Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor
Open accessAbstract
Aims/hypothesis Treatment with glucocorticoids, especially at high doses, induces insulin resistance. The aims of the present study were to identify the potential defects in insulin signalling that contribute to dexamethasone-induced insulin resistance in skeletal muscles, and to investigate whether the glycogen synthase-3 (GSK-3) inhibitor CHIR-637 could restore insulin-stimulated glucose metabolism.Materials and methods Skeletal muscles were made insulin-resistant by treating male Wistar rats with dexamethasone, a glucocorticoid analogue, for 12 days. Insulin-stimulated glucose uptake, glycogen synthesis and insulin signalling were studied in skeletal muscles in vitro.Results Dexamethasone treatment decreased the ability of insulin to stimulate glucose uptake, glycogen synthesis and glycogen synthase fractional activity. In addition, the dephosphorylation of glycogen synthase by insulin was blocked. These defects were paralleled by reduced insulin-stimulated protein kinase B (PKB) and GSK-3 phosphorylation. While expression of PKB, GSK-3 and glycogen synthase was not reduced by dexamethasone treatment, expression of the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase) was increased. Inhibition of GSK-3 by CHIR-637 increased glycogen synthase fractional activity in soleus muscle from normal and dexamethasone-treated rats, although the effect was more pronounced in control rats. CHIR-637 did not improve insulin-stimulated glucose uptake in muscles from dexamethasone-treated rats.Conclusions/interpretation We demonstrated that chronic dexamethasone treatment impairs insulin-stimulated PKB and GSK-3 phosphorylation, which may contribute to insulin resistance in skeletal muscles. Acute pharmacological inhibition of GSK-3 activated glycogen synthase in muscles from dexamethasone-treated rats, but GSK-3 inhibition did not restore insulin-stimulated glucose uptake.
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Written from the paper’s full text.
TL;DR
Chronic dexamethasone treatment in rats impairs insulin-stimulated glucose uptake and glycogen synthesis in skeletal muscle, with reduced PKB and GSK-3 phosphorylation and complete loss of insulin-stimulated glycogen synthase dephosphorylation/activation. The selective GSK-3 inhibitor CHIR-637 activated glycogen synthase in dexamethasone-treated muscle but did not restore insulin-stimulated glucose uptake.
Key findings
- Dexamethasone reduced insulin-stimulated glucose uptake in soleus by 50% at 3 nmol/l and 38% at 60 nmol/l insulin, and in epitrochlearis by 40% and 25%, respectively.
- Insulin-stimulated glycogen synthesis in soleus was reduced by ∼70%, and insulin failed to increase glycogen synthase fractional activity or dephosphorylate glycogen synthase at Ser645, Ser649, Ser653, Ser657.
- Insulin-stimulated PKB Thr308 phosphorylation was reduced to 62.6±5.4% of control (p<0.0001), p70 S6K Thr389 phosphorylation was reduced by ∼65%, and GSK-3α Ser21/GSK-3β Ser9 phosphorylation was reduced by ∼30%/33% at 3 nmol/l and ∼23%/26% at 60 nmol/l insulin.
- p85α expression was 30% higher in dexamethasone-treated rats (130.0±7.7 vs 100.0±3.9%, p<0.002), while CHIR-637 increased glycogen synthase fractional activity in soleus from normal and dexamethasone-treated rats but did not improve insulin-stimulated glucose uptake or PKB phosphorylation.
Methods
- Male Wistar rats were weight-matched into control and dexamethasone groups (n=28–29) and given daily intraperitoneal dexamethasone (1.0 mg/kg) or 0.9% NaCl for 12 days; 18 h before experiments they received 5 g chow.
- Isolated soleus strips and intact epitrochlearis muscles were incubated in vitro to measure glucose uptake, glycogen synthesis, glycogen synthase activity, and insulin signalling by Western blot; CHIR-637 was used at 500 nmol/l.
- Data are means±SEM; comparisons used ANOVA with least significant difference post hoc tests, with p<0.05 considered statistically significant.
Limitations
- Stated: the study only investigated the effect of a high concentration of dexamethasone on PKB phosphorylation, and further studies are needed to confirm whether similar impairments occur in humans during clinical glucocorticoid treatment.
- Stated: it was difficult to accurately gauge the percentage of GSK-3 inhibited, and the incomplete/slow glycogen synthase dephosphorylation suggested a lack of protein phosphatase-1 activity; short-term CHIR-637 incubation did not increase glucose transport, though prolonged exposure might.
- Evident from the text: findings are from a rat model with in vitro muscle incubations and a supraphysiological dexamethasone dose, with no direct measurement of protein phosphatase-1 activity or human data.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 46 cited sources checked · 0 supported · 0 flagged
- Findingown data
Insulin did not stimulate dephosphorylation of glycogen synthase in soleus from dexamethasone-treated rats.
“but insulin did not stimulate dephosphorylation of glycogen synthase soleus from dexamethasone-treated rats (Fig. 2c).”
Quote in the paperSubstantial claim - Findingown data
Basal glycogen synthesis was not significantly reduced in soleus from dexamethasone-treated rats.
“Insulin-stimulated glycogen synthesis was decreased in soleus from dexamethasone-treated rats, whereas basal glycogen synthesis was not significantly reduced.”
Quote in the paperNot a substantial claim - Findingown data
In muscles from dexamethasone-treated rats, insulin was unable to increase glycogen synthase fractional activity.
“In muscles from dexamethasone-treated rats, insulin was unable to increase glycogen synthase fractional activity (Fig. 2b) and glycogen synthase activity in the independent form (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Expression of the p85α subunit of PI 3-kinase was 30% higher in dexamethasone-treated rats than in control rats.
“Interestingly, expression of the p85α subunit of PI 3-kinase was 30% higher in dexamethasone-treated rats than in control rats (130.0±7.7 and 100.0±3.9% in dexamethasonetreated and control rats, respectively; n=7 in each group, p<0.002).”
Quote in the paperNot a substantial claim - Findingown data
Glycogen synthase total activity was similar in soleus from control and dexamethasone-treated rats.
“Glycogen synthase total activity was similar in soleus from control and dexamethasone-treated rats (data not shown).”
Quote in the paperNot a substantial claim
- Findingown data
In muscles from dexamethasone-treated rats, insulin was unable to increase glycogen synthase activity in the independent form.
“In muscles from dexamethasone-treated rats, insulin was unable to increase glycogen synthase fractional activity (Fig. 2b) and glycogen synthase activity in the independent form (data not shown).”
Quote in the paperSubstantial claim - Findingown data
In soleus, insulin-stimulated glucose uptake was lower in dexamethasone-treated rats than control at 3 nmol/l (50%) and 60 nmol/l insulin (38%).
“In the soleus, insulin-stimulated glucose uptake was lower in dexamethasone-treated rats than in control rats at 3 nmol/l (50%) and 60 nmol/l insulin (38%) (Fig. 1a).”
Quote in the paperSubstantial claim - Findingown data
Insulin decreased glycogen synthase phosphorylation at Ser645, Ser649, Ser653, Ser657 in soleus from control rats.
“In agreement with these data, insulin decreased glycogen synthase phosphorylation (Ser 645 , Ser 649 , Ser 653 , Ser 657 ) in soleus from control rats”
Quote in the paperSubstantial claim - Findingown data
After fasting, glycogen concentration was slightly higher in skeletal muscles of dexamethasone-treated rats than control rats.
“After fasting, the glycogen concentration was slightly higher in skeletal muscles of dexamethasone-treated rats than control rats (Table 2).”
- Also stated in: § Discussion · plain
“and glycogen content was slightly higher in muscles from dexamethasone-treated rats, as expected [19,37].”
Quote in the paperNot a substantial claim - Also stated in: § Discussion · plain
- Findingcitation
Dexamethasone treatment caused slight hyperglycaemia.
“As observed by others, glucocorticoid excess caused slight hyperglycaemia and muscle atrophy (Table 1).”
Quote in the paperNot a substantial claim - Findingown data
In epitrochlearis, dexamethasone inhibited insulin-stimulated glucose uptake by 40% at 3 nmol/l and 25% at 60 nmol/l insulin.
“In epitrochlearis, dexamethasone inhibited insulin-stimulated glucose uptake by 40% at 3 nmol/l and 25% at 60 nmol/l insulin (Fig. 1b).”
Quote in the paperSubstantial claim - Findingcitation
Dexamethasone treatment caused muscle atrophy.
“As observed by others, glucocorticoid excess caused slight hyperglycaemia and muscle atrophy (Table 1).”
Quote in the paperNot a substantial claim - Findingown data
Expression of glycogen synthase, PKBα, PKBβ, GSK-3α and GSK-3β was similar in control and dexamethasone-treated rats.
“Expression of glycogen synthase, PKBα, PKBβ, GSK-3α and GSK-3β, as determined by quantification on blots, was similar in control and dexamethasone-treated rats (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Insulin increased glycogen synthase activity in the independent form in soleus from control rats.
“Insulin increased glycogen synthase fractional activity (Fig. 2b) and glycogen synthase activity in the independent form (data not shown) in soleus from control rats.”
Quote in the paperSubstantial claim - Findingown data
Insulin-stimulated glycogen synthesis was decreased in soleus from dexamethasone-treated rats.
“Insulin-stimulated glycogen synthesis was decreased in soleus from dexamethasone-treated rats, whereas basal glycogen synthesis was not significantly reduced.”
Quote in the paperSubstantial claim - Findingown data
A concentration of 500 nmol/l GSK-3 inhibitor fully activates glycogen synthase in cells.
“A concentration of 500 nmol/l GSK-3 inhibitor was found to fully activate glycogen synthase in cells (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Insulin increased glycogen synthase fractional activity in soleus from control rats.
“Insulin increased glycogen synthase fractional activity (Fig. 2b) and glycogen synthase activity in the independent form (data not shown) in soleus from control rats.”
Quote in the paperSubstantial claim - Findingown data
Rates of glycogen synthesis were reduced by ~70% at physiological and supraphysiological insulin concentrations in soleus from dexamethasone-treated rats compared with control.
“Rates of glycogen synthesis were reduced by ∼70% at physiological and supraphysiological insulin concentrations in soleus from dexamethasone-treated rats compared with control rats (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
Rats treated with dexamethasone had lower body weight than control rats.
“Rats treated with dexamethasone had lower body weight and epididymal fat pad weight than control rats (Table 1).”
Quote in the paperNot a substantial claim - Findingown data
Insulin-stimulated GSK-3 phosphorylation was reduced by about 30% compared with control rats.
“Despite a reduction in insulin-stimulated GSK-3 phosphorylation by about 30% compared with control rats”
Quote in the paperSubstantial claim - Findingown data
Dexamethasone did not affect expression of PKBα, PKBβ, GSK-3α, GSK-3β or glycogen synthase in skeletal muscles.
“In the present study, dexamethasone did not affect expression of PKBα, PKBβ, GSK-3α, GSK-3β or glycogen synthase in skeletal muscles.”
Quote in the paperSubstantial claim - Findingown data
CHIR-637 increased glycogen synthase fractional activity in soleus from control and dexamethasone-treated rats.
“CHIR-637 increased glycogen synthase fractional activity in soleus from control and dexamethasone-treated rats (Fig. 7a,b).”
Quote in the paperSubstantial claim- The authors state this as an assumption: CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
- Findingown data
Insulin-stimulated GSK-3α Ser21 and GSK-3β Ser9 phosphorylation were significantly reduced in dexamethasone-treated rats at 3 nmol/l and 60 nmol/l insulin.
“Insulin-stimulated GSK-3α Ser 21 and GSK-3β Ser 9 phosphorylation were, however, significantly reduced in dexamethasone-treated rats at 3 nmol/ l insulin (∼30% for GSK-3α Ser 21 phosphorylation and ∼33% for GSK-3β Ser 9 phosphorylation) and at 60 nmol/l of insulin (∼23% for GSK-3α Ser 21 phosphorylation and ∼26% for GSK-3β Ser 9 phosphorylation) (Fig. 6a,b).”
Quote in the paperSubstantial claim - Findingown data
Phosphorylation of p70 S6K at Thr389 was not detectable in the absence of insulin.
“Phosphorylation of p70 S6K at Thr 389 was not detectable in the absence of insulin.”
Quote in the paperNot a substantial claim - Findingown data
In epitrochlearis, GLUT4 expression was higher in muscles from dexamethasone-treated rats than in control rats.
“In epitrochlearis, GLUT4 expression was higher in muscles from dexamethasone-treated rats than in control rats (183.7±23.3vs 100.0±12.3% in dexamethasone-treated and control rats, respectively; n=7 in each group, p<0.0001).”
Quote in the paperNot a substantial claim - Findingreasoning
CHIR-637 treatment caused dephosphorylation of glycogen synthase in soleus from control and dexamethasone-treated rats.
“As expected from the glycogen synthase fractional activity data, CHIR-637 treatment caused dephosphorylation of glycogen synthase in soleus from control and dexamethasone-treated rats (Fig. 7c,d).”
Quote in the paperSubstantial claim- The authors state this as an assumption: CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
- Findingnone given
Insulin-stimulated phosphorylation of GSK-3α and GSK-3β was reduced in muscles from dexamethasone-treated rats.
“Insulin-stimulated phosphorylation of GSK-3α and GSK-3β was reduced in muscles from dexamethasonetreated rats.”
Quote in the paperSubstantial claim - Findingown data
Insulin increased tyrosine phosphorylation of the insulin receptor to similar extents in soleus muscles from control and dexamethasone-treated rats.
“Insulin increased tyrosine phosphorylation of the insulin receptor to similar extents in soleus muscles from control and dexamethasone-treated rats (Fig. 4).”
Quote in the paperSubstantial claim - Findingown data
In the basal state, PKB Ser473 phosphorylation was undetectable in control and dexamethasone-treated rats.
“In the basal state, PKB Ser 473 phosphorylation was undetectable in control and dexamethasone-treated rats (Fig. 5a).”
Quote in the paperNot a substantial claim - Findingown data
Insulin-stimulated PKB Ser473 phosphorylation was reduced in soleus and epitrochlearis from dexamethasone-treated rats compared with control rats.
“Insulin-stimulated PKB Ser 473 phosphorylation was reduced in soleus and epitrochlearis from dexamethasone-treated rats compared with control rats (Fig. 5a,b).”
Quote in the paperSubstantial claim - Findingown data
CHIR-637 did not change basal glucose uptake.
“CHIR-637 did not change basal glucose uptake (Fig. 8a,b).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
- Findingown data
Insulin-stimulated glycogen synthase activation and dephosphorylation were completely abolished in dexamethasone-treated rats.
“The fact that insulin-stimulated glycogen synthase activation and dephosphorylation were completely abolished in dexamethasone-treated rats”
- Also stated in: § Discussion · plain
“However, the fact that insulin-stimulated glycogen synthase activation was completely blocked in muscles from dexamethasone-treated rats”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
GLUT4 expression was similar in soleus from control and dexamethasone-treated rats.
“GLUT4 expression was similar in soleus from control and dexamethasone-treated rats.”
Quote in the paperNot a substantial claim - Findingown data
Insulin reduced glycogen synthase phosphorylation at these sites by ~50% in soleus from normal rats.
“and insulin reduced glycogen synthase phosphorylation at these sites by ∼50% in soleus from normal rats.”
Quote in the paperSubstantial claim - Findingown data
PKB Thr308 phosphorylation at 60 nmol/l insulin was decreased in soleus muscles from dexamethasone-treated rats.
“PKB Thr 308 phosphorylation was investigated at 60 nmol/l insulin and was found to be decreased in soleus muscles from dexamethasone-treated rats (100.0±10.0 and 62.6±5.4% in control and dexamethasone-treated rats, respectively; n=7 in each group, p<0.0001).”
Quote in the paperSubstantial claim - Findingown data
In both groups, insulin increased GSK-3α Ser21 phosphorylation and GSK-3β Ser9 phosphorylation in a dose-dependent manner.
“In both groups, insulin increased GSK-3α Ser 21 phosphorylation and GSK-3β Ser 9 phosphorylation in a dose-dependent manner (Fig. 6a,b).”
Quote in the paperSubstantial claim - Findingown data
In the basal state, phosphorylation of GSK-3α Ser21 and GSK-3β Ser9 were similar in soleus from control and dexamethasone-treated rats.
“In the basal state, phosphorylation of GSK-3α Ser 21 and phosphorylation of GSK-3β Ser 9 were similar in soleus from control and dexamethasone-treated rats (Fig. 6a,b).”
Quote in the paperNot a substantial claim - Findingcitation
The glycogen concentration in muscles from dexamethasone-treated rats was not above the content found in non-fasted rats.
“The glycogen concentration in muscles from dexamethasone-treated rats was, however, not above the content found in non-fasted rats, in which insulin activates glycogen synthase [38].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Jensen J, Aslesen R, Jebens E et al (1999) Adrenaline-mediated glycogen phosphorylase activation is enhanced in rat soleus muscle with increased glycogen content. Biochim Biophys Acta 1472:215–221 source
Not checked in the free run.
- Findingown data
Incubation with CHIR-637 did not increase glycogen synthase fractional activity to a similar extent in soleus muscles from dexamethasone-treated and control rats.
“However, incubation with CHIR-637 did not increase glycogen synthase fractional activity to a similar extent in soleus muscles from dexamethasone-treated and control rats (p<0.05).”
Quote in the paperSubstantial claim- The authors state this as an assumption: CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
- Findingown data
Dexamethasone treatment did not change GLUT4 expression in soleus.
“dexamethasone treatment did not change GLUT4 expression in soleus.”
Quote in the paperSubstantial claim - Findingown data
Dexamethasone treatment reduced insulin-stimulated PKB Ser 473 and Thr 308 phosphorylation by about 50% in the present study.
“In the present study, dexamethasone treatment reduced insulin-stimulated PKB Ser 473 and Thr 308 phosphorylation by about 50%.”
- Also stated in: § Discussion · boosted
“our data convincingly show reduced insulin-stimulated PKB phosphorylation in insulin-resistant muscles from dexamethasone-treated rats.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Findingown data
CHIR-637 did not increase insulin-stimulated glucose uptake in soleus muscles from control or dexamethasone-treated rats.
“More importantly, CHIR-637 did not increase insulin-stimulated glucose uptake (Fig. 8a,b) and PKB phosphorylation (Fig. 8c,d) in soleus muscles from control or dexamethasone-treated rats.”
Quote in the paperSubstantial claim- The authors state this as an assumption: CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
- Findingown data
PKB Thr308 phosphorylation was not detectable in the absence of insulin.
“PKB Thr 308 phosphorylation was not detectable in the absence of insulin.”
Quote in the paperNot a substantial claim - Findingown data
Phosphorylation of p70 S6K at Thr389 was reduced by ~65% in soleus from dexamethasone-treated rats incubated with 60 nmol/l insulin.
“Phosphorylation of p70 S6K , another PI 3-kinase downstream signalling protein, was reduced at Thr 389 by ∼65% in soleus from dexamethasone-treated rats incubated with 60 nmol/l insulin (100.0±22.0 and 34.9±3.9% in control and dexamethasone-treated rats, respectively; n=7 in each group, p<0.0001).”
Quote in the paperSubstantial claim - Findingown data
CHIR-637 did not increase PKB phosphorylation in soleus muscles from control or dexamethasone-treated rats.
“More importantly, CHIR-637 did not increase insulin-stimulated glucose uptake (Fig. 8a,b) and PKB phosphorylation (Fig. 8c,d) in soleus muscles from control or dexamethasone-treated rats.”
Quote in the paperSubstantial claim- The authors state this as an assumption: CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
- Findingown data
In epitrochlearis, pretreatment with CHIR-637 did not increase insulin-stimulated glucose uptake in control or dexamethasone-treated rats.
“In epitrochlearis, pretreatment with CHIR-637 did not increase insulin-stimulated glucose uptake in control or dexamethasone-treated rats (data not shown).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
- Findingown data
Insulin still elicited a significant increase in GSK-3 phosphorylation in soleus from dexamethasone-treated rats.
“insulin still elicited a significant increase in GSK-3 phosphorylation in soleus from dexamethasonetreated rats.”
Quote in the paperSubstantial claim - Findingown data
The GSK-3 inhibitor CHIR-637 increased glycogen synthase fractional activity in soleus from normal and dexamethasone-treated rats.
“In the present study, we found that the GSK-3 inhibitor CHIR-637 increased glycogen synthase fractional activity in soleus from normal and dexamethasone-treated rats.”
- Also stated in: § Discussion · plain
“Short-term pharmacological inhibition of GSK-3 increased glycogen synthase fractional activity in muscles from dexamethasone-treated rats”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
CHIR-637 was unable to restore glycogen synthase activation in muscle from dexamethasone-treated rats to that found in muscles from normal rats.
“In the present study, CHIR-637 was unable to restore glycogen synthase activation in muscle from dexamethasone-treated rats to that found in muscles from normal rats.”
Quote in the paperSubstantial claim - Premisecitation
A daily intraperitoneal injection of dexamethasone (1.0 mg/kg) for 12 days induces a state of insulin resistance in rats.
“This concentration has previously been reported to induce a state of insulin resistance [16,26].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] Haber RS, Weinstein SP (1992) Role of glucose transporters in glucocorticoid-induced insulin resistance. GLUT4 isoform in rat skeletal muscle is not decreased by dexamethasone. Diabetes 41:728–735 source
Not checked in the free run.
- cites [26] Saad MJ, Folli F, Kahn JA et al (1993) Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest 92:2065–2072 source
Not checked in the free run.
- Premisecitation
Dexamethasone-induced insulin resistance does not alter tyrosine phosphorylation of the insulin receptor.
“Dexamethasone-induced insulin resistance does not alter tyrosine phosphorylation of the insulin receptor [18,26]”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] Leighton B, Challiss RA, Lozeman FJ et al (1987) Effects of dexamethasone treatment on insulin-stimulated rates of glycolysis and glycogen synthesis in isolated incubated skeletal muscles of the rat. Biochem J 246:551–554 source
Not checked in the free run.
- cites [26] Saad MJ, Folli F, Kahn JA et al (1993) Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest 92:2065–2072 source
Not checked in the free run.
- Premisecitation
Chronic treatment with dexamethasone decreases insulin-stimulated glucose uptake and GLUT4 translocation in skeletal muscle without reducing total GLUT4 content.
“Chronic treatment with the glucocorticoid analogue dexamethasone decreases insulinstimulated glucose uptake and GLUT4 translocation in skeletal muscle without reducing the total content of GLUT4 [16,17].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] Haber RS, Weinstein SP (1992) Role of glucose transporters in glucocorticoid-induced insulin resistance. GLUT4 isoform in rat skeletal muscle is not decreased by dexamethasone. Diabetes 41:728–735 source
Not checked in the free run.
- cites [17] Dimitriadis G, Leighton B, Parry-Billings M et al (1997) Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle. Biochem J 321:707–712 source
Not checked in the free run.
- Premisecitation
Glucocorticoids in excess induce insulin resistance.
“Glucocorticoids in excess induce insulin resistance.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Nosadini R, Del Prato S, Tiengo A et al (1983) Insulin resistance in Cushing’s syndrome. J Clin Endocrinol Metab 57:529–536 source
Not checked in the free run.
- cites [2] Quddusi S, Browne P, Toivola B et al (1998) Cushing syndrome due to surreptitious glucocorticoid administration. Arch Intern Med 158:294–296 source
Not checked in the free run.
- cites [3] Pagano G, Cavallo-Perin P, Cassader M et al (1983) An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest 72:1814–1820 source
Not checked in the free run.
- Premisecitation
The concentration of GSK-3 inhibitor causing half-maximal glycogen synthase stimulation (EC50) in CHO-IR cells was 66 nmol/l.
“The concentration of GSK-3 inhibitor causing half-maximal glycogen synthase stimulation (EC 50 ) in CHO-IR cells was 66 nmol/l [35], which is similar to the EC 50 observed in soleus muscles in this study (data not shown).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Wagman AS, Johnson KW, Bussiere DE (2004) Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Curr Pharm Des 10:1105–1137 source
Not checked in the free run.
- Premisecitation
CHIR-637 exhibits >2,500-fold selectivity against a panel of 16 other protein kinases, including cdc2 and erk2.
“Like other GSK-3 inhibitors in this class, it exhibits >2,500-fold selectivity against a panel of 16 other protein kinases, including cdc2 and erk2, which are the closest homologues of GSK-3.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Wagman AS, Johnson KW, Bussiere DE (2004) Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Curr Pharm Des 10:1105–1137 source
Not checked in the free run.
- Premisecitation
CHIR-637 is approximately equipotent against both isoforms of GSK-3 (α/β).
“This inhibitor is approximately equipotent against both isoforms of GSK-3 (α/β).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Wagman AS, Johnson KW, Bussiere DE (2004) Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Curr Pharm Des 10:1105–1137 source
Not checked in the free run.
- Premisecitation
Pharmacological inhibition of GSK-3 with selective inhibitors can improve insulin sensitivity in insulin-resistant muscles from ZDF rats.
“Pharmacological inhibition of GSK-3 with highly selective, reversible, cell-permeable small molecules can improve insulin sensitivity in insulin-resistant muscles from Zucker diabetic fatty (ZDF) rats [27][28][29].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [27] Henriksen EJ, Kinnick TR, Teachey MK et al (2003) Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 284:E892–E900 source
Not checked in the free run.
- cites [28] Ring DB, Johnson KW, Henriksen EJ et al (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52:588–595 source
Not checked in the free run.
- cites [29] Cline GW, Johnson K, Regittnig W et al (2002) Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats. Diabetes 51:2903–2910 source
Not checked in the free run.
- Premisecitation
Dexamethasone-induced insulin resistance inhibits insulin-stimulated IRS-1-associated PI 3-kinase activity.
“but inhibits insulin-stimulated IRS-1 associated PI 3-kinase activity [26].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Saad MJ, Folli F, Kahn JA et al (1993) Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest 92:2065–2072 source
Not checked in the free run.
- Interpretationreasoning
The fact that insulin did not dephosphorylate and activate glycogen synthase in muscles from dexamethasone-treated rats shows that glycogen synthesis is more severely affected than glucose uptake.
“The fact that insulin did not dephosphorylate and activate glycogen synthase in muscles from dexamethasone-treated rats shows that glycogen synthesis is more severely affected than glucose uptake.”
Quote in the paperSubstantial claim - Premisecitation
Dexamethasone treatment reduces IRS-1-associated PI 3-kinase activity.
“whereas dexamethasone treatment reduces IRS-1-associated PI 3-kinase activity [26].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Saad MJ, Folli F, Kahn JA et al (1993) Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest 92:2065–2072 source
Not checked in the free run.
- Interpretationreasoning
High glycogen content does not explain the inability to dephosphorylate and activate glycogen synthase during insulin stimulation in muscles from dexamethasone-treated rats.
“High glycogen content, therefore, does not explain the inability to dephosphorylate and activate glycogen synthase activation during insulin stimulation.”
Quote in the paperSubstantial claim - Interpretationown data
Impaired insulin-stimulated PKB and GSK-3 phosphorylation may contribute to insulin resistance in skeletal muscles.
“We dem-onstrated that chronic dexamethasone treatment impairs insulin-stimulated PKB and GSK-3 phosphorylation, which may contribute to insulin resistance in skeletal muscles.”
Quote in the paperSubstantial claim - Premisecitation
Overexpression of p85α reduces insulin signalling in L6 myotubes.
“overexpression of p85α reduces insulin signalling in L6 myotubes [45]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] Ueki K, Algenstaedt P, Mauvais-Jarvis F et al (2000) Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85alpha regulatory subunit. Mol Cell Biol 20:8035–8046 source
Not checked in the free run.
- Study design and conductnone given
The present study only investigated the effect of a high concentration of dexamethasone on PKB phosphorylation.
“A weakness of the present study is that we have only investigated the effect of a high concentration of dexamethasone on PKB phosphorylation”
Quote in the paperNot a substantial claim - Premisecitation
Glucocorticoid treatment increased GLUT4 expression in the fast-twitch epitrochlearis muscles.
“as reported previously [16], glucocorticoid treatment increased GLUT4 expression in the fast-twitch epitrochlearis muscles”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Haber RS, Weinstein SP (1992) Role of glucose transporters in glucocorticoid-induced insulin resistance. GLUT4 isoform in rat skeletal muscle is not decreased by dexamethasone. Diabetes 41:728–735 source
Not checked in the free run.
- Interpretationreasoning
The complete abolition of insulin-stimulated glycogen synthase activation and dephosphorylation in dexamethasone-treated rats is explained only in part by increased GSK-3 activity.
“seems, therefore, to be explained only in part by increased GSK-3 activity.”
Quote in the paperSubstantial claim - Interpretationown data
Dexamethasone induces skeletal muscle insulin resistance by impairing phosphorylation of insulin signalling proteins rather than reducing expression of GLUT4, PKB, GSK-3 or glycogen synthase.
“Our data therefore suggest that dexamethasone induces skeletal muscle insulin resistance by impairing phosphorylation of insulin signalling proteins rather than reducing expression of GLUT4, PKB, GSK-3 or glycogen synthase.”
Quote in the paperSubstantial claim - Interpretationreasoning
The incomplete and slow dephosphorylation of glycogen synthase suggests a lack of protein phosphatase-1 activity in dexamethasone-treated rat muscle.
“the incomplete and slow dephosphorylation of glycogen synthase suggests a lack of protein phosphatase-1 activity in dexamethasonetreated rat muscle.”
Quote in the paperNot a substantial claim - Premisecitation
In human skeletal muscle cells, this class of GSK-3 inhibitor only enhanced insulin-stimulated glucose uptake after prolonged (>6 h) exposure.
“In human skeletal muscle cells, however, this class of GSK-3 inhibitor only enhanced insulin-stimulated glucose uptake after prolonged (>6 h) exposure [48].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Nikoulina SE, Ciaraldi TP, Mudaliar S et al (2002) Inhibition of glycogen synthase kinase 3 improves insulin action and glucose metabolism in human skeletal muscle. Diabetes 51:2190–2198 source
Not checked in the free run.
- Study design and conductown data
The specific effect of CHIR-637 is supported by reduced glycogen synthase phosphorylation at sites phosphorylated by GSK-3.
“It is noteworthy that the specific effect of CHIR-637 is supported by reduced glycogen synthase phosphorylation at sites phosphorylated by GSK-3.”
Quote in the paperSubstantial claim - Interpretationown data
Reduced GSK-3 phosphorylation may contribute to, but not fully explain, the ability of insulin to activate glycogen synthase.
“Reduced GSK-3 phosphorylation may contribute to, but not fully explain, the ability of insulin to activate glycogen synthase.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 20
- May combine two claims. 17
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataRats treated with dexamethasone had lower epididymal fat pad weight than control rats.
“Rats treated with dexamethasone had lower body weight and epididymal fat pad weight than control rats (Table 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataDaily food consumption was lower in dexamethasone-treated rats than control rats.
“The daily food consumption in control and dexamethasone-treated rats was 23.1±1.8(n=12) and 15.5±1.0 g (n=8), respectively.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenDexamethasone induces insulin resistance in skeletal muscle without reducing tyrosine phosphorylation of insulin receptor.
“Dexamethasone induces insulin resistance in skeletal muscle without reducing tyrosine phosphorylation of insulin receptor.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataShort-term incubation with CHIR-637 did not increase insulin-stimulated glucose uptake or PKB phosphorylation in muscles from dexamethasone-treated rats.
“Short-term incubation with CHIR-637 did not increase insulin-stimulated glucose uptake or PKB phosphorylation in muscles from dexamethasone-treated rats.”
- Also stated in: § Discussion · plain
“did not improve insulinstimulated glucose uptake.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
May combine two claims.
Findingown dataDexamethasone treatment impairs insulin-stimulated glucose uptake and glycogen synthesis in muscle.
“In conclusion, dexamethasone treatment impairs insulinstimulated glucose uptake and glycogen synthesis in muscle”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCHIR-637 is an ATP-competitive inhibitor of GSK-3β with an IC50 of 4 nmol/l in a cell-free binding assay.
“CHIR-637, a low-molecular weight (531 Da) small molecule, is an ATP-competitive inhibitor of GSK-3β giving an IC 50 of 4 nmol/l in a cell-free binding assay [35].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Wagman AS, Johnson KW, Bussiere DE (2004) Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Curr Pharm Des 10:1105–1137 source
Not checked in the free run.
May combine two claims.
PremisecitationDexamethasone treatment inhibits insulin-stimulated glycogen synthesis and glycogen synthase activation.
“Dexamethasone treatment, in addition, inhibits insulin-stimulated glycogen synthesis and glycogen synthase activation [18,19].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] Leighton B, Challiss RA, Lozeman FJ et al (1987) Effects of dexamethasone treatment on insulin-stimulated rates of glycolysis and glycogen synthesis in isolated incubated skeletal muscles of the rat. Biochem J 246:551–554 source
Not checked in the free run.
- cites [19] Coderre L, Srivastava AK, Chiasson JL (1992) Effect of hypercorticism on regulation of skeletal muscle glycogen metabolism by insulin. Am J Physiol Endocrinol Metab 262:E427–E433 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRats were divided into two weight-matched groups.
“Rats were housed individually for 1 week and were divided in two weight-matched groups (280.8±2.9 g for control rats and 282.9±2.8 g for dexamethasone-treated rats, n=28-29).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationGSK-3 inhibitors increase insulin-stimulated glucose transport in epitrochlearis and soleus muscles from insulin-resistant ZDF rats, but not from insulin-sensitive lean Zucker rats.
“GSK-3 inhibitors increased insulin-stimulated glucose transport in epitrochlearis and soleus muscles from insulin-resistant ZDF rats, but not from insulin-sensitive lean Zucker rats [27,28].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [27] Henriksen EJ, Kinnick TR, Teachey MK et al (2003) Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 284:E892–E900 source
Not checked in the free run.
- cites [28] Ring DB, Johnson KW, Henriksen EJ et al (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52:588–595 source
Not checked in the free run.
May combine two claims.
PremisecitationBinding of free p85α monomer to IRS-1 does not increase PI 3-kinase activity, but instead competes with binding of the p85α-p110 heterodimer, and consequently impairs PI 3-kinase activation.
“Binding of free p85α monomer to IRS-1 does not increase PI 3-kinase activity, but instead competes with binding of the p85α-p110 heterodimer, and consequently impairs PI 3-kinase activation [44].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Giorgino F, Pedrini MT, Matera L et al (1997) Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. J Biol Chem 272:7455–7463 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningFast-twitch muscles atrophy more than slow-twitch muscles, resulting in higher relative content of membrane proteins.
“probably reflecting the fact that fast-twitch muscles atrophy more than slow-twitch muscles, resulting in higher relative content of membrane proteins.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe phospho-specific antibodies against PKB Ser 473 and PKB Thr 308 bind to both isoforms, and it is not possible to separate them on blots.
“The phospho-specific antibodies against PKB Ser 473 and PKB Thr 308 bind to both isoforms, and it is not possible to separate them on blots.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreased expression of GSK-3 causes insulin resistance.
“Reduced expression of PKB [40], reduced expression of glycogen synthase [41] or increased expression of GSK-3 [42] causes insulin resistance.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Nikoulina SE, Ciaraldi TP, Mudaliar S et al (2000) Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49:263–271 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn non-fasted rats, insulin activates glycogen synthase.
“in which insulin activates glycogen synthase [38].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Jensen J, Aslesen R, Jebens E et al (1999) Adrenaline-mediated glycogen phosphorylase activation is enhanced in rat soleus muscle with increased glycogen content. Biochim Biophys Acta 1472:215–221 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPI 3-kinase is activated when the dimer binds to IRS-1.
“PI 3-kinase is activated when the dimer binds to IRS-1 [9].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Shepherd PR, Withers DJ, Siddle K (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333:471–490 source
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.
Premisecitationp85α exists as a free monomer or bound to p110.
“It has been hypothesised that p85α exists as a free monomer or bound to p110 [44].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Giorgino F, Pedrini MT, Matera L et al (1997) Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. J Biol Chem 272:7455–7463 source
Not checked in the free run.
May combine two claims.
PremisecitationGSK-3 phosphorylates Ser645, Ser649, Ser653, Ser657 of glycogen synthase, which are the most important sites for regulation of glycogen synthase activity.
“GSK-3 phosphorylates these sites, which are the most important for regulation of glycogen synthase activity [11]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Lawrence JC Jr, Roach PJ (1997) New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 46:541–547 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPKBβ seems to regulate insulin-stimulated glucose uptake.
“PKBβ seems to regulate insulinstimulated glucose uptake [12,13]”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [12] Jiang ZY, Zhou QL, Coleman KA et al (2003) Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc Natl Acad Sci U S A 100:7569–7574 source
Not checked in the free run.
- cites [13] Katome T, Obata T, Matsushima R et al (2003) Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions. J Biol Chem 278:28312–28323 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationReduced expression of glycogen synthase causes insulin resistance.
“Reduced expression of PKB [40], reduced expression of glycogen synthase [41] or increased expression of GSK-3 [42] causes insulin resistance.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Park KS, Ciaraldi TP, Carter L et al (2000) Induction of insulin resistance in human skeletal muscle cells by downregulation of glycogen synthase protein expression. Metabolism 49:962–968 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPKBα seems to regulate muscle growth.
“PKBα seems to regulate muscle growth [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Glass DJ (2003) Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol 5:87–90 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningDexamethasone treatment also impairs activation of protein phosphatase-1, and therefore dephosphorylation of glycogen synthase in response to insulin.
“We suggest that dexamethasone treatment also impairs activation of protein phosphatase-1, and therefore dephosphorylation of glycogen synthase in response to insulin.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationReduced expression of PKB causes insulin resistance.
“Reduced expression of PKB [40], reduced expression of glycogen synthase [41] or increased expression of GSK-3 [42] causes insulin resistance.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Garofalo RS, Orena SJ, Rafidi K et al (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 112:197–208 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPI 3-kinase is a heterodimer composed of a regulatory subunit (p85α) and a catalytic sub-unit (p110).
“PI 3-kinase is a heterodimer composed of a regulatory subunit (p85α) and a catalytic sub-unit (p110)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Shepherd PR, Withers DJ, Siddle K (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333:471–490 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlycogen content is a strong regulator of glycogen synthase activity.
“Glycogen content is a strong regulator of glycogen synthase activity [36]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Danforth W (1965) Glycogen synthetase activity in skeletal muscle. Interconversion of two forms and control of glycogen synthesis. J Biol Chem 240:588–593 source
Not checked in the free run.
May combine two claims.
PremisecitationReduced p85α expression improves glucose homeostasis and insulin signalling in normal and insulin-resistant mice.
“reduced p85α expression improves glucose homeostasis and insulin signalling in normal and insulin-resistant mice [46,47].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46] Mauvais-Jarvis F, Ueki K, Fruman DA et al (2002) Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest 109:141–149 source
Not checked in the free run.
- cites [47] Terauchi Y, Tsuji Y, Satoh S et al (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet 21:230–235 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationGSK-3 phosphorylates IRS-1, which reduces activation of PI 3-kinase and PKB.
“GSK-3 has been reported to phosphorylate IRS-1, which reduces activation of PI 3-kinase and PKB [49].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] Eldar-Finkelman H, Krebs EG (1997) Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc Natl Acad Sci U S A 94:9660–9664 source
Not checked in the free run.
May combine two claims.
Interpretationown dataInsulin resistance may result from increased expression of the p85α subunit of PI 3-kinase and reduced PKB phosphorylation.
“our data suggest that insulin resistance may result from increased expression of the p85α subunit of PI 3-kinase and reduced PKB phosphorylation.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPharmacological inhibition of GSK-3 increases insulin-stimulated glucose uptake in insulin-resistant skeletal muscles from obese ZDF rats but not in muscle from insulin-sensitive lean ZDF rats.
“Pharmacological inhibition of GSK-3 increases insulin-stimulated glucose uptake in insulin-resistant skeletal muscles from obese ZDF rats but not in muscle from insulin-sensitive lean ZDF rats [27,28].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Henriksen EJ, Kinnick TR, Teachey MK et al (2003) Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 284:E892–E900 source
Not checked in the free run.
- cites [28] Ring DB, Johnson KW, Henriksen EJ et al (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52:588–595 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningInhibition of GSK-3 by CHIR-637 may increase glucose transport in ZDF rats by reducing IRS-1 serine phosphorylation.
“Inhibition of GSK-3 by CHIR-637 may increase glucose transport in ZDF rats by reducing IRS-1 serine phosphorylation”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGSK-3 inhibitors activate glycogen synthase in cultured human skeletal muscle cells from normal and type 2 diabetics.
“in cultured human skeletal muscle cells from normal and type 2 diabetics [48].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Nikoulina SE, Ciaraldi TP, Mudaliar S et al (2002) Inhibition of glycogen synthase kinase 3 improves insulin action and glucose metabolism in human skeletal muscle. Diabetes 51:2190–2198 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningIncreased expression of p85α and competitive inhibition of PI 3-kinase activity may mediate glucocorticoid-induced insulin resistance.
“Our data support the possibility that increased expression of p85α and competitive inhibition of PI 3-kinase activity may mediate glucocorticoid-induced insulin resistance.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Study design and conductnone givenIt is difficult to accurately gauge the percentage of GSK-3 which was inhibited in these experiments.
“While it is difficult to accurately gauge the percentage of GSK-3 which was inhibited in these experiments”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGSK-3 inhibitors activate glycogen synthase in lean and ZDF rats.
“GSK-3 inhibitors activate glycogen synthase in lean and ZDF rats [27]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Henriksen EJ, Kinnick TR, Teachey MK et al (2003) Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 284:E892–E900 source
Not checked in the free run.
The authors state this as an assumption.
CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.
“To the best of our knowledge, CHIR-637 does not interfere with kinases (with the exception of GSK-3) that are involved in the insulin signalling pathway.”
The paper relies on this without support.
Dexamethasone-treated rats are a valid model of glucocorticoid-induced insulin resistance in human skeletal muscle.
“Further studies have to confirm whether similar impairments occur in humans during clinical treatment with glucocorticoids.”
The paper relies on this without support.
The high concentration of dexamethasone used in the study is representative of clinical glucocorticoid treatment.
“A weakness of the present study is that we have only investigated the effect of a high concentration of dexamethasone on PKB phosphorylation”
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?
GCs are well known to impair the insulin-stimulated glycogen synthesis pathway.
“GCs are well known to impair the insulin-stimulated glycogen synthesis pathway [29]”
From Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial (2011) · cites this paper as [29]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 5 significance note refers to an inhibitor comparison absent from the figure
MinorThe Figure 5 caption describes comparisons across dexamethasone treatment and insulin concentrations, but its significance note instead refers to a comparison with muscles incubated without CHIR-637. No CHIR-637 treatment is described for Figure 5.
“b p<0.05 vs muscle incubated without CHIR-637 and with a similar insulin concentration;”
“Muscles from control (C, open bars) and dexamethasone-treated (D, filled bars) rats were incubated for 30 min with different concentrations of insulin.”
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Insulin Resistance in Cushing’s Syndrome*
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BackgroundResultInfluentialMuscle insulin resistance amended with exercise training: role of GLUT4 expression.
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Effects of epinephrine on glucose metabolism in contracting rat skeletal muscles
Aslesen, R., & Jensen, J. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.3.e448 · Cited by 63 · see citing works
Self-citationNormal Akt/PKB with reduced PI3K activation in insulin-resistant mice
Nadler, S. T., Stoehr, J. P., Rabaglia, M. E., Schueler, K. L., Birnbaum, M. J., & Attie, A. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.6.e1249 · Cited by 58 · see citing works
Franch, J., Aslesen, R., & Jensen, J. (1999) · Biochemical Journal · doi:10.1042/bj3440231 · Cited by 54 · see citing works
Self-citationWHITEHEAD, J. P., SOOS, M. A., ASLESEN, R., O'RAHILLY, S., & JENSEN, J. (2000) · Biochemical Journal · doi:10.1042/bj3490775 · Cited by 48 · see citing works
Self-citationThe Glucocorticoid Receptor: Molecular Mechanism and New Therapeutic Opportunities
Buckbinder, B. S. P. L., & Robinson, B. S. P. R. P. (2002) · Current Drug Targets - Inflammation & Allergy · doi:10.2174/1568010023344751 · Cited by 48 · see citing works
Kusunoki, M., Cooney, G. J., Hara, T., & Storlien, L. H. (1995) · Diabetes · doi:10.2337/diab.44.6.718 · Cited by 47 · see citing works
Cushing Syndrome Due to Surreptitious Glucocorticoid Administration
Quddusi, S., Browne, P., Toivola, B., & Hirsch, I. B. (1998) · Archives of Internal Medicine · doi:10.1001/archinte.158.3.294 · Cited by 44 · see citing works
Effect of hypercorticism on regulation of skeletal muscle glycogen metabolism by epinephrine
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Jensen, J., Aslesen, R., Jebens, E., & Skrondal, A. (1999) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(99)00122-1 · Cited by 24 · see citing works
Self-citationMechanism of glucocorticoid action.
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Effect of hypercorticism on regulation of skeletal muscle glycogen metabolism by insulin
Coderre, L., Srivastava, A. K., & Chiasson, J. L. (1992) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1992.262.4.e427 · Cited by 17 · see citing works
Park, K. S., Ciaraldi, T. P., Carter, L., Mudaliar, S., Nikoulina, S. E., Webster, N. J. G., & Henry, R. R. (2000) · Metabolism · doi:10.1053/meta.2000.7717 · Cited by 9 · cited 1× · see citing works
“Reduced expression of PKB [40], reduced expression of glycogen synthase [41] or increased expression of GSK-3 [42] causes insulin resistance.”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Regulation 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
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The Role of Skeletal Muscle Glycogen Breakdown for Regulation of Insulin Sensitivity by Exercise
Jensen, J., Rustad, P. I., Kolnes, A. J., & Lai, Y.-C. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00112 · Cited by 412 · see citing works
Self-citationTamez-Pérez, H. E. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i8.1073 · Cited by 387 · see citing works
Muscle sparing in muscle RING finger 1 null mice: response to synthetic glucocorticoids
Baehr, L. M., Furlow, J. D., & Bodine, S. C. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.212845 · Cited by 234 · see citing works
Pathophysiology of Diabetes Mellitus in Cushing’s Syndrome
Pivonello, R., De Leo, M., Vitale, P., Cozzolino, A., Simeoli, C., De Martino, M. C., Lombardi, G., & Colao, A. (2010) · Neuroendocrinology · doi:10.1159/000314319 · Cited by 190 · see citing works
Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management
Scaroni, C., Zilio, M., Foti, M., & Boscaro, M. (2017) · Endocrine Reviews · doi:10.1210/er.2016-1105 · Cited by 140 · see citing works
Insulin action and signalling in fat and muscle from dexamethasone-treated rats
Burén, J., Lai, Y. C., Lundgren, M., Eriksson, J. W., & Jensen, J. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.02.034 · Cited by 125 · see citing works
Self-citationChronic Stress and Diabetes Mellitus: Interwoven Pathologies
Sharma, V. K., & Singh, T. G. (2020) · Current Diabetes Reviews · doi:10.2174/1573399815666191111152248 · Cited by 116 · see citing works
van Raalte, D. H., Brands, M., van der Zijl, N. J., Muskiet, M. H., Pouwels, P. J. W., Ackermans, M. T., Sauerwein, H. P., Serlie, M. J., & Diamant, M. (2011) · Diabetologia · doi:10.1007/s00125-011-2174-9 · Cited by 109 · see citing works
“GCs are well to known to impair the insulin-stimulated glycogen synthesis pathway [29] and therefore, increased glucose oxidation was proposed to serve as a mechanisms to compensate for reduced glycogen synthesis, in the presence of higher glucose levels within the skeletal muscle [28].”
BackgroundRole of aldosterone and angiotensin II in insulin resistance: an update
Lastra‐Lastra, G., Sowers, J. R., Restrepo‐Erazo, K., Manrique‐Acevedo, C., & Lastra‐González, G. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03498.x · Cited by 90 · see citing works
Jensen, J., & Lai, Y.-C. (2009) · Archives of Physiology and Biochemistry · doi:10.1080/13813450902778171 · Cited by 90 · see citing works
Self-citationGlucocorticoid Modulation of Insulin Signaling in Human Subcutaneous Adipose Tissue
Gathercole, L. L., Bujalska, I. J., Stewart, P. M., & Tomlinson, J. W. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1399 · Cited by 73 · see citing works
McGing, J. J., Radford, S. J., Francis, S. T., Serres, S., Greenhaff, P. L., & Moran, G. W. (2021) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.16465 · Cited by 60 · see citing works
Glucocorticoid-Induced Hyperglycemia: A Neglected Problem
Cho, J.-H., & Suh, S. (2024) · Endocrinology and Metabolism · doi:10.3803/enm.2024.1951 · Cited by 63 · see citing works
Le Foll, C., Corporeau, C., Le Guen, V., Gouygou, J.-P., Bergé, J.-P., & Delarue, J. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00446.2006 · Cited by 45 · see citing works
- Authors
- Ruzzin, J., Wagman, A. S., & Jensen, J.
- Affiliations
- National Institute of Occupational Health (NO)
- Corresponding author
- Jensen, J.
- ORCID
- Venue
- Diabetologia
- Published
- 2005-08-03
- Volume
- 48
- Issue
- 10
- Pages
- 2119-2130
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2131714425
- Semantic Scholar
- 708fcea4c3490059f8c5d397167684e405901b62
- Cited by
- 243
- References
- 51
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 13 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 7 · 2019: 13 · 2018: 19 · 2017: 10 · 2016: 17 · 2015: 13 · 2014: 8 · 2013: 15 · 2012: 10
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk
- Norges Forskningsråd
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- glucocorticoid-induced insulin resistance, dexamethasone, skeletal muscle, insulin signaling, glycogen synthase kinase-3, glycogen synthase, Akt, phosphatidylinositol 3-kinase, insulin-stimulated glucose uptake, glycogen synthesis, soleus muscle
- MeSH terms
- Animals, Antibodies, Blood Glucose, Body Weight, Enzyme Inhibitors, Glucocorticoids, Glucose, Glycogen, Insulin, Insulin Resistance, Male, Phosphorylation, Blotting, Western, Signal Transduction, Rats, Wistar, Muscle, Skeletal, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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