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© 2008 American Society for Nutrition J. Nutr. 138:426S-430S, February 2008

Supplement: Second International Acid-Base Symposium, Nutrition–Health–Disease

Renal Net Acid Excretion and Plasma Leptin Are Associated with Potentially Bioactive Free Glucocorticoids in Healthy Lean Women1–3,

Thomas Remer4,*, Triantafillia Dimitriou4 and Christiane Maser-Gluth5

4 Research Institute of Child Nutrition, 44225 Dortmund, Germany and 5 University of Heidelberg, Department of Pharmacology, 69120 Heidelberg, Germany

* To whom correspondence should be addressed. E-mail: remer{at}fke-do.de.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
Primarily experimental evidence suggests that endogenous glucocorticoids may be suppressed by adipocyte-derived leptin and elevated by dietary acidity. Therefore, we examined whether these factors may also be relevant in healthy adults on unrestricted diets. For this we used a new methodological approach in which potentially bioactive free glucocorticoids were determined as the sum of urinary free cortisol and urinary free cortisone and that also takes into account total adrenal glucocorticoid secretion assessed by the sum of the 3 major urinary glucocorticoid metabolites tetrahydrocortisone, tetrahydrocortisol, and 5{alpha}-tetrahydrocortisol. Body composition, plasma cortisol, plasma leptin, and 24-h urinary excretion rates of net acid and glucocorticoid metabolites were examined cross-sectionally in 30 healthy adults (15 women; 22–44 y old; BMI 20–25 kg/m2). Plasma leptin, percentage body fat, and body surface area-corrected adrenal glucocorticoid secretion showed the usual sex dimorphism (male vs. female, P < 0.05 in each case: 2.8 ± 1.6 µg/L vs. 7.6 ± 4.9 µg/L, 16.8 ± 4.2% vs. 26.9 ± 4.9%, and 5.1 ± 1.6 mg · m–2 · d–1 vs. 4.0 ± 1.3 mg · m–2 · d–1, respectively), whereas net acid excretion, plasma cortisol, and potentially bioactive free glucocorticoids did not differ between the sexes. Potentially bioactive free glucocorticoids correlated positively with body fat and leptin in men (P < 0.05) but not in women. After adjustment for total adrenal glucocorticoid secretion, net acid excretion was a positive and leptin a negative predictor (P < 0.05) of potentially bioactive free glucocorticoids in women only (total explained variability R2 = 0.71). Our findings indicate that, at least in women, variability of potentially bioactive free glucocorticoids is not only explained by adrenal glucocorticoid secretion but is also metabolically affected by circulating leptin and diet-dependent net acid excretion.


   Introduction
TOP
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
Glucocorticoids play an important role in the ability of the kidney to excrete acid loads (1). In line with this are the associations of metabolic acidosis and hyperglucocorticoidism in various illnesses (1,2). In both humans and animals, experimentally induced metabolic acidosis has been shown to increase circulating glucocorticoids (1,3). As explained in detail by Hamm et al. (1), this increase in glucocorticoids with acidosis is necessary to ensure the physiological responses that allow a more efficient renal elimination of hydrogen ions: increased ammonium excretion and increased proximal tubule sodium-hydrogen (Na+/H+) exchange.

Some experimental diet studies in healthy subjects suggest that even small changes in acid loads can impact on glucocorticoids. Maurer et al. have reported both reduced plasma cortisol and reduced 24-h excretion rates of urinary free cortisol in normal volunteers after neutralization of a Western-type diet by administration of alkalizing sodium and potassium bicarbonate (4). Corresponding decreases in urinary free cortisol were seen in a short-term diet experiment (5) after healthy adults switched from a high-protein, high-acid-load diet to a lactovegetarian diet with a low renal net acid excretion (6).

Urinary free cortisol excretion in 24-h urine samples is a frequently measured parameter to assess functional glucocorticoid activity. It serves as an integrated measure of blood free cortisol concentrations during the entire day (7). However, there is now a growing body of clinical and physiological evidence that variations in activity of 11β-hydroxysteroid dehydrogenase type2 (11β-HSD2),6 a highly expressed enzyme in the human kidney that inactivates cortisol to cortisone, can considerably confound renal free cortisol output. Accordingly, the finding of normal excretion rates of urinary free cortisol does not allow one to preclude the presence of elevated bioactive glucocorticoid levels or a stress condition. If appropriate measurement methods are used, the urinary excretion rates of free cortisone are twice that of free cortisol in healthy subjects (8,9), again demonstrating the physiologically high renal 11β-HSD2 activity. Because cortisone can be readily activated to cortisol in almost all extrarenal tissues, it is a potentially bioactive glucocorticoid, and hence, a physiologically plausible assessment of functional glucocorticoid activity should embrace urinary free cortisone along with urinary free cortisol (9–12).

Therefore, in this study, we aimed to examine whether the sum of urinary free cortisol and urinary free cortisone, referred to as potentially bioactive free glucocorticoids (12,13), may show an association with the net endogenous acid production even in healthy subjects on unrestricted diets.

Because recent endocrine-metabolic findings suggested that only ~50% of the variation of plasma free (potentially bioactive) cortisol can be explained by cortisol production (14), it appears consequential that, in addition to net endogenous acid production, other relevant metabolic (endocrine, nutritional) influences on potentially bioactive glucocorticoids exist apart from their primary source, i.e., adrenal gland glucocorticoid secretion. We thus also included protein intake, assessed via urinary 24-h total nitrogen measurement, and circulating levels of the fat tissue hormone leptin, both known to interfere with the glucocorticoid status, in our examination.


   Subjects and Methods
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 Discussion
 LITERATURE CITED
 
    Subjects and anthropometry. Thirty lean healthy adults (15 men, 15 women; age range 22–44 y; BMI 20–25 kg/m2) collected a 24-h urine sample and provided a venous blood sample at the morning after completion of urine collection. Body weight was measured to the nearest 0.1 kg using an electronic scale, and body height was determined to the nearest 0.1 cm using a digital stadiometer. From these measurements, BMI and body surface area (BSA) were calculated, according to Du Bois and Du Bois's formula (15). Skinfold thicknesses were measured on the right side of the body at the biceps, triceps, and subscapular and suprailiac sites to the nearest 0.1 mm with a Holtain caliper. Percentage body fat (%BF) was calculated using the equations of Durnin and Womersley (16). The study was approved by the institutional review board of the Research Institute of Child Nutrition.

    Analyte measurements. Urinary free cortisol, urinary free cortisone, tetrahydrocortisone (THE), tetrahydrocortisol (THF), 5{alpha}-tetrahydrocortisol (5{alpha}-THF), and plasma cortisol were measured by specific radioimmunoassays using tritiated steroids (Amersham Pharmacia Biotech) and specific antibodies raised and characterized in our laboratory, as described elsewhere (17). Before radioimmunoassay, urinary free cortisol and cortisone and plasma cortisol were extracted from the samples with dichloromethane and chromatographically purified using Celite columns (Celite columns 545 AW; Sigma-Aldrich Chemie). THE, THF, and 5{alpha}-THF were quantified after treatment with β-glucuronidase (Roche Diagnostics) in a final dilution of 1:1200 (vol:vol). Intra- and interassay coefficients of variation were <10 and <13%, respectively. Plasma leptin was quantified by a monoclonal double-antibody-based enzyme immunoassay (Quantikine, Human Leptin Immunoasssay, R&D Systems) after a 50-fold dilution of each plasma sample with assay-specific calibrator diluent. Intra- and interassay coefficients of variation for leptin were <5.5%.

Titratable acidity, ammonium, and bicarbonate were measured according to the method of Lüthy et al. (18). Based on these analytes, net acid excretion was determined conventionally with titratable acidity plus ammonium minus bicarbonate (6). Creatinine was quantified according to the kinetic Jaffé procedure using the Beckman-2 creatinine analyzer (Beckman Instruments), and total urinary nitrogen by the Kjeldahl technique (Buechi 430 Digestor and Buechi Distillation Unit B-324).

    Calculations and assessments. To assess the adrenal gland's total daily glucocorticoid secretion, the 24-h excretion rates of the analyzed major urinary glucocorticoid metabolites THE, THF, and 5{alpha}-THF were summed (GC3) (19,20). This sum comprises ~50% of the overall amount of glucocorticoids secreted per day (19) and is therefore a reasonable estimate of total cortisol and cortisone secretion but not an appropriate estimate of bioavailable or potentially bioactive glucocorticoids (12). Potentially bioactive free glucocorticoids were assessed by the sum of urinary free cortisol and urinary free cortisone (11–13). A global index for the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyzes the reduction (reactivation) of cortisone to cortisol in many tissues (including liver, subcutaneous and visceral fat), was also determined. Global activity of 11β-HSD1 was conventionally assessed by the ratio 5{alpha}-THF plus THF to THE (12,21), and the net balance between 5{alpha}- and 5β-reductase by the ratio {alpha}-THF to THF (22,23). In case of normal THF values, the ratio {alpha}-THF/THF reflects 5{alpha}-reductase activity. 5{alpha}-Reduction flattens the steroid molecule and irreversibly inactivates glucocorticoids. As a consequence cortisol clearance increases, bioavailable cortisol decreases, and adrenal glucocorticoid secretion or adrenocortical activity (e.g., GC3) responds with a rise to bring bioavailable cortisol back to the regular range.

There is a close functional-anatomic correlation between the adrenal gland's volume and BSA (24,25). Urinary glucocorticoid metabolite excretion rates have to be normalized to BSA to account for body size differences if, for example, a sex difference is examined (26). A corresponding BSA correction also applies for renal net acid excretion measurements (27), and therefore, urinary excretion data were corrected for body size by dividing the respective 24-h excretion rates by individual BSA.

    Statistical analysis. Pearson correlation, simple linear regression, and unpaired t test were applied for statistical analysis. All tests were 2-tailed, and differences with P < 0.05 were considered significant. Data are presented as the mean ± SD. A stepwise multiple regression analysis (model a priori adjusted for GC3; for explanation, see Discussion) was used to examine the contribution of dietary and hormonal factors [others than adrenal glucocorticoid secretion (GC3)] to the explained variation of potentially bioactive free glucocorticoids.

In this multiple regression model, both the dependent variable and the major independent variables were renal excretion rates measured in the same urine samples, which implies that correlated measurement errors could occur (28) as a result of incorrectly reported collection periods or missing micturitions. Correlated measurement errors violate a crucial assumption of standard multiple regression analyses (28) and can introduce bias of unpredictable direction and magnitude (29) as well as spurious associations between some covariates and the dependent variable, leading to instability of the parameter estimates (29). With regard to urine variables, such compliance-based measurement errors can be controlled for by using the analyte/creatinine ratio for the respective covariates and the outcome. However, creatinine excretion itself is influenced by age, sex, and weight (30,31). In the present analysis, we did not take age into account because the 10-y changes in body weight-corrected 24-h excretion rates of creatinine in 20- to 45-y-old adults are only moderate (32) when compared with those in children (31). However, the influence of sex and weight was controlled for. To obtain daily excretion rates that are controlled for the latter factors and that lack the above-mentioned correlated measurement errors, each individually determined 24-h analyte/creatinine ratio was multiplied by the individual body weight and by published constant sex-specific body weight-related creatinine reference values of young adults [0.201 and 0.182 mmol · kg–1 · d–1 for men and women, respectively (31)]. The resulting creatinine-standardized 24-h excretions rates of GC3, potentially bioactive free glucocorticoids, and net acid excretion showed high correlation coefficients of r = 0.93, r = 0.94, and r = 0.96, respectively, with the corresponding conventionally determined 24-h excretion rates using the 24-h urine volume. All statistical analyses were carried out using the SAS program, Version 8.2.


   Results
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
Discussion
 LITERATURE CITED
 
The %BF and plasma leptin were lower, and BSA and BSA-corrected GC3 were higher in men than in women (Table 1). Also significantly higher in men were the urinary indices for 11β-HSD1 and 5{alpha}-reductase. All other measurements including plasma cortisol and potentially bioactive free glucocorticoids did not differ between the sexes. Circulating leptin showed a positive correlation with %BF in both sexes (Fig. 1A), whereas potentially bioactive free glucocorticoids correlated positively with plasma leptin (Fig. 1B) and %BF (r = 0.56, P < 0.05) in men only.


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  		TABLE 1 Age, body composition, plasma hormones, enzyme activity indices, and creatinine-standardized 24-h urinary excretion rates of glucocorticoid metabolites, net acid, and total urinary nitrogen of the study subjects1

 

Figure 1
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  		FIGURE 1  Association of (A) plasma leptin concentration with %BF and (B) potentially bioactive free glucocorticoids with plasma leptin in 30 healthy lean adults. Pearson correlation coefficients were derived from log-transformed leptin values.

 
In the multiple regression model on BSA-corrected urine variables, net acid excretion proved to be a positive and plasma leptin a negative predictor of potentially bioactive free glucocorticoids in women but not in men (Table 2). Total explained variability reached 71% (R2 = 0.71, P < 0.005), whereas neither urinary nitrogen nor 5{alpha}-reductase or 11β-HSD1 entered the model at P < 0.1. In men, only GC3 explained variation of potentially bioactive free glucocorticoids (R2 = 0.49, P < 0.005).


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  		TABLE 2 Stepwise multiple regression results for BSA-corrected potentially bioactive free glucocorticoids in urine

 
When the regression was run again with the same variables but without BSA correction of the 24-h urinary excretion rates, net acid excretion remained no longer significant in the model. Instead, total urinary nitrogen excretion entered the model, and total R2 slightly increased to 0.72 (P < 0.005). As with net acid excretion in the BSA-corrected model, the regression coefficient was also positive for nitrogen excretion (partial R2 = 0.29, P < 0.005) and negative for plasma leptin (partial R2 = 0.22, P < 0.005). Additionally, a trend was seen for a negative association between 5{alpha}-reductase activity and the potentially bioactive free glucocorticoids (partial R2 = 0.09, P = 0.06) (11), which was in line with the known effect of 5{alpha}-reductase to increase cortisol clearance (12).


   Discussion
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
LITERATURE CITED
 
Our findings in healthy lean adults on unrestricted diets, covering the normal range of daily acid loads, indicate that potentially bioactive free glucocorticoids not only are influenced by adrenal glucocorticoid secretion but also are metabolically affected by diet-dependent net endogenous acid production and circulating leptin. Leptin and the hypothalamic-pituitary-adrenal (H-P-A) axis show complex interactions. Glucocorticoids can stimulate leptin secretion either directly within adipose tissue (33–35) or in the long run via a stimulation of fat gain. Consistent with this is our finding of a positive association of plasma leptin and potentially bioactive free glucocorticoids in lean men (Fig. 1B). The complex interplay of glucocorticoids and leptin is further seen in the fact that higher leptin levels can exert a long-loop feedback on the H-P-A axis by down-regulating adrenal steroidogenesis (34) and/or bioavailable cortisol as indexed by measurement of urinary free cortisol (35).

In accord with recent observations in rhesus monkeys, which showed a blunting effect of leptin on the corticotrophin (ACTH)-induced rise in cortisol and ACTH in females (36) but not in males (37), our regression results also suggest a lowering effect of leptin on potentially bioactive free glucocorticoids in females only. This corresponds with the findings of Misra et al. (35), who observed a negative relation between pulsatile leptin secretion and urinary free cortisol excretion in adolescent girls. However, in the latter study urinary free cortisol was not reduced because of diminished cortisol secretion but because of a reduction in cortisol half-life (35). Thus, it appears that the stress-attenuating effect of higher leptin levels (i.e., the reduction in potentially bioactive free glucocorticoids) may involve 2 mechanisms, an inhibition of adrenal cortisol secretion and a stimulation of cortisol catabolism. Regarding the effect of metabolic acidosis on the H-P-A axis, only an ACTH-mediated stimulation of adrenal glucocorticoid secretion has been reported as the underlying mechanism (1).

The fact that in our study, influences of leptin and net acid loads on potentially bioactive free glucocorticoids were discernible only after statistical accounting for GC3 indicates that the cross-sectional identification of metabolic and dietary effects in healthy subjects requires an adjustment for the primary determinant of bioavailable or free glucocorticoids, i.e., an adjustment for adrenal glucocorticoid secretion. In regression models with functional free glucocorticoids as an outcome, adrenal glucocorticoid secretion is a major confounder.

Average daily adrenal glucocorticoid secretion by the adrenal gland of healthy adults is high (in the milligram range) and shows a considerable interindividual variation (26). This glucocorticoid (mostly cortisol) secretion ensures a certain, also individually determined, level of functional free (potentially bioactive free) glucocorticoids. Some authors prefer to use only glucocorticoid secretion (e.g., GC3) as an indicator for functional free glucocorticoids; however, this is not plausible for the following reasons: 1) Changes in potentially bioactive free glucocorticoids (microgram range) induced by nutritional and/or metabolic factors that directly stimulate the H-P-A axis require only moderate changes in the 24-h level of adrenal glucocorticoid secretion (milligram range), and these may be difficult to detect. 2) Metabolically induced changes (e.g., catabolically induced decreases) in functionally free glucocorticoids usually result in reciprocal responses (e.g., increases) in adrenal glucocorticoid secretion necessary to readjust the H-P-A system, i.e., to increase free glucocorticoids again. 3) Furthermore, the high interindividual variation of adrenal glucocorticoid secretion (26) can mask a cross-sectional identification of moderate changes. However, as a primary determinant of the free glucocorticoid fraction [explaining only some part of free hormone variation (14)], the adrenal glucocorticoid secretion itself constitutes a confounder for the association between nutritional and/or metabolic factors and functionally free glucocorticoids.

Accordingly, an a priori adjustment for glucocorticoid secretion may generally be appropriate to identify other determinants of bioactive free glucocorticoids, and we hope that its use may also find its way into nutrition research as a noninvasive sensitive endocrine tool. However, the methodological appropriateness of this approach needs to be longitudinally confirmed because of the limitation of the cross-sectional design of our study, which does not allow proof of causal relationships.

The fact that, in a second regression model (without BSA correction of the urine variables), urinary total nitrogen replaces net acid excretion as a predictor of potentially bioactive free glucocorticoids indicates that not only the acid load per se may be a stimulus for glucocorticoid increases, but a high protein intake may also have an influence (38,39).

Using a new methodological approach to examine functional glucocorticoid activity, our findings indicate that diet-dependent net acid load and adipocyte-derived leptin can metabolically influence the potentially bioactive free glucocorticoids at least in lean healthy females. Accordingly, higher leptin levels and lower acid loads may contribute to a reduction in bioactive glucocorticoids or functional stress activity.


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented as part of the Second International Acid-Base Symposium, Nutrition–Health–Disease, held in Munich, Germany, September 8–9, 2006. Financial support for this symposium was provided by Protina Pharmaceutical Company. Guest Editors for the supplement publication were Thomas Remer and Juergen Vormann. Guest Editor disclosures: J. Vormann is a consultant to Protina Pharmaceutical Company; T. Remer received an unrestricted research grant from Protina Pharmaceutical Company. Back

2 Supported by the Ministry of Science and Research North Rhine-Westphalia, Germany. Back

3 Author disclosure: T. Remer, travel expenses to attend the conference were paid by Protina Pharm. GmbH; T. Dimitriou and C. Maser-Gluth, no conflicts of interest. Back

6 Abbreviations used: ACTH, corticotrophin; BSA, body surface area; GC3, sum of the 3 major urinary glucocorticoid metabolites, reflecting adrenal glucocorticoid secretion; H-P-A, hypothalamic-pituitary-adrenal; 11β-HSD, 11β-hydroxysteroid dehydrogenase; %BF, percentage body fat; THE, tetrahydrocortisone; 5{alpha}-THF, 5{alpha}-tetrahydrocortisol; THF, tetrahydrocortisol. Back


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 

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