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Elevated Plasma Cortisol in Glucose-Intolerant Men: Differences in Responses to Glucose and Habituation to Venepuncture

Medical Research Council Environmental Epidemiology Unit, University of Southampton (R.M.R., H.E.S., C.B.W., D.I.W.P.), SO16 6YD Southampton, United Kingdom; Department of Medical Sciences, University of Edinburgh (R.M.R., B.R.W.), Western General Hospital, Edinburgh, Scotland EH4 2XU, United Kingdom; Regional Endocrine Unit, Southampton General Hospital (P.J.W.), SO16 6YD Southampton, United Kingdom

Address all correspondence and requests for reprints to: Dr. R. M. Reynolds, MA MRCP, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom. E-mail: r.reynolds{at}ed.ac.uk

	Abstract

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Recent evidence suggests that variations in cortisol activity within the physiological range contribute to associations between multiple cardiovascular risk factors. Plasma cortisol measurements during a glucose tolerance test differ in men with hypertension, insulin resistance, and glucose intolerance, but it is unclear whether this reflects altered responses of cortisol to glucose, altered circadian rhythm, or altered habituation to multiple sampling. We performed a single-blind randomized cross-over study comparing 75 g oral glucose with placebo in 39 fasted men (22 glucose intolerant and 17 controls) aged 68–77 yr. In all subjects, plasma cortisol fell during the glucose tolerance test. Subjects with glucose intolerance had significantly higher plasma cortisol following placebo (P = 0.001), suggesting an altered circadian rhythm. Treatment with an oral glucose load blunted the circadian fall in plasma cortisol (P = 0.002), but this response was no different in controls or glucose intolerant subjects. In addition, 0900 h plasma cortisol was higher in the first study phase in controls (P = 0.01) but not in glucose-intolerant subjects (P = 0.18), who showed a lack of habituation to repeated plasma measurements. These data support the hypothesis that alterations in central regulation of the hypothalamic-pituitary-adrenal axis may be important in glucose intolerance.

	Introduction

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PATIENTS with high circulating cortisol due to Cushing’s syndrome develop glucose intolerance, insulin resistance, and other risk factors for cardiovascular disease including hypertension and dyslipidemia. There is now increasing evidence that physiological variations in cortisol action could also contribute to development of these risk factors. Plasma cortisol and the cortisol response to the administration of corticotrophin are increased in men and women with type 2 diabetes mellitus (1, 2). Furthermore, differences in activity of the hypothalamic-pituitary-adrenal (HPA) axis have been demonstrated in subjects with cardiovascular risk factors. These include elevated morning plasma cortisol (3, 4, 5, 6, 7), increased excretion of cortisol metabolites (7, 8), abnormalities of diurnal cortisol secretion (9), and impaired peripheral inactivation of cortisol (7).

The mechanisms leading to variations in plasma cortisol action in subjects with glucose intolerance are unknown. Differences in glucose and/or insulin concentrations may be important: for example, insulin may modulate adrenal steroidogenesis by inhibiting 17,20-lyase, thereby favoring cortisol synthesis in preference to dehydroepiandrosterone and androstenedione (10). Insulin may also affect cortisol metabolism by decreasing the activity of 11ß-hydroxysteroid dehydrogenase type 1, which acts primarily as a reductase mediating conversion of inactive cortisone to active cortisol (11). Such effects may be important determinants of acute changes in plasma cortisol, for example during a glucose tolerance test. It is known that plasma cortisol levels fall during a glucose tolerance test (12, 13) and that this effect may differ in subjects with cardiovascular risk factors (14, 15). However, it is not known whether this reflects the circadian fall in circulating plasma cortisol and whether ingestion of glucose affects the response. We therefore performed a placebo-controlled study of the effect of oral glucose on circulating plasma cortisol. To further explore the associations between cortisol and glucose tolerance, we studied both subjects with glucose intolerance and normoglycaemic controls.

	Subjects and Methods

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Participants

We studied 40 men, aged 68 to 77 yr, selected from a well-characterized cohort from Hertfordshire who have participated in previous investigations of the relationships between early life events and subsequent Type 2 diabetes (16). The subjects were selected by their previous glucose tolerance data from 1991 with the aim of studying equal numbers with glucose intolerance and normal controls. None had a history of endocrine disease or had received systemic or topical glucocorticoid treatment within the previous 6 months. Ethical approval was obtained from East and North Hertfordshire Local Research Ethics Committee and written informed consent was obtained.

Clinical protocol

Following an overnight fast, subjects attended a local clinic at 0830 h for oral glucose tolerance tests. A 21-g butterfly cannula was inserted in an antecubital vein and after 30-min rest, a baseline blood sample was obtained. Subjects then drank either 75 g oral glucose (as 389 ml Traditional Lucozade Sparkling Glucose Drink) or placebo (identical in appearance and taste to Lucozade but containing no glucose, supplied by SmithKline Beecham). They returned a week later for a repeat test with the alternative solution in a single-blind cross-over design. Twenty-nine subjects (17 glucose intolerant, 12 controls) received glucose in the first phase, whereas 10 subjects (5 glucose intolerant, 5 controls) received placebo first. Venous blood was sampled from the cannula at 30, 60, 90, and 120 min following the glucose or placebo load. Placebo and glucose phases were separated by at least 1 week.

Laboratory methods

Blood samples were centrifuged, processed immediately and stored at -80 C for subsequent hormone analysis. RIAs were used to measure plasma cortisol using Guildhay antisera (17) and corticosteroid-binding globulin (CBG) (Medgenics Diagnostics, Fleurus, Belgium). Plasma glucose was measured by the hexokinase method.

Statistical methods

As the distributions of cortisol measurements were skewed, log_e transformed variables were used in all analyses. Independent two-sample t tests were used to compare cortisol concentrations for control compared with glucose intolerant subjects. ANOVA for repeated measures was used to analyze the plasma cortisol measurements during the glucose tolerance test.

	Results

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One subject completed only one phase of the study and was therefore excluded from analysis. Using plasma glucose measurements following the 75 g oral glucose load, we defined 22 subjects as glucose intolerant [either impaired glucose tolerance (2 h plasma glucose 7.8 to 11.0 mmol/L) or Type 2 diabetes (2 h plasma glucose 11.1 mmol/L)], and 17 subjects as normal controls.

Differences in plasma cortisol between controls and glucose intolerant subjects without glucose

In all subjects, plasma cortisol concentrations declined over the 120 min of the test following placebo. Glucose intolerant subjects had significantly higher cortisol concentrations following placebo than controls (P = 0.001) (Fig. 1). This difference was most marked at baseline and during the first 90 min of the test but was no longer present at 120 min. The differences in cortisol between glucose intolerant subjects and controls were not accounted for by variations in CBG (data not shown).

View larger version (12K): [in this window] [in a new window]   Figure 1. Differences in plasma cortisol between controls and glucose intolerant subjects following placebo. P = 0.001 from ANOVA for repeated measures for difference in plasma cortisol following placebo between glucose intolerant (–•–) and control (––) subjects.

Figure 2 shows that treatment with an oral glucose load blunted the circadian fall in plasma cortisol in both controls and glucose intolerant subjects (P = 0.002). There was no significant difference in the effect of the glucose load in controls compared with those with glucose intolerance (controls P = 0.02, glucose intolerant P = 0.04, interaction P = 0.50).

View larger version (11K): [in this window] [in a new window]   Figure 2. Effect of glucose on plasma cortisol. –•– plasma cortisol following placebo. –– plasma cortisol following glucose. P = 0.002 from ANOVA for repeated measures for effect of glucose in raising plasma cortisol in all subjects. No significant difference in effect of glucose between controls and glucose intolerant subjects (P = 0.02 for controls, P = 0.04 for glucose intolerant subjects).

0900 h plasma cortisol concentrations were significantly higher in the first phase of the study than in the second phase in controls (P = 0.01) (Fig. 3). However, in glucose intolerant subjects, 0900 h plasma cortisol concentrations in the two-study phases were not different (P = 0.18), as this measurement did not fall in the second study phase.

View larger version (15K): [in this window] [in a new window]   Figure 3. Effect of order on 0900 h plasma cortisol effect of order of study phase (first phase, black columns, second phase, white columns) on 0900 h plasma cortisol in glucose intolerant and control subjects. P = 0.01 for effect of order in control subjects; no significant order effect in glucose intolerant subjects.

Both plasma glucose and insulin concentrations were higher after treatment with glucose than placebo (P < 0.001) and were significantly higher in glucose intolerant subjects than controls. In contrast to the plasma cortisol concentrations, plasma glucose and insulin concentrations were no different in the two study phases in either glucose intolerant subjects or controls.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have shown that treatment with an oral glucose load blunts the normal circadian fall in plasma cortisol in subjects with glucose intolerance and in normoglycaemic controls. However, subjects with glucose intolerance had higher cortisol concentrations following placebo, suggesting that their normal diurnal fall in plasma cortisol differed from controls. We also found that baseline plasma cortisol concentrations were higher during the first phase of the study in control subjects suggesting a stress response associated with the novelty of first clinic attendance. In addition, subjects with glucose intolerance had high plasma cortisol concentrations at the second clinic attendance suggesting a lack of habituation to repeated measurement of plasma cortisol.

Our findings accord with early reports showing that plasma cortisol concentrations fall during an oral glucose tolerance test (12, 13). It was not known whether this reflects the fall in circadian fall in plasma cortisol or whether glucose ingestion affects the response. We performed our studies in the morning when any alterations in circadian rhythm should be most clearly demonstrated. Indeed, we found higher plasma cortisol in subjects with glucose intolerance than controls during the first 90 min of the placebo phase of the study. Altered diurnal rhythms of salivary cortisol in subjects with glucose intolerance have been reported (9), and our finding is consistent with the previously reported associations between 0900 h plasma cortisol and glucose intolerance (5, 6). However, the difference between subjects with glucose intolerance and controls was no longer apparent at 120 min. This finding could explain why associations between cortisol measurements and glucose tolerance are still evident at 120 min following glucose in some reports (14) but to a lesser extent than the fasting measurements in others (15). The current study, therefore, implies that where two measurements of plasma cortisol are separated by 2 h, during which cortisol will fall due to diurnal variation, the timing of measurements is critical.

Despite the differences in circadian fall of plasma cortisol, the effect of glucose ingestion was to raise plasma cortisol in both normal and glucose intolerant subjects. Plasma and salivary cortisol concentrations rise following a meal (9), particularly if the meal is of high protein content (18), as protein ingestion stimulates pituitary ACTH secretion (19). Although it has previously been suggested that carbohydrate ingestion has little effect on the hypothalamic-pituitary-adrenal (HPA) axis (20), we have now demonstrated that an oral glucose load raises plasma cortisol. It remains unknown whether this is a consequence of the glucose load itself, or whether the associated insulin release affects cortisol metabolism (10, 11). Insulin may also act centrally on the HPA axis regulating drive, although results of studies to date are conflicting, either showing a decreased cortisol response to CRH following insulin infusion (21), or increased adrenocorticotrophic hormone (ACTH) secretion following supraphysiological hyperinsulinaemia (22). Likewise, the changes in cortisol induced by the glucose load could influence subsequent glucose and insulin metabolism. Manipulation of cortisol levels within the physiological range alters insulin sensitivity (23). And although subject to the limitations of measurement of hepatic glucose output in man, cortisol has been shown to impair insulin-dependent glucose uptake in the periphery and enhance gluconeogenesis in the liver (24, 25). However, as the effect of treatment with the glucose load did not differ between glucose intolerant subjects and controls, it would appear less likely that the hyperglycaemia or changes in insulin concentrations associated with glucose intolerance influenced the fall in cortisol concentrations during the test.

One alternative hypothesis to explain the elevated plasma cortisol during the glucose tolerance test is a response to stress. We attempted to reduce any effect of stress by conducting the study in familiar surroundings, with staff previously known to the subjects. Yet we have found that fasting plasma cortisol measured at the first phase attendance, and so arguably the most stressful visit, was significantly higher than that at the second phase in control subjects. Elevated plasma and salivary cortisol concentrations are observed in situations of increased perceived stress (9), and the stress of venepuncture is known to raise plasma cortisol (26). The effect of psychosocial stress on raising cortisol has also been reported to be greater after a glucose load (27).

Most interestingly, we found that glucose intolerant subjects also had high baseline plasma cortisol concentrations in the second phase of the study, indicating a lack of habituation to repeated stress. A similar lack of habituation of blood pressure and heart rate responses to repeated restraint stress is seen in spontaneously hypertensive rats compared with normal controls (28). Subjects with glucose intolerance have evidence of increased activation of the HPA axis (29), and so elevated plasma cortisol from stress of venous sampling would be consistent with enhanced drive to CRH, ACTH, and cortisol secretion from higher centers in these subjects. Lack of habituation to stress and increased activation of the HPA axis in subjects with glucose intolerance would support the hypothesis that chronic stress in man leads to development of cardiovascular risk factors. Such variations in HPA axis activity may also contribute to the observed relationships between psychosocial stress and subsequent cardiovascular disease (30).

In conclusion, this study supports the hypothesis that alterations in central regulation of the HPA axis may be an important mechanism underlying the development of glucose intolerance and subsequent cardiovascular disease.

	Acknowledgments

 
The placebo Lucozade was a gift from SmithKline Beecham. We are grateful to C. Glenn for technical assistance and to the MRC research nurses at Hertford County Hospital.

	Footnotes

 
¹ Wellcome Trust Clinical Training Fellow.

² British Heart Foundation Senior Research Fellow.

Received May 16, 2000.

Accepted November 10, 2000.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reynolds, R. M. Articles by Phillips, D. I. W. Search for Related Content PubMed PubMed Citation Articles by Reynolds, R. M. Articles by Phillips, D. I. W. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB HYDROCORTISONE