help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Perry, C. G.
Right arrow Articles by Connell, J. M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Perry, C. G.
Right arrow Articles by Connell, J. M. C.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*DEXAMETHASONE
Medline Plus Health Information
*Steroids
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 6008-6014
Copyright © 2003 by The Endocrine Society

Glucocorticoids and Insulin Sensitivity: Dissociation of Insulin’s Metabolic and Vascular Actions

C. G. Perry, A. Spiers, S. J. Cleland, G. D. O. Lowe, J. R. Petrie and J. M. C. Connell

University Department of Medicine, Western Infirmary (C.G.P., S.J.C., J.M.C.C.); University Department of Medicine, Royal Infirmary (G.D.O.L., J.R.P.); and Institute of Biomedical and Life Sciences, University of Glasgow (A.S.), Glasgow, Scotland, United Kingdom G11 6NT

Address all correspondence and requests for reprints to: Dr. Colin Perry, Division of Cardiovascular and Medical Sciences, Gardiner Institute, Western Infirmary, Church Street, Glasgow, United Kingdom G11 6NT. E-mail: colin{at}fulcrum.u-net.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1–40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as D-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RESISTANCE TO INSULIN-MEDIATED glucose uptake is the fundamental metabolic abnormality underpinning type 2 diabetes mellitus. Using fasting hyperinsulinemia as a surrogate, several studies have suggested that insulin resistance is an independent cardiovascular risk factor (1, 2, 3); in addition, along with traditional cardiovascular risk factors such as hypertension and dyslipidemia, insulin resistance is a key component of the metabolic syndrome (4, 5). Insulin is now known to have important vascular effects as an endothelium-dependent vasodilator (6, 7). Recent evidence demonstrates that insulin-mediated vasodilation is reduced in insulin-resistant individuals (8, 9, 10), suggesting that insulin action in the vasculature may be coupled to its effects in skeletal muscle, liver, and adipose tissue. Indeed, we have previously shown that this is the case in healthy volunteers and in patients with hypertension and diabetes (8, 11, 12), supporting the idea that insulin’s vascular and metabolic effects may use common intracellular signaling pathways and are similarly affected by insults, whether environmental or genetic in origin. Thus, manipulation of insulin-stimulated glucose disposal may be accompanied by parallel changes in vascular insulin action.

Glucocorticoids are known to reduce insulin sensitivity; potential candidate mechanisms include reduced insulin binding to its receptor, changes in early protein-protein interactions in the insulin cascade, increased lipolysis and disrupted glucose transporter 4 trafficking and subcellular distribution (13, 14, 15). Moreover, there has been recent interest in the role of excessive glucocorticoid action (16) as an underlying factor in the metabolic syndrome. For example, it has been suggested that insulin resistance may be associated with elevated tissue levels of cortisol, relative to its inactive metabolite cortisone, as a result of dysregulation of the 11ß-hydroxysteroid dehydrogenase enzymes (types I and II) or increased expression of glucocorticoid receptors, particularly in liver and adipose tissue.

To investigate the relationship between the effect of glucocorticoid excess on metabolic and vascular function, we undertook a double-blind, placebo-controlled, cross-over study of the effect of dexamethasone on insulin action in healthy male subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study protocol

The effects of dexamethasone (1 mg twice daily) or placebo were compared in a double-blind, randomized, placebo-controlled, cross-over trial with a 4-wk washout between treatment periods (Fig. 1Go). The ethics committee of the West Glasgow Hospitals University National Health Service Trust approved the protocol. Twenty volunteers were recruited by advertisement. Exclusion criteria were body mass index of 27 kg/m2or more, blood pressure of 150/85 mm Hg or higher, fasting glucose of 6.0 mmol/liter or more, and any history of intercurrent illness or drug therapy. Volunteers were asked not to smoke or drink alcohol during the two study phases and were taking no medication at the time of study. They were reimbursed for expenses directly incurred in the course of the study, and where appropriate, a contribution was made toward loss of earnings.



View larger version (24K):
[in this window]
[in a new window]
  		FIG. 1. Study protocol.

 
On the fifth day of treatment with dexamethasone or placebo, volunteers attended the Clinical Investigation and Research Unit at 0830 h for a biopsy of sc fat from the gluteal region. With the volunteer lying prone, one buttock was exposed, and the area was sterilized with 10% iodine. One percent lignocaine hydrochloride was then instilled sc to anesthetize an area of 6 x 4 cm. An elliptical incision no greater than 3 x 0.75 cm was made, and a diamond-shaped segment of skin and adipose tissue was removed. Skin stitches were then inserted to close the wound. Ten days later the stitches were removed. One investigator (A.S.), blinded to treatment allocation, dissected small resistance vessels from the biopsy for vascular studies using the Mulvany wire myograph method (17). For the next 24 h, volunteers collected urine for measurement of urinary free cortisol. The following morning, they underwent fasting serum lipid measurements, followed by measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp method. After a 4-wk washout period, they underwent an identical second series of investigations while taking the alternative treatment (Fig. 1Go).

Euglycemic hyperinsulinemic clamp

The euglycemic hyperinsulinemic clamp protocol was carried out as previously described (8, 11, 12). Volunteers attended after an overnight fast. Venous cannulas were inserted into the left antecubital fossa for administration of insulin (Actrapid, NovoNordisk, Copenhagen, Denmark) and 20% glucose (IMED Gemini Volumetric, Abingdon, UK) and into the right wrist, with the hand heated to 55 C, to obtain arterialized venous blood. After an initial priming dose of 4.5 mU/kg·min, a constant rate of insulin (1.5 mU/kg·min) was infused (Braun Perfusor, Melsungen, Germany) in a 10% (vol/vol) solution of the volunteer’s own blood in saline (0.9% NaCl). Twenty percent glucose was infused (iv infusion system, IVAC, Basingstoke, UK), and the rate adjusted to maintain euglycemia (5.2 mmol/liter), based upon glucose samples obtained from the arterialized (heated) right hand. At steady state, the whole body glucose disposal rate (milligrams per kilogram per minute) was calculated from the glucose infusion rate and the serum glucose concentrations by applying DeFronzo’s space correction (18).

At baseline and 60, 120, 150, and 180 min, blood samples were collected for determination of serum insulin and electrolytes. Samples for C peptide were collected at 0 and 180 min. Blood samples for determination of cortisol, circulating markers of endothelial function, total cholesterol, and triglycerides were assayed at baseline. During the procedure, blood pressure and heart rate were recorded every 15 min (Dinamap, Bracknell, UK).

Analysis of peripheral blood samples

Serum for electrolytes, urea, creatinine, cortisol, and lipid fractions was measured using an Olympus AU5200 autoanalyzer. Samples for insulin and C peptide were analyzed by commercially available RIA (DiaSorin, London, UK). Plasma levels of tissue plasminogen activator antigen and D-dimer were measured using commercially available ELISAs (Biopool AB, Umea, Sweden). Plasma von Willebrand factor antigen levels were measured using an in-house ELISA, employing rabbit antihuman polyclonal antibodies obtained from DAKO (High Wycombe, UK).

Vascular studies

Preparation of arteries. Resistance arteries were dissected from the gluteal biopsy. Where possible, four segments of artery (~200–400 µm average diameter and 2 mm in length) were mounted as ring preparations on two 40-µm stainless steel wires in a four-channel small vessel myograph (Danish MyoTechnology, Aarhus, Denmark), as described in detail previously (9, 19). One wire was attached to an isometric force transducer, and the other to a movable micrometer. Vessels were bathed in a physiological salt solution (PSS; 118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4H2O, 24.9 mM NaHCO3, 2.5 mM CaCl2, 11.1 mM glucose, and 0.0023 mM EDTA). Temperature and pH were maintained at 37 C and 7.4, respectively, with a gas mixture of 5% CO2 and 95% O2 constantly being bubbled through the PSS.

Normalization of vessels. After a rest period of 30 min, each artery was stretched at 1-min intervals to determine the resting tension-internal circumference (L) relationship. The LaPlace equation, P = T/r (P is the effective pressure, T is the wall tension, and r is the internal radius), was used to determine L100. This is the calculated internal diameter the vessel would have in vivo when relaxed and subjected to a transmural pressure of 100 mm Hg (13.3 kilopascals). To achieve optimal contraction, each vessel was then set to the normalized internal diameter: L1 = 0.9L100.

Myography protocol

A single investigator (A.S.), blinded to treatment allocation, undertook all myography studies. After the normalization procedure described above, the vessels were maintained in PSS at 37 C for a further 60 min, then exposed twice to PSS solution, with KCl substituted for NaCl on an equimolar basis. Vessels were then incubated for 30 min in PSS before a cumulative concentration-response curve (CRC) to norepinephrine (NE) (1 nM to 30 µM) was performed. After a further 30-min incubation, a plateau contraction was obtained with 10 µM NE before a CRC to acetylcholine (1 nM to 30 µM) was performed. If vessels were either unable to contract to PSS with potassium or NE or showed no relaxation to acetylcholine, they were excluded from the study. Vessels were then preincubated for 30 min in PSS alone (control, vessel 1), 1 nM insulin (vessel 2), or 100 pM insulin (vessel 3) before a further NE CRC. Where possible, one vessel was used as a time control. This vessel underwent an identical protocol to the others without insulin incubation.

Responses are expressed as the pD2, [the negative log of the concentration of agonist (NE) required to produce 50% of the maximal contractile response], the percentage of the maximum contractile response to NE, and the area under the curve (AUC) of the CRC.

Small vessel myography is now an established technique used in the measurement of small vessel contractility and relaxation, particularly in response to vasoactive agents. The measurement of insulin-mediated vasorelaxation by assessing its effect on NE-induced vasoconstriction has been described previously by our own (9) and other groups (20).

Statistical analysis

Statistical analysis was performed using Minitab 13.1 (State College, PA). Data are expressed as the mean ± SD, except where stated. Myography data are expressed as the mean and SE. For paired data (metabolic variables, myography data from both phases), comparisons were made using the paired sample t test where data were normally distributed or a Wilcoxon signed rank sum where data were skewed. For comparison of data that included subjects with only one myography result (i.e. those with no paired result for comparison), a Mann-Whitney test was employed.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Twenty volunteers were recruited to the study, with 1 failing to attend for the second study phase for personal reasons. The study protocol was well tolerated by all subjects, the only reported complication being 4 minor infections at biopsy sites. Sixteen volunteers had at least 1 successful biopsy, with 11 having myography data from both study phases. An absence of vessels of suitable diameter was the reason for failure to obtain vessels from the remaining biopsies. The baseline characteristics of the subjects are detailed in Table 1Go.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Baseline characteristics of healthy volunteers

 
Blood pressure, body weight, and insulin sensitivity

No significant change in blood pressure or weight was observed between phases (Table 2Go). Glucose disposal, measured by the euglycemic hyperinsulinemic clamp, was significantly reduced after 6 d of dexamethasone (mean fall, 30%; 95% confidence interval, 19.1–40.0%; (Table 2Go and Fig. 2Go). In addition, fasting serum insulin was higher during this phase (Table 2Go). Steady state serum insulin concentrations were similar during placebo and dexamethasone (115 ± 36.4 and123 ± 36.3 µU/ml; P = 0.33).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Characteristics of volunteers during both study phases

 


View larger version (20K):
[in this window]
[in a new window]
  		FIG. 2. Insulin sensitivity and dexamethasone exposure. Insulin sensitivity was compared after placebo and dexamethasone study phases. There was a significant reduction in insulin sensitivity after 6 d of dexamethasone exposure compared with placebo (P < 0.001). Values are the mean for each phase.

 
Lipids and lipid subfractions

The fasting lipid profile was measured before the commencement of the euglycemic clamp during both phases. No change was observed in total cholesterol; however, small, but statistically significant, increases in both high density lipoprotein cholesterol and triglycerides were observed during dexamethasone treatment (Table 2Go).

Vascular studies

The effect of dexamethasone on norepinephrine-induced vasoconstriction. For this analysis, results were obtained from 16 volunteers, with 12 volunteers having data from both placebo and dexamethasone phases. Each volunteer had data from between two and four arteries available for analysis, the mean of which was used as the CRC for that volunteer. As shown in Fig. 3Go, there was no statistically significant change in the pD2 or AUC of NE-induced vasoconstriction between phases [mean pD2 during placebo, 6.8 ± 0.09; pD2 during dexamethasone, 7.0 ± 0.11 (P > 0.05); mean AUC during placebo, 444 ± 17.3; mean AUC during dexamethasone, 478 ± 13.5 (P > 0.05)].



View larger version (14K):
[in this window]
[in a new window]
  		FIG. 3. The effect of dexamethasone on NE-induced vasoconstriction. NE-induced vasoconstriction in human resistance vessels (n = 32) dissected from subjects (n = 12) after 5 d of dexamethasone was compared with that after an equivalent period of matched placebo. No statistically significant difference in the pD2 for NE-induced vasoconstriction was observed (P > 0.05). Error bars represent the SE.

 
Acetylcholine-mediated vasodilation

Data were available from 10 subjects during the placebo phase and 13 subjects during the dexamethasone phase. No difference in acetylcholine-mediated vasodilation was observed between phases [Fig. 4Go; mean pD2 for acetylcholine-mediated vasodilation during placebo, 7.1 ± 0.10; during dexamethasone, 7.1 ± 0.09 (paired data; n = 10; P > 0.05); unpaired data, mean pD2 for acetylcholine-mediated vasodilation during placebo, 6.9 ± 0.09 (n = 10); mean pD2 for acetylcholine-mediated vasodilation during dexamethasone, 7.0 ± 0.11 (n = 13; P > 0.05)].



View larger version (13K):
[in this window]
[in a new window]
  		FIG. 4. The effect of dexamethasone on acetylcholine (Ach)-mediated vasodilation. Acetylcholine-mediated vasodilation was compared between placebo and dexamethasone phases. There was a significant effect of acetylcholine during both phases, although there was no difference between phases (P > 0.05 for comparison of acetylcholine effect between phases). Error bars represent the SE.

 
Insulin-mediated attenuation of NE-induced vasoconstriction

Placebo phase. Figure 5Go, A and B, demonstrates the effect of preincubation of vessels with insulin on NE-mediated vasoconstriction during the placebo phase. Vessels were preincubated with insulin [1 nM (Fig. 5AGo) or 100 pM (Fig. 5BGo)]. Insulin-mediated attenuation of NE-induced vasoconstriction was demonstrated at both concentrations (for 1 nM insulin (n = 12): pD2 control, 6.8 ± 0.12; pD2 insulin, 6.6 ± 0.4 (P > 0.05); maximum contraction, 92 ± 2.4% (P < 0.01 vs. control); AUC control, 447 ± 28.3; insulin, 389 ± 31.1 (P < 0.05); for 100 pM insulin (n = 12): pD2 control, 6.8 ± 0.12; pD2 insulin, 6.6 ± 0.11 (P < 0.01); maximum contraction, 90 ± 2.2% (P < 0.01 vs. control); AUC control, 441 ± 21.0; AUC insulin, 369 ± 26.4 (P < 0.01)].



View larger version (24K):
[in this window]
[in a new window]
  		FIG. 5. The effect of insulin on NE- induced vasoconstriction. A, Placebo phase, 1 nM insulin (n = 12); B, placebo phase, 100 pM insulin (n =12); C, dexamethasone phase, 1 nM insulin (n = 13); D, dexamethasone phase, 100 pM insulin (n = 12). Insulin preincubation resulted in significant attenuation of NE-induced vasoconstriction during both phases and at both insulin concentrations. See text. Error bars represent the SE.

 
Dexamethasone phase. Figure 5Go, C and D, demonstrates the effect of preincubation of vessels with insulin on NE-mediated vasoconstriction during the dexamethasone treatment phase. Vessels were preincubated with insulin [1 nM (Fig. 5CGo) or 100 pM (Fig. 5DGo)]. Insulin-mediated vasodilation was demonstrated at both concentrations by a reduction in pD2, maximum contraction, and AUC [for 1 nM insulin (n = 13): pD2 control, 7.1 ± 0.13; pD2 insulin, 6.7 ± 0.2 (P < 0.05); maximum contraction, 95 ± 2.4% (P < 0.05 vs. control); AUC control, 481 ± 18.3; insulin, 402 ± 19.6 (P < 0.05); for 100 pM insulin (n = 12): pD2 control, 6.9 ± 0.08; pD2 insulin, 6.7 ± 0.11 (P < 0.05); maximum contraction, 93 ± 2.3% (P < 0.01 vs. control); AUC control, 475 ± 20.8; insulin, 430 ± 16.8 (P < 0.05)].

Comparison of insulin action during dexamethasone and placebo phases

To compare insulin-mediated relaxation of NE-induced vasoconstriction during placebo and dexamethasone phases, data were analyzed as paired [i.e. subjects with completed myography studies from both phases: 1 nM insulin (n = 11) and 100 pM insulin (n = 10)] or unpaired (i.e. including data from subjects with only one successful biopsy; n = 16). pD2, maximum contraction, and the difference in AUC of NE-induced contraction with or without insulin were compared between phases. On analysis of paired data, there was no significant difference in any of these variables at 1 nM insulin [pD2: placebo, 6.6 ± 0.14; dexamethasone, 6.7 ± 0.09 (P > 0.05); maximal contraction: placebo, 92 ± 2.3%; dexamethasone, 94 ± 1.5% (P > 0.05); AUC: placebo, 404 ± 29.7; dexamethasone, 402 ± 19.6 (P > 0.05)], although at 100 pM insulin there was a borderline significant reduction in maximum contraction (placebo, 91 ± 2.7%; dexamethasone, 95 ± 1.7%; P = 0.05), but not pD2 (placebo, 6.6 ± 0.10; dexamethasone, 6.7 ± 0.12; P > 0.05) or AUC (placebo, 380 ± 29.8; dexamethasone, 430 ± 16.8; P > 0.05). To exclude a confounding effect of the NE response between phases, the attenuation of NE-induced contraction by insulin was analyzed after correction for the NE curve. No difference in insulin action was observed between phases [AUC for 1 nM insulin (n = 11): placebo, 59 ± 20.2; dexamethasone, 79 ± 20.6 (P > 0.05); AUC for 100 pM insulin (n = 10): placebo, 68 ± 13; dexamethasone, 50 ± 16.9 (P > 0.05)]. For unpaired data, there was no difference in any parameter at either insulin concentration.

Circulating markers of endothelial function

Plasma levels of circulating markers of endothelial function were compared between phases for the 19 subjects who completed the study. No differences in tissue plasminogen activator, von Willebrand factor, or D-dimer were observed (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Six days of dexamethasone treatment was associated with a 30% reduction in insulin-stimulated glucose disposal, as measured by the euglycemic hyperinsulinemic clamp. Despite this, there was no associated reduction in insulin- mediated attenuation of norepinephrine-induced vasoconstriction in small resistance arteries, measured using wire myography. Thus, metabolic and vascular insulin responses in this model do not appear to be coupled.

Previous euglycemic hyperinsulinemic clamp studies have shown a reduction in insulin sensitivity in association with glucocorticoid treatment in healthy volunteers (21, 22). Despite good compliance with study medication, as evidenced by serum cortisol reduction and suppression of urinary free cortisol, the 30% reduction observed in the present study is more modest than that reported by others. It may be of relevance that the volunteers were relatively young and insulin sensitive.

In addition to its metabolic action, insulin is an endothelium-dependent vasodilator, acting at least in part by activation of the endothelial isoform of nitric oxide synthase (7). We have previously demonstrated a relationship between insulin resistance and endothelial function by showing a correlation between metabolic insulin sensitivity and basal nitric oxide production (12) (measured by the reduction in forearm blood flow following intraarterial infusion of L-N-monomethylarginine) and subsequently extended this observation in patients with hypertension and type 2 diabetes, demonstrating that subjects with the lowest metabolic response to insulin also had the lowest vascular insulin responses (8, 11). Consistent with these findings are observations in obese (23), hypertensive (24), and diabetic (23) cohorts that have shown impaired acetylcholine-mediated vasodilation.

Despite this, the molecular mechanisms that link endothelial dysfunction and insulin resistance remain uncertain. However, it is clear that insulin effects in vascular tissues are mediated by a signaling pathway similar to that subserving insulin-mediated glucose uptake in fat and muscle, central to which is activation of the lipid kinase phosphatidylinositol 3'-kinase enzyme complex (25) (26). It is possible, therefore, that the same defect(s) in the insulin signaling pathway may occur in both vascular tissue and metabolic cells, such as skeletal muscle and fat, leading to parallel defects in both tissues (27).

In the current study, despite the 30% reduction in metabolic insulin sensitivity associated with dexamethasone, no impairment of insulin’s vascular action was observed, implying that the effect of dexamethasone on metabolic function is distinct from any action on a common insulin-signaling pathway. These findings contrast with those of Tappy et al. and Scherrer et al. (15, 28) in which 48 h of dexamethasone (2 mg daily) prevented insulin-mediated vasodilation of the calf vascular bed during a clamp. However, neither of these studies was blinded or placebo-controlled. These experiments were designed to test the hypothesis that insulin-mediated sympathetic activation was the vasodilating stimulus blocked by dexamethasone; an alternative explanation for the conflicting findings may be that dexamethasone blocks central stimuli to vasodilation that are not relevant in an ex vivo system.

An effect of dexamethasone on vascular responsiveness to norepinephrine was also considered as a confounding factor that may have masked differences in insulin sensitivity. Enhanced constriction to norepinephrine has been demonstrated in aortas from 11ß-hydroxysteroid dehydrogenase knockout mice, suggested as being secondary to reduced basal nitric oxide generation by the endothelium (29). Despite the lack of such an effect in the present study, we excluded this potentially confounding variable by examining insulin action between phases (measured as AUC), corrected for the baseline NE effect. It must also be acknowledged that despite the clear vasodilatory effect of insulin in this vessel system, its effect was modest, and subtle changes in the vascular insulin response may not have been detected.

The mechanisms underlying glucocorticoid-induced insulin resistance remain unclear. Candidate hepatic mechanisms include an increase in phosphoenolpyruvate carboxykinase activity, the rate-limiting step in hepatic gluconeogenesis (21, 30), a reduction in pancreatic ß-cell insulin secretion (31), and an increase in {alpha}-cell glucagon secretion (32). Reduced glucose disposal in peripheral tissues may be secondary to an increase in circulating free fatty acids or a more direct cellular effect on insulin binding at the plasma membrane (33, 34), the insulin-signaling cascade (35, 36), or abnormalities of glucose transporter 4, either in its amount (14) or its distribution (13, 37, 38) within the cell.

Recent data also suggest that dysregulation of cortisol metabolism, such that there is increased availability of glucocorticoids in tissues such as muscle and fat, may modify insulin action. This hypothesis is supported by genetic studies of mice with altered expression of the 11ß-hydroxysteroid dehydrogenase type 1 enzyme (39, 40). That this may also be relevant in man is supported by the observation that there is increased expression of glucocorticoid receptors in males with insulin resistance and hypertension (41).

In summary, using this model, glucocorticoid exposure for 6 d was associated with a reduction in insulin-stimulated glucose disposal, with no associated effect on insulin’s vascular action, raising intriguing questions about the physiological coupling of these responses and the contribution of glucocorticoid metabolism to clinical phenotypes characterized by insulin resistance.


   Footnotes
 
This work was supported by a grant from the British Heart Foundation and a grant from the Wellcome Trust (to C.P.).

Abbreviations: AUC, Area under the curve; CRC, concentration- response curve; NE, norepinephrine; PSS, physiological salt solution.

Received October 16, 2002.

Accepted August 26, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ 1996 Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952–957[Abstract/Free Full Text]
  2. Fontbonne A, Charles MA, Thibult N, Richard JL, Claude JR, Warnet JM, Rosselin GE, Eschwege E 1991 Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up. Diabetologia 34:356–361[CrossRef][Medline]
  3. Pyorala K, Savolainen E, Kaukola S, Haapakoski J 1985 Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 9 1/2-year follow-up of the Helsinki Policemen Study population. Acta Med Scand 701(Suppl):38–52
  4. DeFronzo RA 1992 Insulin resistance, hyperinsulinemia, and coronary artery disease: a complex metabolic web. J Cardiovasc Pharmacol 20(Suppl 11):S1–S16
  5. Reaven GM 1988 Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607[Abstract]
  6. Chen YL, Messina EJ 1996 Dilation of isolated skeletal muscle arterioles by insulin is endothelium dependent and nitric oxide mediated. Am J Physiol 270:H2120–H2124
  7. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD 1994 Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 94:1172–1179
  8. Cleland SJ, Petrie JR, Small M, Elliott HL, Connell JM 2000 Insulin action is associated with endothelial function in hypertension and type 2 diabetes. Hypertension 35:507–511[Abstract/Free Full Text]
  9. Kelly CJ, Speirs A, Gould GW, Petrie JR, Lyall H, Connell JM 2002 Altered vascular function in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 87:742–746[Abstract/Free Full Text]
  10. Laakso M, Edelman SV, Brechtel G, Baron AD 1990 Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 85:1844–1852
  11. Cleland SJ, Petrie JR, Ueda S, Elliott HL, Connell JM 1999 Insulin-mediated vasodilation and glucose uptake are functionally linked in humans. Hypertension 33:554–558[Abstract/Free Full Text]
  12. Petrie JR, Ueda S, Webb DJ, Elliott HL, Connell JM 1996 Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease. Circulation 93:1331–1333[Abstract/Free Full Text]
  13. Carter-Su C, Okamoto K 1987 Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes. Am J Physiol 252:E441–E453
  14. Coderre L, Vallega GA, Pilch PF, Chipkin SR 1996 In vivo effects of dexamethasone and sucrose on glucose transport (GLUT-4) protein tissue distribution. Am J Physiol 271:E643–E648
  15. Tappy L, Randin D, Vollenweider P, Vollenweider L, Paquot N, Scherrer U, Schneiter P, Nicod P, Jequier E 1994 Mechanisms of dexamethasone-induced insulin resistance in healthy humans. J Clin Endocrinol Metab 79:1063–1069[Abstract]
  16. Walker BR 1996 Abnormal glucocorticoid activity in subjects with risk factors for cardiovascular disease. Endocr Res 22:701–708[Medline]
  17. Mulvany M, Halpern W 1976 Mechanical properties of vascular smooth muscle cells in situ. Nature 260:617–619[CrossRef][Medline]
  18. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223
  19. Padmanabhan N, Jardine AG, McGrath JC, Connell JM 1999 Angiotensin-converting enzyme-independent contraction to angiotensin I in human resistance arteries. Circulation 99:2914–2920[Abstract/Free Full Text]
  20. McNally PG, Lawrence IG, Watt PA, Hillier C, Burden AC, Thurston H 1995 The effect of insulin on the vascular reactivity of isolated resistance arteries taken from healthy volunteers. Diabetologia 38:467–473[Medline]
  21. Rooney DP, Neely RD, Cullen C, Ennis CN, Sheridan B, Atkinson AB, Trimble ER, Bell PM 1993 The effect of cortisol on glucose/glucose-6-phosphate cycle activity and insulin action. J Clin Endocrinol Metab 77:1180–1183[Abstract]
  22. Paquot N, Schneiter P, Jequier E, Tappy L 1995 Effects of glucocorticoids and sympathomimetic agents on basal and insulin-stimulated glucose metabolism. Clin Physiol 15:231–240[Medline]
  23. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD 1996 Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 97:2601–2610[Medline]
  24. Panza JA, Quyyumi AA, Brush JEJ, Epstein SE 1990 Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323:22–27[Abstract]
  25. Zeng G, Quon MJ 1996 Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 98:894–898[Medline]
  26. Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T, Feener EP, Herbert TP, Rhodes CJ, King GL 2000 Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 101:676–681[Abstract/Free Full Text]
  27. Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL 1999 Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 104:447–457[Medline]
  28. Scherrer U, Vollenweider P, Randin D, Jequier E, Nicod P, Tappy L 1993 Suppression of insulin-induced sympathetic activation and vasodilation by dexamethasone in humans. Circulation 88:388–394[Abstract/Free Full Text]
  29. Hadoke PW, Christy C, Kotelevtsev YV, Williams BC, Kenyon CJ, Seckl JR, Mullins JJ, Walker BR 2001 Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11ß-hydroxysteroid dehydrogenase. Circulation 104:2832–2837[Abstract/Free Full Text]
  30. Rizza RA, Mandarino LJ, Gerich JE 1982 Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. J Clin Endocrinol Metab 54:131–138[Abstract/Free Full Text]
  31. Lambillotte C, Gilon P, Henquin JC 1997 Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets. J Clin Invest 99:414–423[Medline]
  32. Dinneen S, Alzaid A, Miles J, Rizza R 1993 Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J Clin Invest 92:2283–2290
  33. Montiel F, Ortiz-Caro J, Villa A, Pascual A, Aranda A 1987 Glucocorticoids regulate insulin binding in a rat glial cell line. Endocrinology 121:258–265[Abstract/Free Full Text]
  34. Yasuda K, Hines E, Kitabchi AE 1982 Hypercortisolism and insulin resistance: comparative effects of prednisone, hydrocortisone, and dexamethasone on insulin binding of human erythrocytes. J Clin Endocrinol Metab 55:910–915[Abstract/Free Full Text]
  35. Giorgino F, Almahfouz A, Goodyear LJ, Smith RJ 1993 Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. J Clin Invest 91:2020–2030
  36. Saad MJ, Folli F, Kahn JA, Kahn CR 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
  37. Dimitriadis G, Leighton B, Parry-Billings M, Sasson S, Young M, Krause U, Bevan S, Piva T, Wegener G, Newsholme EA 1997 Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle. Biochem J 321:707–712
  38. Horner HC, Munck A, Lienhard GE 1987 Dexamethasone causes translocation of glucose transporters from the plasma membrane to an intracellular site in human fibroblasts. J Biol Chem 262:17696–17702[Abstract/Free Full Text]
  39. Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS 2001 A transgenic model of visceral obesity and the metabolic syndrome. Science 294:2166–2170[Abstract/Free Full Text]
  40. Morton NM, Holmes MC, Fievet C, Staels B, Tailleux A, Mullins JJ, Seckl JR 2001 Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11ß-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem 276:41293–41300[Abstract/Free Full Text]
  41. Reynolds RM, Chapman KE, Seckl JR, Walker BR, McKeigue PM, Lithell HO 2002 Skeletal muscle glucocorticoid receptor density and insulin resistance. JAMA 287:2505–2506[Free Full Text]



This article has been cited by other articles:


Home page
 Diabetes CareHome page
P. L. Brubaker
Adventure Travel and Type 1 Diabetes: The complicating effects of high altitude
Diabetes Care, October 1, 2005; 28(10): 2563 - 2572.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Perry, C. G.
Right arrow Articles by Connell, J. M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Perry, C. G.
Right arrow Articles by Connell, J. M. C.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*DEXAMETHASONE
Medline Plus Health Information
*Steroids

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals