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Division of Endocrinology, Metabolism, and Nutrition (R.B., A.B., E.G.C., R.A.R.), and Departments of Laboratory Medicine and Pathology (R.J.S.) and Vascular and Interventional Radiology (M.C.J.), Mayo Clinic, Rochester, Minnesota 55905; and Department of Information Engineering (G.T., C.C.), University of Padua, 35131 Padua, Italy
Address all correspondence and requests for reprints to: Robert A. Rizza, M.D., Mayo Clinic, 200 1st Street SW, Room 5-194 Joseph, Rochester, Minnesota 55905. E-mail: rizza.robert{at}mayo.edu.
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Abstract |
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Objective: The objective of the study was to determine whether obesity alone or in combination with type 2 diabetes increases splanchnic and/or leg cortisol production.
Design: Splanchnic and leg cortisol production were measured using the hepatic and leg catheterization technique combined with infusion of D4-cortisol.
Setting: The study was conducted in a General Clinical Research Center.
Participants: Nine lean nondiabetic, 10 obese nondiabetic, and 11 obese diabetic subjects were studied.
Interventions: Diabetic volunteers were withdrawn from their glucose-lowering medications before study.
Main Outcome Measures: Rates of total body, splanchnic and leg cortisol, and D3-cortisol production were measured.
Results: Rates of splanchnic cortisol production equaled or exceeded those occurring in extrasplanchnic tissues (e.g. the adrenals) in all three groups. However, because concurrent splanchnic cortisol uptake also occurred, net splanchnic cortisol release was minimal. Splanchnic cortisol production and splanchnic D3-cortisol production (an index of splanchnic 11ß-hydroxysteroid dehydrogenase type 1 activity) did not differ among the three groups. In addition, splanchnic cortisol production did not correlate with either visceral fat or endogenous glucose production. On the other hand, splanchnic cortisol uptake was greater in the obese diabetic than lean nondiabetic subjects (25 ± 2.9 vs. 15.3 ± 2.5 µg/min; P < 0.05). Splanchnic, but not leg, D3-cortisol production was correlated with total body D3-cortisol production (r = 0.70; P < 0.001).
Conclusions: Although large amounts of cortisol are produced within the splanchnic bed, implying high intrahepatic glucocorticoid concentrations, rates do not differ in lean and obese nondiabetic humans and are not influenced by the presence of type 2 diabetes mellitus. On the other hand, obesity but not diabetes increases splanchnic cortisol uptake.
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Introduction |
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11ß-HSD-2 (which primarily converts cortisol to cortisone) is mostly present in the kidney, whereas 11ß-HSD-1 (which primarily converts cortisone to cortisol) is present in the liver, muscle, and adipose tissue, with activity being higher in omental than sc fat (1, 3, 4, 5). Inhibition (6) or knockout (7, 8, 9) of 11ß-HSD-1 in mice improves hepatic insulin action and protects against obesity and hyperglycemia. Conversely, overexpression of 11ß-HSD-1 in adipose tissue of mice results in visceral obesity, hyperglycemia, hyperlipidemia, and hypertension (10, 11). Similarly, selective hepatic overexpression of 11ß-HSD-1 causes insulin resistance and hypertension (12). However, in contrast to mice, the effect of obesity or diabetes on production of cortisol by 11ß-HSD-1 in humans has been more controversial. Obesity has been reported to either increase (5, 13, 14, 15) or have no effect (16) on adipocyte 11ß-HSD-1 mRNA concentration or activity. Urinary ratios of cortisol to cortisone metabolites (commonly used to estimate whole-body 11ß-HSD-1 activity) have been reported to be increased (17, 18, 19), decreased (20, 21), or not different (15, 22, 23) in obese nondiabetic or diabetic subjects compared with lean nondiabetic subjects. The latter discrepancies likely have been observed, at least in part, because urinary ratios of cortisol and cortisone metabolites are influenced by multiple factors, including the pattern of cortisol metabolism (15). Therefore, the relationship among obesity, diabetes, 11ß-HSD-1 activity, and tissue-specific cortisol production are unknown.
Andrew et al. (24) overcame this limitation by using a novel tracer infusion method to specifically measure the rate of whole-body cortisone to cortisol conversion. They demonstrated that infusion of [9,11,12,12-2H4] cortisol (D4-cortisol) in fasting nondiabetic humans resulted in the formation of measurable amounts of plasma [9,12,12-2H3] cortisol (D3-cortisol). Because conversion of D4-cortisol to D3-cortisone by 11ß-HSD-2 causes the loss of the 11 
deuterium and the generation of D3-cortisone that in turn forms D3-cortisol when D3-cortisone is converted back to cortisol, this observation provided strong experimental evidence that cortisone to cortisol conversion occurs in humans (24). We subsequently used the same method in combination with the hepatic venous and leg catheterization technique to determine the site(s) of cortisone to cortisol conversion (25). Those studies led to the surprising discovery that rates of splanchnic cortisol production in healthy nondiabetic individuals equaled or exceed those produced by extrasplanchnic tissues (e.g. the adrenals). However, because concomitant uptake of cortisol also occurred within the splanchnic bed, only a small amount of cortisol was released by the liver into the systemic circulation.
Although those experiments clearly established that cortisol is produced within the splanchnic bed in humans, the number of subjects studied was too small to determine whether the rate of splanchnic cortisol production was greater in obese than in lean individuals. Perhaps more importantly, we could not determine whether splanchnic cortisol production was increased by the presence of type 2 diabetes because only nondiabetic subjects were studied. To address these questions, we expanded our previous studies to include additional lean and obese nondiabetic subjects as well obese type 2 diabetic subjects. We report that, although substantial splanchnic cortisol production via the 11ß-HSD-1 pathway occurred in all subjects, rates did not differ in lean and obese subjects or in the presence or absence of type 2 diabetes. Conversely, splanchnic, but not leg, cortisol uptake was increased in the obese diabetic and nondiabetic subjects.
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Subjects and Methods |
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After approval from the Mayo Institutional Review Board, 10 lean nondiabetic subjects (body mass index < 24 kg/m2), 10 obese nondiabetic subjects (body mass index > 28 kg/m2), and 11 obese subjects with type 2 diabetes gave informed written consent to participate in the study. The data from one lean nondiabetic subject was subsequently excluded from analysis due to technical difficulty with catheter placement. Of the 19 nondiabetic subjects, data from 11 (five lean and six obese) were included in our previous report (25). All subjects were in good health and at a stable weight. None regularly engaged in vigorous physical exercise. None of the parents, siblings, and children (first-degree relatives) of the nondiabetic subjects had a history of diabetes mellitus. At the time of screening, three of the diabetic subjects were being treated with lifestyle modifications alone, one with a sulfonylurea alone, two with metformin alone, two on a combination of a sulfonylurea and metformin, two with insulin alone, and one with both insulin and metformin. Oral hypoglycemic agents were discontinued 2 wk before study, and long-acting insulin was switched to regular insulin with meals beginning with the midday meal 2 d before study. Two type 2 diabetic subjects were on replacement doses of T4. In addition, two diabetic subjects, one lean nondiabetic, and one obese nondiabetic subject were on an angiotensin-converting inhibitor. All subjects were instructed to follow a weight maintenance diet (55% carbohydrate, 30% fat, and 15% protein) for at least 3 d before the day of study. Subject characteristics are given in Table 1
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Subjects were admitted to the Mayo Clinic General Clinical Research Center at 1700 h on the evening before the study. A standard 10 cal/kg meal (55% carbohydrate, 30% fat, and 15% protein) was eaten between 1730 and 1800 h. At 0500 h on the morning of study, an intravenous catheter was placed in a forearm vein in the left arm for infusions of saline, isotopes, and hormone solutions. A urinary bladder catheter was placed at approximately 0530 h. At approximately 0600 h, a primed continuous infusion of D4-cortisol (0.22 mg prime, 0.19 mg/h continuous; 1.4 mg/ml in 95% ethanol diluted in 80 ml 0.9 normal saline infused 0.1 ml/min; Cambridge Isotope Laboratories, Andover, MA) was started into a forearm vein. 2H2O also was given the evening before, and an infusion of [3-3H] glucose and insulin was started on the morning of the study as part of a separate protocol. Subjects were taken to an interventional radiology suite, where catheters were inserted distal to the inguinal ligament and advanced into the femoral artery, femoral vein, and hepatic vein (26, 27). At approximately 0930 h, an infusion of indocyanine green dye (Akorn Inc., Buffalo Grove, IL) was started via the femoral arterial sheath. The venous catheters and the arterial catheter were used for blood sampling.
Analytical technique
All plasma samples were placed in ice, centrifuged at 4 C, and separated. Plasma indocyanine green concentration was measured spectrophotometrically at 805 nm on the day of study. All other samples were stored at –20 C until analysis. Plasma glucose was measured by a glucose oxidase method using a YSI (Yellow Springs, OH) glucose analyzer. Plasma insulin was measured using a chemiluminescence method with the Access Ultrasensitive Immunoenzymatic assay system (Beckman Coulter, Chaska, MN). Free fatty acid concentrations were measured using a calorimetric assay (COBAS; Roche Diagnostics, Indianapolis, IN). Hepatic venous, femoral artery, and femoral venous cortisol, D4-cortisol, and D3-cortisol concentrations were measured using liquid chromatography tandem mass spectrometer as described previously (28). In brief, prednisolone was added as an internal standard, and methylene chloride was used to extract the relevant steroids. The dried extract was then reconstituted and injected into a liquid chromatography tandem mass spectrometer. Cortisol, D4-cortisol, D3-cortisol, cortisone, and D3-cortisone ions were generated with electrospray source in positive mode and were detected with multiple reaction monitoring using the specific transitions for mass/charge 363 to 121, 367 to 121, 366 to 121, 361 to 163, and 364 to 164, respectively. This approach enabled simultaneous monitoring of both the pronated parent ion and fragmented daughter ion, thereby increasing specificity. The relative extraction efficiency was approximately 97%. Total body fat, leg fat, and lean body mass were measured using dual-energy x-ray absorptiometry (DPX-IQ scanner; Hologic, Waltham, MA) (Slice-o-matic, version 4.2, revision 1, Tomovision, Montreal, Quebec, Canada), combined with a single-slice computerized tomograph scan at the level of L3/L4 to measure visceral fat (29).
Calculations
Splanchnic plasma flow was calculated by dividing the indocyanine green infusion rate by the arterial hepatic venous concentration gradient of the dye, and leg plasma flow was calculated by dividing the dye infusion rate by the concentration gradient across the leg. The corresponding blood flows were calculated by dividing the respective plasma flow by (1 – hematocrit). Calculation of splanchnic and leg net cortisol balance, cortisol uptake, and cortisol production has been described previously in detail (25). In brief, net cortisol and D3-cortisol balance were calculated by multiplying the arterial venous difference in cortisol and D3-cortisol concentrations across either the splanchnic bed or leg by blood flow. Cortisol and D3-cortisol uptake was calculated by multiplying the fractional extraction of D4-cortisol across the splanchnic bed or leg times the product of blood flow and either cortisol or D3-cortisol concentration. Cortisol and D3-cortisol production were calculated by subtracting cortisol or D3-cortisol uptake from net balance. Total body cortisol and D3-cortisol production were calculated by dividing the D4-cortisol infusion rate by plasma D4-cortisol enrichment or the plasma ratio of D4-cortisol to D3-cortisol. Plasma D4-cortisol enrichment and the plasma ratio of D4-cortisol to D3-coritsol remained constant during the final hour before the study and did not change significantly during the succeeding 4 h of tracer performed as part of a separate experiment (data not shown). Endogenous glucose production was calculated by dividing the infusion rate of [3-3H] glucose by the plasma [3-3H] glucose-specific activity.
Statistical analysis
Data in the text and figures are expressed as mean ± SEM. Rates are expressed as micromoles per minute. Responses during the study period were determined by taking a mean of the results present, respectively, from 1000 to 1030 h. ANOVA was used to compare results among the three groups (e.g. lean nondiabetic subjects vs. obese nondiabetic subjects vs. obese type 2 diabetic subjects), followed by Student’s paired t test whenever appropriate. To determine whether splanchnic and leg cortisol production were detectible, the value observed in each individual was compared with zero (i.e. no cortisol production) using Student’s paired t test. A P value of less than 0.05 was considered as statistically significant.
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Results |
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Plasma glucose concentrations were higher (P < 0.001) in the obese diabetic than obese and lean nondiabetic subjects (10.2 ± 0.8 vs. 5.4 ± 0.4 vs. 5.2 ± 0.1 mmol/liter). Fasting plasma insulin concentrations did not differ in the obese diabetic and nondiabetic subjects but were higher (P < 0.01) in both groups than those present in the lean nondiabetic subjects (52 ± 9 vs. 47 ± 9 vs. 19 ± 2 pmol/liter). Endogenous glucose production (17.2 ± 0.7 vs. 14.0 ± 0.6 vs. 14.0 ± 0.1 µmol/kg·min) also were higher (P < 0.01) in the diabetic than the obese nondiabetic or lean nondiabetic subjects. In contrast, plasma free fatty acids (0.41 ± 0.03 vs. 0.35 ± 0.02 vs. 0.39 ± 0.03 mmol/liter) did not differ among the three groups.
Arterial, hepatic venous, and femoral venous cortisol, D4-cortisol, and D3-cortisol (Fig. 1)
Femoral arterial, hepatic venous, and femoral venous cortisol concentrations did not differ in the lean nondiabetic, obese nondiabetic, or obese diabetic subjects. Hepatic venous D4-cortisol concentrations were lower (P = 0.01 to 0.0001) than femoral arterial D4-cortisol concentrations in all three groups, indicating net splanchnic extraction. Femoral venous D4-cortisol concentrations were lower than femoral arterial D4-cortisol concentrations (P < 0.05) in the obese nondiabetic and type 2 diabetic subjects. Hepatic venous D3-cortisol concentrations were higher (P < 0.001) than femoral arterial D3-cortisol concentrations in all three groups, indicating net splanchnic release. Conversely, femoral venous D3-cortisol concentrations were not greater than femoral arterial concentrations in any group.
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)Femoral artery and femoral venous cortisone and D3-cortisone concentrations did not differ among the three groups. Hepatic venous cortisone and D3-cortisol concentrations also did not differ among the three groups and were substantially lower (P < 0.01) than femoral arterial concentrations in all groups.
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)Total body cortisol production was slightly, but not significantly, greater in the obese diabetic and obese nondiabetic than lean nondiabetic subjects (28. 3 ± 3.7 vs. 25.4 ± 4.8 vs. 19.8 ± 3.1 µg/min). D3-cortisol production did not differ among the obese diabetic, obese nondiabetic, and lean nondiabetic subjects (3.5 ± 0.3 vs. 3.8 ± 0.5 vs. 3.7 ± 0.7 µg/min)
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)Splanchnic blood flow did not differ in the lean nondiabetic, obese nondiabetic, or obese diabetic subjects (1400 ± 165 vs. 1630 ± 125 vs. 1612 ± 140 ml/min). Net splanchnic balance of cortisol also did not differ in the lean nondiabetic, obese nondiabetic, and obese diabetic subjects (–6.6 ± 3.6 vs. –3.6 ± 3.5 vs. –3.4 ± 4.0 µg/min). Fractional splanchnic D4-cortisol extraction was greater in obese diabetic and obese nondiabetic than lean nondiabetic subjects (16 ± 2 vs. 14 ± 2 vs. 11 ± 2%). This resulted in rates of splanchnic cortisol uptake that were greater in obese diabetic subjects than lean nondiabetic subjects (25 ± 2.9 vs. 15.3 ± 2.5 µg/min; P < 0.05). Conversely, rates of splanchnic cortisol uptake did not differ in the obese (21.2 ± 4.7 µg/min) and lean nondiabetic subjects. Splanchnic cortisol production tended to be higher in the obese nondiabetic and obese diabetic subjects compared with the lean nondiabetic subjects; however, this was not statistically significant (23.8 ± 3.5 vs. 25.5 ± 3.2 vs. 29.4 ± 4.9 µg/min, respectively). Of note, splanchnic cortisol production was detectible (i.e. greater than zero in all groups) (P < 0.001). Leg blood flow did not differ in the lean nondiabetic, obese nondiabetic, and obese diabetic subjects (461 ± 43 vs. 657 ± 94 vs. 551 ± 49 ml/min). Net leg cortisol balance also did not differ among the three groups (2.0 ± 1.0 vs. 0.2 ± 0.8 vs. 0.8 ± 1.3 µg/min). Neither leg D4-cortisol extraction (6.0 ± 2 vs. 5.0 ± 1 vs. 6.0 ± 2%) nor leg cortisol uptake (2.1 ± 0.8 vs. 2.4 ± 0.9 vs. 3.0 ± 1.0 µg/min) differed in the lean nondiabetic, obese nondiabetic, and obese diabetic subjects before. In contrast, leg cortisol production was greater (P = 0.02) in the obese diabetic subjects (2.1 ± 0.5 µg/min) and tended to be higher (P = 0.1) in obese nondiabetic (2.0 ± 0.9 µg/min) subjects than lean nondiabetic subjects (0.1 ± 0.6 µg/min). This resulted in detectible (i.e. greater than zero) rates of leg cortisol production in the obese nondiabetic (P = 0.05) and obese diabetic (P < 0.001) subjects
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)Production of D3-cortisol from intravenously infused D4-cortisol provides an index of 11ß-HSD-1 activity. There was net release (P < 0.001) of D3-cortisol from the splanchnic bed in the lean nondiabetic, obese nondiabetic, and obese diabetic subjects (–4.2 ± 0.6 vs. –3.2 ± 0.4 vs. –2.4 ± 0.7 µg/min). Splanchnic D3-cortisol production occurred in all three groups (P < 0.001), further documenting active conversion of cortisone to cortisol. However, net splanchnic D3-cortisol release and splanchnic D3-cortisol production did not differ among the three groups (6.6 ± 0.6 vs. 6.3 ± 0.8 vs.5.4 ± 0.8 µg/min).
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Correlations
Splanchnic D3-cortisol production correlated with total body D3-cortisol production (r = 0.70; P < 0.001). Conversely, leg D3-cortisol production did not correlate with total body D3-cortisol production (r = 0.07; P = 0.72). Of interest, splanchnic D3-cortisol production did not correlate with total body fat (r = 0.27; P = 0.14), visceral fat (r = –0.29; P = 0.12), sc fat (r = 0.39; P = 0.06), or endogenous glucose production (r = 0.20; P = 0.3). Leg D3-cortisol production correlated inversely with both total body fat (r = –0.50; P = 0.006) and leg fat (r = –0.39; P = 0.04) but did not correlate with sc fat (r = –0.4; P = 0.11). Splanchnic and leg D3-cortisol production also did not correlate with either plasma glucose (r = 0.06, P = 0.7; and r = 0.03, P = 0.09) or plasma free fatty acid (r = 0.21, P = 0.30; and r = 0.10, P = 0.72) concentrations.
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Discussion |
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The observation that 11ß-HSD-1 message and activity is present in fat, muscle, and liver has engendered considerable interest regarding the possible contribution of local generation of cortisol to the pathogenesis of insulin resistance (1, 2). This interest has been further heightened by studies showing that overexpression of 11ß-HSD-1 in mice leads to obesity, hypertension, and hyperglycemia (10, 11), whereas inhibition or knockout of this enzyme protects against these abnormalities (7, 8, 9). However, there has been controversy as to whether tissue-specific conversion of cortisone to cortisol via the 11ß-HSD-1 pathway is increased in obese humans. This is perhaps due to fact that ratio urinary metabolites of cortisol (e.g. tetrahydrocortisol plus 5- tetrahydrocortisol) to cortisone (e.g. tetrahydrocortisone) have been used to estimate 11ß-HSD-1 flux. Obesity has been reported to decrease (20, 21), increase (17, 18, 19), or have no effect (15, 22, 23) on this ratio. However, as discussed in detail by Westerbacka et al. (15), this ratio is influenced by multiple factors, including the rate and pattern of cortisone and cortisol metabolism. In addition, measurement of urinary ratios of metabolites provides no insight regarding the site of cortisol synthesis.
To our knowledge, the present studies are the first to examine the effects of obesity and type 2 diabetes on splanchnic cortisol production. These studies establish that substantial cortisol production occurs within the splanchnic bed of both diabetic and nondiabetic humans, suggesting a possible role of high local cortisol concentrations in the regulation of hepatic glucose, fat, and protein metabolism. However, in contrast to our original hypothesis, neither obesity nor type 2 diabetes increased the rate of splanchnic cortisol production. It is important to note in this regard that the combined tracer and hepatic venous catheterization method requires no assumptions regarding precursor enrichment. Rates of splanchnic cortisol production can be directly calculated by measuring blood flow and the concentrations of the tracer (D4-cortisol) and tracee (cortisol) entering and leaving the splanchnic bed. As is evident in Fig. 1
, the concentration of D4 cortisol was consistently lower in the hepatic vein than the femoral artery in all groups, indicating splanchnic cortisol uptake. Conversely, cortisol concentration did not differ in the femoral artery and hepatic vein, indicating concurrent splanchnic cortisol production. Arterial cortisone (and D3-cortisone) concentrations also did not differ among the three groups, indicating that comparable amounts entered the splanchnic bed. Because 11ß-HSD-1 is a bidirectional enzyme, cortisol potentially can be converted to cortisone within the splanchnic bed (30). However, this does not influence the measurement of splanchnic cortisol production because, once formed, the subsequent metabolism of both tracer and tracee occur in parallel. Conversely, if the metabolism of D4-cortisol is delayed relative to unlabeled cortisol (commonly referred to as an "isotope effect"), then the fractional extraction of D4-cortisol would be underestimated, which in turn would lead to an underestimation of the rate of splanchnic cortisol production. However, we are unaware of any data indicating that the presence of deuterium alters the metabolism of cortisol.
Although these data establish that splanchnic cortisol production occurs in nondiabetic and diabetic humans at rates that did not differ among the three groups (Fig. 3, left bottom), they provide no insight as to the origin of that production. Conversely, as discussed previously (24, 25), production of D3-cortisol during infusion of D4-cortisol can only occur by conversion of D3-cortisone to cortisol via the 11ß-HSD-1 pathway. The fact that more D3-cortisol leaves than enters the splanchnic bed (Fig. 4, upper panel) establishes that splanchnic cortisol production is occurring via the 11ß-HSD-1 pathway. The comparable rates of D3-cortisol production in all three groups (Fig. 4, left bottom) indicates that neither obesity nor type 2 diabetes increases flux through this pathway within the splanchnic bed.
The observation that splanchnic cortisol uptake was greater in the obese diabetic than lean nondiabetic subjects is intriguing and perhaps is explained by the fact that visceral fat has an increased number of glucocorticoid receptors compared with sc fat (31, 32). Conversely, there was no suggestion of a difference in splanchnic cortisol uptake between the obese nondiabetic and obese diabetic subjects, suggesting that obesity rather than diabetes increases splanchnic cortisol uptake. Multiple studies have shown that the increment in plasma cortisol after ingestion of cortisone is lower in obese than lean subjects (15, 18, 21, 33). Although those data originally were interpreted as indicating that obesity decreased splanchnic cortisone to cortisol conversion, they are entirely consistent with the present observation that splanchnic cortisol uptake but not production is increased in obese individuals.
To our knowledge, the present experiments also are the first to examine the effects of obesity and type 2 diabetes on leg cortisone to cortisol conversion. Whereas splanchnic cortisol production was easily detected, there is more uncertainty as to whether biologically meaningful amounts of cortisol were produced within the leg in either the diabetic or nondiabetic subjects. In vitro studies have established that 11 ß-HSD-1 activity is present in sc fat (3). 11ß-HSD-1 mRNA also has been detected in muscle (34). Therefore, production of cortisol by tissues within the leg is plausible. However, the present study does not provide a clear answer as to whether leg cortisol production truly occurs in humans. Both leg cortisol and D3-cortisol production were significantly greater than zero (i.e. detectible) in the obese nondiabetic subjects. Conversely, D3-cortisol production was not evident in the diabetic subjects. We interpret these data as suggesting, but not proving, that leg cortisol production occurs in humans. Because even low rates of cortisone to cortisol conversion could result in high local glucocorticoid concentrations, these data leave open the possibility that flux via 11ß-HSD-1 pathway could modulate muscle and fat metabolism. Nevertheless, the rate of cortisone to cortisol conversion within the leg clearly is markedly lower than that which occurs within the splanchnic bed in diabetic as well as nondiabetic subjects.
The present studies suffer from several limitations. As noted above, data from 11 of the 19 nondiabetic subjects were included in our previous publication (25). Although increasing the number of subjects studied permitted examination of the effects of obesity on splanchnic and leg cortisol metabolism, this and our previous publication clearly are not independent. Of interest, when the diabetic and nondiabetic subjects were considered as a single group, splanchnic cortisol production was greater (P < 0.05) in men than women (32.3 ± 4.2 vs. 21.8 ± 2.0 µg/min). However, differences in gender did not account for lack of difference in splanchnic or leg cortisol production among the lean nondiabetic, obese nondiabetic, or diabetic subjects because there were a comparable number of men and women in all three groups (Table 1). D4-cortisol is a stable tracer and therefore is not "massless." D4-cortisol was infused at a rate (3.16 µg/min) that was approximately one eighth of total body cortisol production (
25 µg/min). We do not know whether infusion of this small amount of cortisol altered endogenous cortisol production. However, if it did so, the effects apparently were comparable in the diabetic and nondiabetic subjects because total body and splanchnic cortisol production did not differ among the three groups. Splanchnic and leg cortisol production were only measured in the morning. We, therefore, do not know whether they are influenced by circadian variation of the hypothalamic pituitary adrenal axis. Fat-free mass was greater in the obese nondiabetic and diabetic subjects than the lean nondiabetic subjects. However, the lack of difference among the three groups suggest that muscle mass does not have a major effect on leg cortisol production. Due to ethical considerations, in vivo measurement of cortisol production within the individual tissues of the splanchnic bed was not possible. Of interest in this regard, Aldahi et al. (35) have reported recently that peripheral venous and portal venous cortisol concentrations are the same in obese subjects during bariatric surgery, implying that there is little if any net release by visceral fat of cortisol into the portal vein in humans. Finally, because these were complex and invasive experiments, only 30 subjects were studied. However, assuming that the same variability would be observed in subsequent experiments and an 80% power to detect a true difference if present, we estimate that in excess of 300 additional subjects would have to have been studied for the difference in splanchnic production among the three groups to have become statistically significant. Therefore, if a true difference was present but missed, the size of that difference appears to be quite small.
In summary, the present studies indicate that splanchnic cortisol production occurs in both diabetic and nondiabetic humans. Rates of splanchnic cortisol production equal or exceed those occurring in extrasplanchnic tissues (e.g. the adrenals). Conversely, because splanchnic cortisol uptake also occurs, there is minimal release of cortisol into the systemic circulation. Although obesity appears to increase splanchnic cortisol uptake, the present experiments indicate that the rate of splanchnic cortisol production does not differ in lean and obese nondiabetic humans and is not altered by the presence of type 2 diabetes mellitus.
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Acknowledgments |
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Footnotes |
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First Published Online April 5, 2005
Abbreviations: D3-cortisol, [9,12,12-2H3] Cortisol; D3-cortisone, [9,12,12-2H3] cortisone; D4-cortisol, [9,11,12,12-2H4] cortisol; 11ß-HSD-1, 11ß hydroxysteroid dehydrogenase type 1; 11ß-HSD-2, 11ß hydroxysteroid dehydrogenase type 2.
Received December 8, 2004.
Accepted March 29, 2005.
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cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 84:1022–1027This article has been cited by other articles:
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, P < 0.01 vs. femoral artery; *, P < 0.05 vs. femoral artery.
