased by the nocturnal rise in cortisol.”
Quote in the paperSubstantial claim - Findingown data
The nocturnal rise in cortisol is associated with a decrease in insulin secretion.
“Ifanything, our observa- tion that the nocturnal rise in cortisol is associated with a de- crease in both insulin secretion and action would suggest that the impairment in evening glucose tolerance would have been even greater ifcortisol concentrations had not fallen during the day.”
Quote in the paperSubstantial claim - Findingown data
The nocturnal rise in cortisol can lead to a degree of 'physiologic' insulin resistance.
“While our experi- ment was not designed to assess the effects ofthe nocturnal rise in cortisol on early morning insulin requirements, our data do show that this rise can lead to a degree of”
Quote in the paperSubstantial claim - Findingown data
An increase in cortisol concentration of a magnitude similar to that observed in healthy nonstressed humans during sleep can influence glucose metabolism.
“In conclusion, the present studies demonstrate that an in- crease in cortisol concentration of a magnitude similar to that observed in healthy nonstressed humans during sleep can influ- ence glucose metabolism.”
Quote in the paperSubstantial claim - Findingown data
Growth hormone concentrations did not differ in the presence or absence of the nocturnal rise in cortisol.
“In our study, growth hormone concentrations did not differ in the presence or absence of the nocturnal rise in cortisol.”
Quote in the paperSubstantial claim - Findingown data
The nocturnal rise in cortisol is associated with a decrease in insulin action.
“Ifanything, our observa- tion that the nocturnal rise in cortisol is associated with a de- crease in both insulin secretion and action would suggest that the impairment in evening glucose tolerance would have been even greater ifcortisol concentrations had not fallen during the day.”
Quote in the paperSubstantial claim - Findingown data
Postprandial muscle glucose uptake was lower in the presence than in the absence of a nocturnal rise in cortisol.
“Postprandial hepatic glucose release was higher and postprandial muscle glucose uptake was lower in the presence than in the absence ofa nocturnal rise in corti- sol.”
Quote in the paperSubstantial claim - Interpretationown data
The increase in palmitate concentration and appearance indicates enhanced adipose tissue lipolysis.
“The concomitant increase in plasma alanine and fl-OHB concentrations suggests enhanced proteolysis and ketogenesis whereas the increase in palmitate concentration and appearance indicates enhanced adipose tis- sue lipolysis.”
Quote in the paperNot a substantial claim - Interpretationown data
The greater incorporation of 14CO2 into glucose suggests that accelerated gluconeogenesis contributed to the increase in glucose output.
“The greater incorporation of 14CO2 into glucose suggests that accelerated gluconeogenesis contributed to the increase in glucose output.”
Quote in the paperSubstantial claim - Premisecitation
Glucocorticoid excess is associated with insulin resistance.
“Glucocorticoid deficiency is asso- ciated with increased insulin sensitivity and glucocorticoid ex- cess is associated with insulin resistance (3)(4)(5)(6).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [3]
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- Interpretationown data
Cortisol appears to impair insulin action as evidenced by lower rates of glucose uptake in the presence of identical glucose and insulin concentrations.
“Cortisol appears to do so by impairing insulin action as evi- denced by lower rates of glucose uptake in the presence of iden- tical glucose and insulin concentrations (Fig. 4).”
Quote in the paperSubstantial claim - Interpretationown data
It is unlikely that hyperinsulinemia had important metabolic effects in the present experiments.
“Since overnight insulin concentrations did not differ during the vari- able and basal cortisol infusions, it is unlikely that hyperinsu- linemia had important metabolic effects in the present experi- ments.”
Quote in the paperSubstantial claim - Premisecitation
Elevation of cortisol in the range of 30-40 μg/dl for 12-24 h impairs insulin-induced suppression of hepatic glucose release.
“Elevation of cortisol in the range of 30-40 kig/dl for 12-24 h enhances lipol- ysis (7) and proteolysis (8) as well as impairs both insulin-in- duced suppression ofhepatic glucose release and stimulation of glucose uptake (5,6).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5]
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- cites [6]
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- Premisecitation
The most marked increase in cortisol in healthy subjects generally occurs from the middle of the night to breakfast time.
“The most marked increase in cortisol in healthy subjects generally occurs from the middle ofthe night to breakfast time with similar but less consistent increases also being observed after food ingestion ( 11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11]
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- Interpretationown data
The nocturnal rise in cortisol reduces postprandial glucose uptake whether measured isotopically or as the arteriovenous difference across the forearm.
“The present studies indicate that the nocturnal rise in corti- sol reduces postprandial glucose uptake whether measured iso- topically or as the arteriovenous difference across the forearm.”
Quote in the paperSubstantial claim - Premisecitation
Elevation of cortisol in the range of 30-40 μg/dl for 12-24 h enhances lipolysis.
“Elevation of cortisol in the range of 30-40 kig/dl for 12-24 h enhances lipol- ysis (7) and proteolysis (8) as well as impairs both insulin-in- duced suppression ofhepatic glucose release and stimulation of glucose uptake (5,6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7]
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- Premisecitation
Elevation of cortisol in the range of 30-40 μg/dl for 12-24 h enhances proteolysis.
“Elevation of cortisol in the range of 30-40 kig/dl for 12-24 h enhances lipol- ysis (7) and proteolysis (8) as well as impairs both insulin-in- duced suppression ofhepatic glucose release and stimulation of glucose uptake (5,6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8]
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- Interpretationown data
The nocturnal rise in cortisol is important in the regulation of postprandial carbohydrate metabolism in normal humans.
“Thus our data suggest that the nocturnal rise in cortisol is important in the regulation ofpostprandial carbohydrate metabolism in normal humans.”
Quote in the paperSubstantial claim - Interpretationown data
Physiologic increases in cortisol can antagonize insulin action.
“The observation that physiologic increases in cortisol can antagonize insulin action is con- sistent with earlier studies which have examined the effects of higher or more prolonged elevations of cortisol (4-6).”
Quote in the paperSubstantial claim - Study design and conductown data
Postprandial glucose concentrations were matched in the basal cortisol plus glucose study to those observed in the same individual during the variable cortisol infusion.
“Postprandial glucose concentrations were matched in the basal cortisol plus glucose study to those observed in the same individual during the variable cortisol infusion.”
Quote in the paperSubstantial claim - Premisecitation
Glucocorticoid deficiency is associated with increased insulin sensitivity.
“Glucocorticoid deficiency is asso- ciated with increased insulin sensitivity and glucocorticoid ex- cess is associated with insulin resistance (3)(4)(5)(6).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [3]
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- Premisecitation
Elevation of cortisol in the range of 30-40 μg/dl for 12-24 h impairs insulin-induced stimulation of glucose uptake.
“Elevation of cortisol in the range of 30-40 kig/dl for 12-24 h enhances lipol- ysis (7) and proteolysis (8) as well as impairs both insulin-in- duced suppression ofhepatic glucose release and stimulation of glucose uptake (5,6).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5]
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- cites [6]
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- Interpretationown data
The decrease in extraction of glucose across the forearm implies that skeletal muscle participates in this response.
“The decrease in extraction ofglucose across the forearm implies that skeletal muscle participates in this response.”
Quote in the paperSubstantial claim - Study design and conductnone given
Dilution of labeled precursors within the oxaloacetate pool will result in an underestimate of gluconeogenesis.
“Dilution of labeled precursors within the oxaloacetate pool will result in an underestimate of gluconeogenesis.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The increase in palmitate appearance does not necessarily reflect the true rate of lipolysis in all tissue compartments.
“Therefore, although the increase in palmitate appearance indi- cates that more free fatty acids reached the systemic circulation during the variable than during the basal cortisol infusion, it does not necessarily reflect the true rate of lipolysis in all tissue compartments.”
Quote in the paperNot a substantial claim - Premisecitation
People treated with high doses of prednisone for several days have elevated fasting glucagon concentrations.
“people treated with high doses of prednisone for sev- eral days have elevated fasting glucagon concentrations”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50]
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- Interpretationown data
Physiologic changes in cortisol have minimal impact on absorption of a mixed meal.
“The lack ofa detectable effect on the systemic appear- ance of ingested glucose suggests that physiologic changes in cortisol have minimal impact on either absorption of a mixed meal or on splanchnic uptake of glucose.”
Quote in the paperSubstantial claim - Study design and conductcitation
Measurement of the rate of incorporation of 14CO2 into glucose only provides an index of gluconeogenesis since the intramitochondrial specific activity is not known.
“As previously discussed in detail ( 14, 54, 55 ), measurement of the rate of incorporation of '4CO2 into glucose only provides an index of gluconeogenesis since the intramitochondrial specific activity is not known.”
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- Premisecitation
In vitro studies have demonstrated that very high cortisol concentrations can inhibit insulin synthesis and secretion.
“In vitro studies have demonstrated that very high cortisol concen- trations can inhibit insulin synthesis and secretion (47-49).”
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- Interpretationreasoning
The inhibitory effect of cortisol on insulin secretion would explain the absence of peripheral hyperinsulinemia despite a state of insulin resistance.
“In addi- tion, the inhibitory effect ofcortisol on insulin secretion would explain the absence of peripheral hyperinsulinemia despite a state ofinsulin resistance.”
Quote in the paperSubstantial claim - Premisecitation
Cortisol-induced stimulation of lipolysis could increase gluconeogenesis by increasing the intrahepatic redox potential.
“Second, cortisol-induced stimulation of lipolysis could increase gluco- neogenesis by increasing the intrahepatic redox potential as well as by increasing the supply of glycerol (7,42).”
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- Interpretationown data
The present data indicate that physiologic concentrations of glucocorticoids inhibit insulin secretion.
“While these studies indicate that very high concentrations of gluco- corticoids can inhibit insulin and stimulate glucagon secretion, somewhat surprisingly the present data indicate that physio- logic concentrations do so as well.”
Quote in the paperSubstantial claim - Interpretationreasoning
Assuming that C-peptide and glucagon clearance remained constant on the two study days, glucagon secretion was higher during the variable cortisol infusion.
“Assuming that C- peptide and glucagon clearance remained constant on the two study days these data taken together indicate that insulin secre- tion was lower and glucagon secretion higher during the vari- able cortisol infusion.”
Quote in the paperSubstantial claim- The authors state this as an assumption: C-peptide and glucagon clearance remained constant on the two study days.
- Interpretationcitation
Enhanced hepatic glucose release during the nocturnal rise in cortisol is consistent with what would be predicted from previous experiments using supraphysiologic concentrations of cortisol.
“En- hanced hepatic glucose release during the nocturnal rise in cor- tisol is consistent with what would be predicted from previous experiments using supraphysiologic concentrations of cortisol (5-8).”
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- cites [7]
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- cites [8]
Not checked in the free run.
- Premisecitation
Gluconeogenesis could also be enhanced by increased plasma alanine availability.
“Gluconeo- genesis could also be enhanced by increased plasma alanine availability (8).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8]
Not checked in the free run.
- Interpretationown data
A relatively brief elevation of cortisol (i.e., -6 h) can result in a substantial change in insulin action in both muscle and adipose tissue.
“Regardless of the cellular mecha- nism, our data indicate that a relatively briefelevation ofcorti- sol (i.e., -6 h) can result in a substantial change in insulin action in both muscle and adipose tissue.”
Quote in the paperSubstantial claim - Interpretationcitation
Reesterification is likely to be minimal in humans.
“However, since the ratio of FFA/glycerol appearance has been shown to be close to 3:1 under a variety of circumstances (57-59), this suggests that reesterification is likely to be minimal in humans.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Assuming that C-peptide and glucagon clearance remained constant on the two study days, insulin secretion was lower during the variable cortisol infusion.
“Assuming that C- peptide and glucagon clearance remained constant on the two study days these data taken together indicate that insulin secre- tion was lower and glucagon secretion higher during the vari- able cortisol infusion.”
Quote in the paperSubstantial claim- The authors state this as an assumption: C-peptide and glucagon clearance remained constant on the two study days.
- Interpretationown data
Physiologic changes in cortisol have minimal impact on splanchnic uptake of glucose.
“The lack ofa detectable effect on the systemic appear- ance of ingested glucose suggests that physiologic changes in cortisol have minimal impact on either absorption of a mixed meal or on splanchnic uptake of glucose.”
Quote in the paperSubstantial claim - Interpretationreasoning
If such effects occurred in the present experiments, the relatively short lag time from the initial increase in cortisol to detectable changes in hepatic glucose release would seem to favor a change in enzyme activity rather than a change in enzyme mass.
“If such effects occurred in the present experiments, the relatively short lag time from the initial increase in cortisol to detectable changes in hepatic glucose release would seem to favor a change in enzyme activity rather than a change in enzyme mass.”
Quote in the paperSubstantial claim - Premisecitation
The ratio of FFA/glycerol appearance has been shown to be close to 3:1 under a variety of circumstances.
“However, since the ratio of FFA/glycerol appearance has been shown to be close to 3:1 under a variety of circumstances (57-59), this suggests that reesterification is likely to be minimal in humans.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [57]
Not checked in the free run.
- cites [58]
Not checked in the free run.
- cites [59]
Not checked in the free run.
- Interpretationown data
This argues against a major role for changes in circulating fatty acid concentration mediating the effect of cortisol on glucose uptake.
“This argues against a major role for changes in circulating fatty acid concentration mediating the effect of cortisol on glucose uptake.”
Quote in the paperSubstantial claim - Interpretationreasoning
The resultant increase in the portal venous glucagon/insulin ratio potentially could account for much if not all of the associated increase in hepatic glucose release, gluconeogenesis, and β-OHB concentration.
“Therefore the resultant increase in the portal venous glucagon/insulin ratio potentially could account for much if not all ofthe associated increase in hepatic glucose release, gluconeogenesis, and fl-OHB concentration.”
Quote in the paperSubstantial claim - Interpretationown data
Physiologic changes in cortisol can alter the hepatic response to food ingestion.
“The present data also suggest that physiologic changes in cortisol can alter the hepatic response to food ingestion.”
Quote in the paperSubstantial claim - Interpretationown data
The nocturnal rise in cortisol could alter pancreatic alpha and beta cell function.
“Third, and perhaps most importantly, the nocturnal rise in cortisol could alter pancreatic alpha and beta cell function.”
Quote in the paperSubstantial claim - Interpretationown data
The present data indicate that physiologic concentrations of glucocorticoids stimulate glucagon secretion.
“While these studies indicate that very high concentrations of gluco- corticoids can inhibit insulin and stimulate glucagon secretion, somewhat surprisingly the present data indicate that physio- logic concentrations do so as well.”
Quote in the paperSubstantial claim - Study design and conductnone given
Measurement of palmitate appearance will not detect free fatty acids that are oxidized prior to mixing with the systemic circulation (e.g., within muscle or the splanchnic bed).
“Finally, measurement of palmitate appearance will not detect free fatty acids that are oxidized prior to mixing with the sys- temic circulation (e.g., within muscle or the splanchnic bed).”
Quote in the paperSubstantial claim - Premisecitation
Cortisol-induced stimulation of lipolysis could increase gluconeogenesis by increasing the supply of glycerol.
“Second, cortisol-induced stimulation of lipolysis could increase gluco- neogenesis by increasing the intrahepatic redox potential as well as by increasing the supply of glycerol (7,42).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [7]
Not checked in the free run.
- cites [42]
Not checked in the free run.
- Interpretationown data
Our data argue against a causal role for cortisol in the decrease in evening glucose tolerance.
“Although our data provide no insight into circadian variation in glucose toler- ance, they do argue against a causal role for cortisol in the decrease in evening glucose tolerance.”
Quote in the paperSubstantial claim - Interpretationown data
The hepatic actions of cortisol appeared to be mediated (at least in part) by alterations in the secretion of insulin and glucagon.
“The hepatic actions ofcortisol appeared to be mediated (at least in part) by alterations in the secretion of insulin and glucagon while the extrahepatic actions appeared to be due to the ability ofcortisol to create a state of”
Quote in the paperSubstantial claim - Interpretationreasoning
The extrahepatic actions of cortisol appeared to be due to the ability of cortisol to create a state of 'physiologic' insulin resistance.
“The hepatic actions ofcortisol appeared to be mediated (at least in part) by alterations in the secretion of insulin and glucagon while the extrahepatic actions appeared to be due to the ability ofcortisol to create a state of”
Quote in the paperSubstantial claim - Interpretationnone given
Under normal circumstances these effects are offset by a compensatory increase in glucose concentration.
“Under normal circumstances these effects are offset by a compensatory increase in glucose concentration.”
Quote in the paperSubstantial claim - Interpretationreasoning
The impairment in evening glucose tolerance would have been even greater if cortisol concentrations had not fallen during the day.
“Ifanything, our observa- tion that the nocturnal rise in cortisol is associated with a de- crease in both insulin secretion and action would suggest that the impairment in evening glucose tolerance would have been even greater ifcortisol concentrations had not fallen during the day.”
Quote in the paperSubstantial claim
- The quote only partly states this claim. 3
- Classified as probably not a substantial claim. 18
- May combine two claims. 11
The quote only partly states this claim.
Findingown dataThere was no detectable difference in the arteriovenous difference of glucose across the forearm during the variable and basal cortisol infusions when glucose concentrations were allowed to vary.
“There also was no detectable difference in either glucose disappearance, or the arteriovenous difference of glucose across the forearm between studies (Fig. 4).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataThere was no detectable difference in glucose disappearance during the variable and basal cortisol infusions when glucose concentrations were allowed to vary.
“There also was no detectable difference in either glucose disappearance, or the arteriovenous difference of glucose across the forearm between studies (Fig. 4).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataOvernight and postprandial growth hormone concentrations did not differ between studies.
“Overnight and postprandial growth hormone con- centrations did not differ between studies (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataPlasma D-xylose concentration did not differ amongst studies.
“Plasma D-xylose concentration, a marker of carbohydrate absorption, did not differ amongst studies (data not shown).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataβ-OHB concentrations decreased after meal ingestion.
“Lactate and alanine concentration increased and 13-OHB concentrations decreased after meal ingestion.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataInitial splanchnic extraction tended to be lower during the variable than during the basal cortisol plus glucose infusion, but this difference did not reach statistical significance.
“While the systemic rate of appearance of ingested glucose tended to be higher (and therefore initial splanchnic extraction lower) during the variable than during the basal cortisol plus glucose infusion, this difference did not reach statistical signifi- cance.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe systemic rate of appearance of ingested glucose tended to be higher during the variable than during the basal cortisol plus glucose infusion, but this difference did not reach statistical significance.
“While the systemic rate of appearance of ingested glucose tended to be higher (and therefore initial splanchnic extraction lower) during the variable than during the basal cortisol plus glucose infusion, this difference did not reach statistical signifi- cance.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOur data showing increased palmitate flux and increased alanine concentrations are consistent with these possibilities.
“Our data showing increased palmitate flux and increased alanine concentrations are consistent with these pos- sibilities.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe data indicate an inhibitory effect of the variable cortisol infusion on insulin secretion and a stimulatory effect on glucagon secretion.
“Taken together these data indicate an inhibitory effect of the variable cortisol infusion on insulin secretion and a stimula- tory effect on glucagon secretion.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe variable cortisol infusion increased both fasting and postprandial glucose concentrations.
“The present studies extend these observations by demonstrating that cortisol, in concentrations that mimic those normally present in healthy humans during sleep, increased both fasting and postprandial glucose concentrations.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationGlucocorticoids are potent regulators of carbohydrate, fat, and protein metabolism.
“Glucocorticoids are potent regulators of carbohydrate, fat, and protein metabolism ( 1, 2).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1]
Not checked in the free run.
- cites [2]
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May combine two claims.
Interpretationown dataThe increase in plasma alanine and β-OHB concentrations suggests enhanced proteolysis and ketogenesis.
“The concomitant increase in plasma alanine and fl-OHB concentrations suggests enhanced proteolysis and ketogenesis whereas the increase in palmitate concentration and appearance indicates enhanced adipose tis- sue lipolysis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSimilar but less consistent increases in cortisol are also observed after food ingestion in healthy subjects.
“The most marked increase in cortisol in healthy subjects generally occurs from the middle ofthe night to breakfast time with similar but less consistent increases also being observed after food ingestion ( 11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11]
Not checked in the free run.
May combine two claims.
Interpretationown dataCortisol increased glucose concentration by stimulating hepatic glucose output and by inhibiting muscle glucose uptake.
“Cortisol increased glucose concentra- tion by stimulating hepatic glucose output and by inhibiting muscle glucose uptake.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe portal to peripheral glucose gradient appears to have a greater effect on hepatic glucose uptake than does the portal insulin concentration.
“This is not particularly surprising, since the portal to peripheral glucose gradient appears to have a greater effect on hepatic glucose uptake than does the portal insulin concentration (52,53).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [52]
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- cites [53]
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PremisecitationPeople treated with high doses of prednisone for several days have enhanced responses to intravenous arginine.
“enhanced responses to intravenous arginine (50).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50]
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationGlucose tolerance is worse when a meal is eaten later in the day than when the same meal is eaten in the morning.
“The observation that glucose tolerance is worse when a meal is eaten later in the day than when the same meal is eaten in the morning is well established (60, 61).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [60]
Not checked in the free run.
- cites [61]
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIf degradation to mono- or diglycerides is followed by reesterification this will result in release of free fatty acids into the circulation in the absence of net lipolysis.
“If degradation to mono-or diglycerides is followed by reesterification this will result in release of free fatty acids into the circulation in the absence of net lipolysis (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe liver contributes to postprandial carbohydrate tolerance by extracting a portion of the ingested glucose as it travels from the gut to the systemic circulation.
“In addition to reducing its own endogenous production of glucose, the liver also contributes to postprandial carbohydrate tolerance by extracting a portion of the ingested glucose as it travels from the gut to the systemic circulation ( 5 1 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationDuring long-term glucocorticoid excess this inhibitory effect is offset by chronic hyperglycemia.
“Presumably during long-term gluco-- corticoid excess this inhibitory effect is offset by chronic hyper- glycemia (41 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningPalmitate appearance may only provide a qualitative estimate of lipolysis.
“In theory, pal- mitate appearance may only provide a qualitative estimate of lipolysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningCortisol could have increased hepatic glucose production by at least three mechanisms.
“Cortisol could have increased hepatic glucose produc- tion by at least three mechanisms.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningSince it is likely that lipolysis and proteolysis if anything were greater during the variable than basal cortisol infusion, this would result in a conservative error since we observed higher rates of gluconeogenesis with the variable cortisol study.
“However, since it is likely that lipolysis and proteolysis ifanything were greater during the variable than basal cortisol infusion, this would result in a con- servative error since we observed higher rates ofgluconeogene- sis with the variable cortisol study.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA change in alanine concentration could be due to a change in de novo alanine synthesis from pyruvate.
“With regard to our measures of proteolysis and lipolysis, a change in alanine concentration could be due to a change in de novo alanine synthesis from pyruvate, a decrease in alanine utilization and/or release dur- ing proteolysis (56).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA change in alanine concentration could be due to a decrease in alanine utilization and/or release during proteolysis.
“With regard to our measures of proteolysis and lipolysis, a change in alanine concentration could be due to a change in de novo alanine synthesis from pyruvate, a decrease in alanine utilization and/or release dur- ing proteolysis (56).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56]
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationCortisol could increase the concentration as well as the activity of enzymes in the gluconeogenic and glycogenolytic pathways.
“First, cortisol could increase the concentration as well as the activity of enzymes in the glu- coneogenic and glycogenolytic pathways ( 1, 2).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1]
Not checked in the free run.
- cites [2]
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlucocorticoid excess can increase glycogen synthesis in the fasting state.
“Glucocorti- coid excess can increase glycogen synthesis in the fasting state ( 1,2).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1]
Not checked in the free run.
- cites [2]
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Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningA hormone whose primary role is to antagonize insulin action would not impact on this process.
“One would therefore anticipate that a hormone whose primary role is to antagonize insulin action would not impact on this process.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe cortisol-induced increase in palmitate, β-OH butyrate and alanine concentrations are consistent with additional effects on lipolysis, ketogenesis, and perhaps proteolysis.
“The corti- sol-induced increase in palmitate, d-OH butyrate and alanine concentrations are consistent with additional effects on lipolysis, ketogenesis, and perhaps proteolysis.”
Quote in the paperNot a substantial claim
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”
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 effects of glucocorticoids on fuel metabolism are complex, context-dependent, not linear in dose response, and influenced by the diurnal rhythm.
“Glucocorticoids are critical regulators of energy balance; however, their complex effects on fuel metabolism are highly context‐dependent, are not linear in their dose response and are influenced by factors such as the diurnal rhythm.1”
From Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct (2017) · cites this paper as [1]
The Introduction (page unavailable) describes glucocorticoids as regulators of carbohydrate, fat, and protein metabolism, and the Results report effects of a simulated nocturnal cortisol rise on glucose and other fuel measures. This supports the claim that metabolic effects depend on context and diurnal rhythm. The paper does not establish a nonlinear dose response. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTwo studies have examined the effect of physiological cortisol concentrations on in vivo lipolysis and had conflicting results in the fasted state.
“Two studies have examined the effect of physiological cortisol concentrations on in vivo lipolysis and had conflicting results in the fasted state;1, 10”
From Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct (2017) · cites this paper as [1]
Neither of the two studies of physiological cortisol concentrations on in vivo lipolysis used a pancreatic clamp to control counter-regulatory hormones.
“however, neither study used a pancreatic clamp to control counter‐regulatory hormones.”
From Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct (2017) · cites this paper as [1]
Cortisol impairs insulin sensitivity with a latency of four to six hours.
“Cortisol impairs insulin sensitivity with a latency of four to six hours.56,58,59”
From Interacting epidemics? Sleep curtailment, insulin resistance, and obesity (2012) · cites this paper as [59]
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“Although in vitro studies indicate that cortisol can decrease glucose uptake in both muscle and adipocytes, it does not seem to do so by altering the number of glucose transporters or insulin receptors (4, 38-41).”
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Adverse metabolic and cardiovascular consequences of circadian misalignment
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“4 Lower Right panel) could contribute to insulin resistance and hyperglycemia (13, 14).”
BackgroundThe dark side of light at night: physiological, epidemiological, and ecological consequences
Navara, K. J., & Nelson, R. J. (2007) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2007.00473.x · Cited by 795 · see citing works
“In many species, including some birds, rodents, fish, and humans, for example, circulating concentrations of sex steroids [9–11] and glucocorticoids [12] vary with the light/dark cycle throughout the day, causing corresponding changes in reproductive activities [13] and metabolic functions [14].”
BackgroundRegulation of glucose homeostasis by glucocorticoids
Kuo, T., McQueen, A., Chen, T.-C., & Wang, J.-C. (2015) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4939-2895-8_5 · Cited by 723 · see citing works
Glucocorticoids and insulin resistance: old hormones, new targets
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Roles of Circadian Rhythmicity and Sleep in Human Glucose Regulation
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“Indeed, the immediate effect of an increase in plasma cortisol level, even of very small amplitude, was an abrupt inhibition of insulin secretion without change in glucose concentration, consistent with previous in vitro (59–63) and in vivo (57, 64, 65) studies that have shown that glucocorticoids may have a direct im…”
BackgroundResultMorris, C. J., Yang, J. N., Garcia, J. I., Myers, S., Bozzi, I., Wang, W., Buxton, O. M., Shea, S. A., & Scheer, F. A. J. L. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1418955112 · Cited by 523 · see citing works
“Cortisol can decrease glucose uptake and decrease insulin sensitivity (41, 42).”
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Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids
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“31 Experimental elevation of cortisol levels increases postprandial blood glucose and lipid levels in healthy individuals, 31 similar to the situation in type 2 diabetes mellitus.”
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“However, hypercortisolaemia did increase the Ra of palmitate after a mixed meal, despite a higher post-prandial insulin response suggesting resistance to the inhibition of lipolysis by insulin (Dinneen et al. 1993).”
BackgroundMethodInfluentialDissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease
Nielsen, T. S., Jessen, N., Jørgensen, J. O. L., Møller, N., & Lund, S. A. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0277 · Cited by 380 · see citing works
“In agreement with this, elevated cortisol levels in humans have been found to reduce the postprandial suppression of FFA release, suggesting a decreased antilipolytic effect of insulin (Dinneen et al .”
Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids.
Delaunay, F., Khan, A. R., Cintra, A., Davani, B., Ling, Z. C., Andersson, A., Östenson, C., Gustafsson, J.-Α., Efendić, S., & Okret, S. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119743 · Cited by 331 · see citing works
“However, this increase in plasma insulin is probably attenuated by a direct inhibitory effect of glucocorticoids on insulin release from b cells as suggested by in vitro (6–10) and in vivo (11, 12) studies.”
BackgroundThe Hypothalamic‐Pituitary‐Adrenal Axis Activity in Obesity and the Metabolic Syndrome
Pasquali, R., Vicennati, V., Cacciari, M., & Pagotto, U. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1367.009 · Cited by 335 · see citing works
The Effect of Training at a Specific Time of Day
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“2A) did not exceed the level of concentrations seen during the “quiescent period” of cortisol secretion and, by itself, was unlikely to have a significant impact on glucose tolerance and SI (33).”
BackgroundMetabolic consequences of stress during childhood and adolescence
Pervanidou, P., & Chrousos, G. P. (2012) · Metabolism · doi:10.1016/j.metabol.2011.10.005 · Cited by 316 · see citing works
“[31] Dinneen S, Alzaid A, Miles J, Rizza R.”
BackgroundAlterations in Glucose Disposal in Sleep-disordered Breathing
Punjabi, N. M., & Beamer, B. A. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200809-1392oc · Cited by 304 · see citing works
“Glucocorticoids inhibit insulin secretion and induce insulin resistance by increasing free fatty acid flux and modifying multiple aspects of the insulin-mediated glucose transport system (38, 39).”
BackgroundOccult Cushing’s syndrome in type-2 diabetes
Catargi, B., Rigalleau, V., Poussin, A., Ronci-Chaix, N., Bex, V., Vergnot, V., Gin, H., Roger, P., & Tabarin, A. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030254 · Cited by 287 · see citing works
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Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans
Djurhuus, C. B., Gravholt, C. H., Nielsen, S., Mengel, A., Christiansen, J. S., Schmitz, O. E., & Møller, N. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00544.2001 · Cited by 219 · see citing works
“Whereas it is well established that glucocorticoids induce insulin resistance (2, 6) and promote proteolysis (13), studies in the field of intermediary lipid metabolism have yielded more conflicting results.”
ResultPlat, L., Leproult, R., L’Hermite-Baleriaux, M., Fery, F., Mockel, J., Polonsky, K. S., & Van Cauter, E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.5978 · Cited by 225 · see citing works
“The possibility that the variations in cortisol concentrations that normally occur over a 24-h period could contribute to the diurnal variation in glucose tolerance had been previously discarded because glucose tolerance is best in the morning (when cortisol levels are high) and worst in the early part of the night (w…”
BackgroundHepatic glucose metabolism in humans—its role in health and disease
Roden, M., & Bernroider, E. (2003) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/s1521-690x(03)00031-9 · Cited by 201 · see citing works
Knutsson, U., Dahlgren, J., Marcus, C., Rosberg, S., Brönnegård, M., Stierna, P., & Albertsson-Wikland, K. G. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.2.3769 · Cited by 209 · see citing works
Interacting epidemics? Sleep curtailment, insulin resistance, and obesity
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Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM
Dinneen, S., Alzaid, A., Turk, D., & Rizza, R. (1995) · Diabetologia · doi:10.1007/bf00400639 · Cited by 190 · see citing works
“In non-diabetic individuals glucagon concentrations fall as glucose concentrations rise, and rise as glucose concentrations return toward preprandial levels [12-14].”
BackgroundMethodInfluentialSelf-citationYu, C.-Y., Mayba, O., Lee, J. V., Tran, J., Harris, C. L., Speed, T. P., & Wang, J.-C. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015188 · Cited by 179 · see citing works
“For the former, glucocorticoids inhibit insulinstimulated glucose uptake [11,12,13].”
BackgroundChristiansen, J. J., Djurhuus, C. B., Gravholt, C. H., Iversen, P., Christiansen, J. S., Schmitz, O., Weeke, J., Jørgensen, J. O. L., & Møller, N. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0445 · Cited by 176 · see citing works
“These findings are in line with previous studies reporting insulin resistance during short-term cortisol excess (2, 3, 27) and that cortisol promotes lipolysis (28), rendering it possible that increased levels of FFAs in the circulation may contribute to the observed insulin resistance.”
BackgroundResultINTERACTIONS OF CORTISOL, TESTOSTERONE, AND RESISTANCE TRAINING: INFLUENCE OF CIRCADIAN RHYTHMS
Hayes, L., Bickerstaff, G., & Baker, J. (2010) · Chronobiology International · doi:10.3109/07420521003778773 · Cited by 192 · see citing works
“The morning rise in C accelerates metabolism (Florini, 1987) and stimulates gluconeogenesis and proteolytic activity, resulting in increased skeletal protein turnover (Dinneen et al., 1993).”
BackgroundYu, H., Xia, F., Lam, K. S., Wang, Y., Bao, Y., Zhang, J., Gu, Y., Zhou, P., Lu, J., Jia, W., et al. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2010.155184 · Cited by 170 · see citing works
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“High levels of circulating cortisol stimulate gluconeogenesis and glycogenolysis resulting in increased blood glucose concentrations [29].”
BackgroundRoden, M., Perseghin, G., Petersen, K. F., Hwang, J., Cline, G. W., Gerow, K., Rothman, D. L., & Shulman, G. I. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118460 · Cited by 157 · see citing works
“Although peripheral plasma glucagon concentrations in IDDM patients are typically only slightly higher than in healthy subjects (35, 36), the glucagon secretion pattern has been shown to be altered (37), and the insulin/glucagon ratio is substantially lower during mixed meal ingestion (2, 38).”
BackgroundHew, F. L., Koschmann, M., Christopher, M., Rantzau, C., Vaag, A. A., Ward, G. M., Beck‐Nielsen, H., & ALFORD, F. P. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.2.8636267 · Cited by 168 · see citing works
Subchronic sleep restriction causes tissue-specific insulin resistance
Rao, M. N., Neylan, T. C., Grunfeld, C., Mulligan, K., Schambelan, M., & Schwarz, J.-M. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3911 · Cited by 156 · see citing works
Adrenal function and dysfunction in critically ill patients
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Vicennati, V., & Pasquali, R. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.11.6946 · Cited by 146 · see citing works
“In addition to the insulin-resistant state that characterizes Cushing’s syndrome (49), manipulation of cortisol levels within the physiological range alters insulin sensitivity in healthy subjects ( 50 ), and a modest excess of glucocorticoid may contribute to insulin resistance in non-Cushing conditions in humans (5).”
BackgroundStress‐related Development of Obesity and Cortisol in Women
Vicennati, V., Pasqui, F., Cavazza, C., Pagotto, U., & Pasquali, R. (2009) · Obesity · doi:10.1038/oby.2009.76 · Cited by 138 · see citing works
Effects of morning cortisol elevation on insulin secretion and glucose regulation in humans
Plat, L., Byrne, M. M., Sturis, J., Polonsky, K. S., Mockel, J., Fery, F., & Van Cauter, E. (1996) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1996.270.1.e36 · Cited by 132 · see citing works
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Metabolic Adaptations to Dexamethasone‐Induced Insulin Resistance in Healthy Volunteers
Nicod, N., Giusti, V., Besse, C., & Tappy, L. (2003) · Obesity Research · doi:10.1038/oby.2003.90 · Cited by 125 · see citing works
11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes
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“In contrast to the well-known secondary hyperinsulinaemia in response to acute cortisol exposure in healthy subjects [72], glucocorticoids even in physiological concentrations directly inhibit insulin secretion from pancreatic islets in vitro and in vivo [10, 73, 74, 75, 76].”
Stress induced obesity: lessons from rodent models of stress
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“In many tissues, glucocorticoids serve an opposing function to insulin’s attempt at storing energy, in part by suppressing insulin secretion (Dinneen et al., 1993).”
BackgroundEffect of glucocorticoids on adiponectin: a study in healthy subjects and in Cushing's syndrome
Fallo, F., Scarda, A., Sonino, N., Paoletta, A., Boscaro, M., Pagano, C., Federspil, G., & Vettor, R. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500339 · Cited by 119 · see citing works
“It promotes abdominal fat distribution (24), enhances sympathetic nervous system activity (25), and has complex effects on vascular tone promoting endothelial dysfunction (27), hypercoagul-ability (28) and hypertension (29).”
Davani, B., Khan, A., Hult, M., Mårtensson, E., Okret, S., Efendić, S., Jörnvall, H., & Oppermann, U. C. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000600200 · Cited by 112 · see citing works
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Post-prandial hyperglycemia. post-prandial hyperglycemia and diabetes.
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The Unexplored Crossroads of the Female Athlete Triad and Iron Deficiency: A Narrative Review
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“During study B, metyrapone, as described above, plus a constant, low dose infusion of hydrocortisone (0.2 mg/kgzmin), was given to eliminate the endogenous circadian rhythm of cortisol (Fig. 1) ( 19 ).”
BackgroundInfluentialReynolds, R. M., Walker, B. R., Syddall, H. E., Whorwood, C. B., Wood, P. J., & Phillips, D. I. W. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.3.7300 · Cited by 89 · see citing works
“Manipulation of cortisol levels within the physiological range alters insulin sensitivity ( 23 ).”
BackgroundThe Roles of Time of Day and Sleep Quality in Modulating Glucose Regulation: Clinical Implications
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“Other factors which may have also contributed to the decline of glucose levels during late sleep include the hypoglycemic activity of previously secreted insulin during early sleep, the increased insulin-dependent glucose disposal due to transient mild hyperglycemia, and the increase in body movements associated with…”
BackgroundThe influence of sleep and sleep loss upon food intake and metabolism
Crispim, C. A., Zimberg, I. Z., Dattilo, M., Padilha, H. G., Edwards, B., Waterhouse, J. M., Tufik, S., & de Mello, M. T. (2007) · Nutrition Research Reviews · doi:10.1017/s0954422407810651 · Cited by 79 · see citing works
Sleep‐Disordered Breathing and Obesity
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- Authors
- Dinneen, S., Alzaid, A., Miles, J., & Rizza, R.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Dinneen, S
- Venue
- Journal of Clinical Investigation
- Published
- 1993-11-01
- Volume
- 92
- Issue
- 5
- Pages
- 2283-2290
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC288409
- 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
- bronze
- doi.org
- 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 › Surgery › 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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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.
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