An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects.
Open accessAbstract
Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 microCi/min) was performed for 120 min before and during a euglycemic clamp repeated at approximately 100, approximately 1,000, and approximately 10,000 microU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 +/- 7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5 +/- 2.1 vs. 83.7 +/- 1.9 mg/dl) and mean fasting plasma insulin values (17.8 +/- 1.2 vs. 14.3 +/- 0.8 microU/ml) were significantly higher (P less than 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P less than 0.001) after prednisone at all three steady state plasma insulin levels: 2.8 +/- 0.3 vs. 7.4 +/- 1.1 at approximately 100 microU/ml; 6.0 +/- 0.5 vs. 12.2 +/- 1.1 at approximately 1,000 microU/ml; 7.4 +/- 0.6 vs. 14.4 +/- 0.5 at approximately 10,000 microU/ml. Fasting glucose production (in mg/kg per min) was significantly higher after prednisone: 3.7 +/- 0.2 vs. 2.9 +/- 0.2, P less than 0.001. Suppression of glucose production at steady state plasma insulin level of approximately 100 microU/ml was less after prednisone (1.01 +/- 0.35 vs. 0.14 +/- 0.13, NS), and total at approximately 1,000 and approximately 10,000 microU/ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40 +/- 8 yr (10 treated with placebo and 6 with prednisone as above). No significant difference was observed with regard to specific insulin binding (tested with 1 ng/ml hormone only), whereas significant transport differences were noted at the basal level (0.40 +/- 0.10 vs. 0.54 +/- 0.12 pmol/10(5) cells, P less than 0.05), and at increasing concentrations up to the maximum stimulation values (5 ng/ml): 0.59 +/- 0.04 vs. 0.92 +/- 0.12 pmol/10(5) cells, P less than 0.005. These results suggest that (a) administration of an anti-inflammatory dose of prednisone for 7 d induces insulin resistance in man; (b) this is more dependent on depressed peripheral glucose utilization than on increased endogenous production; (c) total insulin binding on isolated adipocytes is not significantly affected; (d) insulin resistance is primarily the outcome of postreceptor defect (impaired glucose transport).
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- Findingown data
In healthy subjects, 7-day prednisone significantly increased mean fasting plasma insulin compared with placebo (17.8±1.2 vs. 14.3±0.8 μU/ml, P<0.01).
“Mean fasting blood glucose (89.5±2.1 vs. 83.7±1.9 mg/dl) and mean fasting plasma insulin values (17.8±1.2 vs. 14.3±0.8AU/ml) were sig- nificantly higher (P < 0.01) after prednisone.”
Quote in the paperSubstantial claim - Findingown data
In healthy subjects, 7-day prednisone (15 plus 15 mg/d) significantly increased mean fasting blood glucose compared with placebo (89.5±2.1 vs. 83.7±1.9 mg/dl, P<0.01).
“Mean fasting blood glucose (89.5±2.1 vs. 83.7±1.9 mg/dl) and mean fasting plasma insulin values (17.8±1.2 vs. 14.3±0.8AU/ml) were sig- nificantly higher (P < 0.01) after prednisone.”
Quote in the paperSubstantial claim - Findingown data
In healthy subjects, 7-day prednisone significantly reduced the insulin sensitivity index (glucose metabolic clearance rate) at steady-state plasma insulin levels of 100, 1000, and 10,000 μU/ml compared with placebo (2.8±0.3 vs. 7.4±1.1; 6.0±0.5 vs. 12.2±1.1; 7.4±0.6 vs. 14.4±0.5 ml/kg/min, P<0.001).
“The in- sulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P < 0.001) after prednisone at all three steady state plasma insulin levels: 2.8±0.3 vs. 7.4±1.1 at '100 MU/ml; 6.0±0.5 vs. 12.2±1.1 at -1,000 psU/ml; 7.4±0.6 vs. 14.4±0.5 at -10,000 ,uU/ml.”
- Also stated in: § 13.4±0.4). · plain
“Glucose metabolic clearance rate (milliliter per ki- logram per minute) was also significantly (P < 0.001) reduced after prednisone at all three steady state plasma insulin levels (Fig. 2): 2.8±0.3 vs. 7.4±1.1 at -100 ,uU/ml; 6.0±0.5 vs. 12.2±1.1 at -1,000 ,uU/ml; 7.4±0.6 vs. 14.4±0.5 at --10,000 ,uU/ml.”
Quote in the paperSubstantial claim - Also stated in: § 13.4±0.4). · plain
- Findingown data
In isolated adipocytes, the percentage of maximal glucose transport response was much the same after placebo and prednisone.
“The percentage of the maximal response was much the same after placebo and prednisone (Fig. 5 B), whereas the percent increase over basal transport was lower after prednisone at insulin concentrations of 0.5 ng/ml (Fig. 5 C).”
Quote in the paperSubstantial claim - Findingown data
In isolated adipocytes, glucose transport was significantly decreased after prednisone at increasing insulin concentrations up to maximum insulin stimulation (5 ng/ml) (0.59±0.04 vs. 0.92±0.12 pmol/10^5 cells, P<0.005).
“The kinetics of glucose transport is significantly different up to the maximum insulin stimulation of transport (5 ng/ml): 0.59±0.04 vs. 0.92±0.12pmol/105 cells, P < 0.005.”
Quote in the paperSubstantial claim
- Findingown data
In healthy subjects, the change in insulin metabolic clearance rate after prednisone was not significant at steady-state plasma insulin levels of 100, 1000, and 10,000 μU/ml (14.3±0.7 vs. 13.9±0.7; 10.1±0.7 vs. 12.1±0.8; 3.6±0.2 vs. 3.7±0.3 ml/kg/min).
“The change in insulin met- abolic clearance rate after prednisone was not signif- icant: 14.3±0.7 vs. 13.9±0.7 ml/kg per min at -100 ,uU/ml; 10.1±0.7 vs. 12.1±0.8at -1,000 AU/ml and 3.6±0.2vs. 3.7±0.3at -10,000 ,uU/ml.”
Quote in the paperSubstantial claim - Findingown data
In healthy subjects, 7-day prednisone significantly increased fasting glucose production compared with placebo (3.7±0.2 vs. 2.9±0.2 mg/kg/min, P<0.01).
“Fasting glucose pro- duction was significantly increased after prednisone: 3.7±0.2vs. 2.9±0.2mg/kg per min (P < 0.01) (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
In isolated adipocytes, the percent increase over basal glucose transport was lower after prednisone at insulin concentration 0.5 ng/ml.
“The percentage of the maximal response was much the same after placebo and prednisone (Fig. 5 B), whereas the percent increase over basal transport was lower after prednisone at insulin concentrations of 0.5 ng/ml (Fig. 5 C).”
Quote in the paperSubstantial claim - Findingown data
In healthy subjects, glucose production was totally suppressed at steady-state plasma insulin levels of 1000 and 10,000 μU/ml after both placebo and prednisone.
“Suppression of glucose production was never com- plete during steady state plasma insulin level of -100 ,uU/ml after prednisone (1.01±0.35 vs. 0.14±0.13mg/ kg per min, NS), whereas total suppression after both placebo and prednisone was observed at steady state plasma insulin levels of --1,000 and --10,000 ,uU/ml.”
Quote in the paperSubstantial claim - Findingown data
In healthy subjects, the increase in insulin basal systemic delivery rate after prednisone was not significant (0.23±0.02 vs. 0.19±0.01 mU/kg/min).
“The increase in insulin basal systemic delivery rate after prednisone was not significant: 0.23±0.02vs. 0.19±0.01mU/kg per min.”
Quote in the paperNot a substantial claim - Findingown data
In isolated adipocytes from normal-weight surgical candidates, specific insulin binding was much the same after prednisone and placebo (4.45 vs. 4.48%).
“Specific insulin binding was determined at only one level of insulin concentration, owing to the difficulty of obtaining enough fat for the study of the glucose transport and the competition curve.It was much the same after prednisone and placebo (4.45 vs. 4.48%) (Fig. 4).”
Quote in the paperSubstantial claim - Findingown data
In isolated adipocytes, glucose transport was significantly decreased after prednisone compared with placebo at baseline (absence of insulin) (0.40±0.10 vs. 0.54±0.12 pmol/10^5 cells, P<0.05).
“There is a sig- nificant decrease after prednisone not only at the base line (absence of insulin) (0.40±0.10 vs. 0.54±0.12pmol/ 105 cells, P < 0.05), but also at increasing insulin con- centrations (Fig. 5 A).”
Quote in the paperSubstantial claim - Findingown data
The sensitivity of 3-OMG transport to insulin in fat cells was similar after placebo and prednisone.
“In addition, insulin sensitivity of 3-OMG transport in fat cells was much the same after both placebo and prednisone (Fig. 5 B).”
Quote in the paperSubstantial claim - Interpretationown data
At the liver, reduced sensitivity to exogenous insulin (a rightward shift of the dose-response curve) occurs without a change in the maximum effect.
“At the hepatic level, therefore, reduced sen- sitivity to exogenous insulin (rightward shift of the dose- response curve) is unaccompanied by a change in the maximum effect.”
Quote in the paperSubstantial claim - Premisecitation
Measuring endogenous glucose production under basal conditions and during a euglycemic-hyperinsulinemic clamp quantifies hepatic insulin resistance.
“Simulta- neous examination of endogenous glucose production under basal conditions and during euglycemic-hyperinsulinemic clamp (13) offers quantification of the he- patic level of insulin resistance as well.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13]
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- May combine two claims. 14
- Classified as probably not a substantial claim. 7
May combine two claims.
Findingown dataIn healthy subjects, suppression of glucose production at steady-state plasma insulin around 100 μU/ml was less after prednisone than placebo, but the difference was not statistically significant (1.01±0.35 vs. 0.14±0.13 mg/kg/min, NS).
“Suppression of glucose production was never com- plete during steady state plasma insulin level of -100 ,uU/ml after prednisone (1.01±0.35 vs. 0.14±0.13mg/ kg per min, NS), whereas total suppression after both placebo and prednisone was observed at steady state plasma insulin levels of --1,000 and --10,000 ,uU/ml.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataInsulin binding is not significantly changed by 7-day treatment with 30 mg/d prednisone, although a change in affinity cannot be excluded.
“Insulin binding, therefore, is not significantly altered by 7-d treatment with 30 mg/d prednisone, though a variation in affinity as suggested by Yasuda and Kitabchi (27) cannot be ruled out.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe first postreceptor step is transmembrane glucose transport, which can now be studied in humans.
“The first postreceptor step, in fact, is that related to the transmembrane transport of glucose.This step can now be investigated in man (11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11]
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Study design and conductown dataInsulin binding to isolated adipocytes was performed in duplicate.
“Insulin binding to iso- lated adipocytes (106 cells) was performed in Krebs-Ringer bicarbonate buffer pH 7.4 (plus 1% bovine serum albumin) at 25°C in a 95:5% 02/CO2 atmosphere per 60 min in du- plicate in the presence of 1 ng/ml monoiodoinsulin.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe euglycemic clamp allows assessment of peripheral insulin action and provisional discrimination between reduced response and reduced sensitivity to insulin.
“In vivo use of the euglycemic clamp enables an as- sessment of insulin action in the periphery and a pro- visional discrimination between reduced response and/ or reduced sensitivity to the hormone (12).”
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PremisecitationPrednisone, like other glucocorticoids, raises blood glucose in humans, and this effect is accompanied by hyperinsulinemia (insulin resistance) that may be due to reduced peripheral insulin sensitivity or increased hepatic glucose production.
“Like other glucocorticoids (1-4), prednisone increases blood glucose in man (5).This effect is accompanied by hyperinsulinemia (insulin resistance) (6) that may be attributable to either reduced peripheral insulin sensitivity or increased hepatic glucose production (6).”
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Interpretationown dataThe fall in glucose metabolic clearance rate after prednisone at the three steady-state insulin levels indicates both a lower maximum insulin effect and a rightward shift of the dose-response curve.
“The significant reduction in glucose metabolic clearance rate after prednisone at steady state plasma insulin, -100, --1,000, and --10,000 WU/ml, points to both a depressed response (reduction of max- imum effect) and reduced sensitivity (rightward shift”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThis result differs quantitatively from that of Rizza et al., indicating that 7-day prednisone, unlike acute cortisol infusion, affects insulin action more in the periphery than in the liver.
“This finding is quantitatively different from that obtained by Rizza et al. (6), indicating that 7-d prednisone administration, unlike acute infusion of cortisol, influences the insulin action in the periphery more than in the liver.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rizza et al. (6)
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Study design and conductown dataPlasma glucose during the in vivo test was checked every 5 minutes with a Beckman II glucose analyzer and showed good reproducibility (less than 5% variation).
“Glucose levels during the in vivo test automatically measured by the Biostator were also checked on plasma every 5 min with a Beckman II glucose analyzer.Good reproducibility was obtained (<5% varia- tion).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationUnder Kahn's model, the insulin resistance defect after prednisone is both receptor and postreceptor, as also suggested by Rizza et al.
“According to Kahn's model (7), therefore, it can be supposed that the defect is both receptor and postreceptor as also suggested by Rizza et al. (6).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kahn's model (7)
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- cites Rizza et al. (6)
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- Rests on an assumption: The glucose transport defect observed in isolated adipocytes reflects a postreceptor defect in peripheral insulin action in vivo.
May combine two claims.
Interpretationown dataThe glucose transport defect in fat cells is clear evidence of a postreceptor defect, consistent with the in vivo data and with Rizza et al.'s deduction.
“This is clear evidence of postreceptor defect, in line with our data in vivo and the deduction of Rizza et al. (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rizza et al. (6)
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- Rests on an assumption: The glucose transport defect observed in isolated adipocytes reflects a postreceptor defect in peripheral insulin action in vivo.
Classified as probably not a substantial claim. May combine two claims.
Study design and conductown dataThe placebo and prednisone tests were given in randomized order with a 1-month interval between them.
“Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe prednisone-treated subjects and controls did not differ markedly in eating habits or physical activity in the months before the study.
“No marked differences were found between the treated subjects and the controls with regard to their eating habits and physical activity in the months before the study.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe fall in glucose production after intravenous insulin was similar in the prednisone and placebo groups, which indicates that the insulin dose used was too high to reveal hepatic insulin resistance.
“The decrease in glucose production following intravenous insulin was quite the same in the two groups (basal minus 100 ,uU/ml glucose produc- tion), indicating that this insulin dose is too high to show the insulin resistance at the hepatic level.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationIt was not known whether glucocorticoid-induced insulin resistance reflects reduced sensitivity, reduced response, or both.
“It is not yet known whether this situation reflects reduced sensitivity (i.e., a receptor defect), a reduced response to insulin (i.e., a postreceptor defect), or both (7,8).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7]
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Interpretationown dataThe in vitro result partly conflicts with the in vivo result: in vitro only the maximum biological effect was reduced, while in vivo the maximum effect reduction was accompanied by a rightward shift of the dose-response curve.
“Lastly, emphasis may be placed on the fact that our in vitro finding partially conflicts with our in vivo re- sults.Thus, in vitro we observed only a reduction of the maximum biological effect, whereas in vivo the reduction of the maximum biologic effect is associated with a rightward shift of the dose-response curve.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDifferent glucocorticoids may have different metabolic effects on hepatic and peripheral sites.
“Different glucocorticoids, too, may exert a different metabolic effect on the hepatic and peripheral sites (4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4]
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PremisecitationGlucocorticoids bind to specific cytoplasmic receptors and affect cell metabolism through a second messenger that also appears to act at the nuclear level.
“Account must also be taken of the fact that glucocorticoids bind to specific cytoplasmatic receptors and influence cell metabolism through a second messenger (9, 10) that also seems to act at the nuclear level.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9]
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- cites [10]
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The paper relies on this without support.
The glucose transport defect observed in isolated adipocytes reflects a postreceptor defect in peripheral insulin action in vivo.
“This is clear evidence of postreceptor defect, in line with our data in vivo and the deduction of Rizza et al. (6).”
“These cells were studied because they are known targets of both insulin (8, 9) and steroids.”
The paper relies on this without support.
30 mg/d prednisone (15 plus 15 mg/d) is an average antiinflammatory dose.
“Joint utilization of this technique in healthy subjects before and after an average antiinflammatory dose (30 mg/d) of pred- nisone should thus permit analysis of the mechanism whereby this corticosteroid induces insulin resistance.”
Claims other papers make about this one
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Skeletal muscle insulin resistance can develop secondary to pharmacological therapy, including glucocorticoids, anti-HIV therapy, and beta blockers.
“Insulin resistance in skeletal muscle also can develop secondary to pharmacological therapy, for example, glucocorticoids [44], anti-HIV therapy [45], and beta blockers [46].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [44]
The hyperglycaemic effect of glucocorticoids is generally attributed to reduced insulin sensitivity in muscle, liver, and adipose tissue.
“This unwanted hyperglycaemic effect is generally attributed to the reduction in sensitivity to insulin action in muscle, liver and adipose tissue.5–7”
From Twenty‐four‐hour profiles of plasma glucose, insulin, C‐peptide and free fatty acid in subjects with varying degrees of glucose tolerance following short‐term, medium‐dose prednisone (20 mg/day) treatment: evidence for differing effects on insulin secretion and action (2012) · cites this paper as [6]
Glucocorticoids in excess induce insulin resistance.
“Glucocorticoids in excess induce insulin resistance.”
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Self-citationGlucocorticoid-Induced Hyperglycemia: A Neglected Problem
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Self-citation
- Authors
- Pagano, G., Cavallo-Perin, P., Cassader, M., Bruno, A., Ozzello, A., Masciola, P., Dall'omo, A. M., & Imbimbo, B.
- Affiliations
- University of Turin (IT)
- Venue
- Journal of Clinical Investigation
- Published
- 1983-11-01
- Volume
- 72
- Issue
- 5
- Pages
- 1814-1820
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC370470
- OpenAlex
- W2119186903
- Semantic Scholar
- 34a1f7682f7875974dcd099ca2bf12eb3caac092
- Cited by
- 259
- References
- 33
- Citations by year
- 2026: 3 · 2024: 9 · 2023: 10 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 11 · 2015: 12 · 2014: 4 · 2013: 9 · 2012: 10
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- prednisone, insulin resistance, euglycemic clamp, glucose metabolic clearance rate, glucose production, insulin sensitivity index, glucocorticoids, hyperinsulinemic-euglycemic clamp, glucose kinetics, healthy volunteers, fasting insulin, fasting blood glucose, insulin kinetics
- MeSH terms
- Adipose Tissue, Adult, Blood Glucose, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Metabolic Clearance Rate, Methylglucosides, Middle Aged, Prednisone, Receptor, Insulin, 3-O-Methylglucose
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 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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