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Original Article |
University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh, United Kingdom EH4 2XU
Address all correspondence and requests for reprints to: Prof. Brian R. Walker, University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh, United Kingdom EH4 2XU. E-mail: b.walker{at}ed.ac.uk.
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Abstract |
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Six diet-controlled nonobese diabetic patients with hemoglobin A1c less than 8%, and six matched controls participated in a double-blind, cross-over comparison of carbenoxolone (100 mg every 8 h, orally, for 7 d) and placebo. They were admitted overnight for infusions of insulin (as required to maintain arterialized plasma glucose of 5.0 mM) and [13C6]glucose. Glucose kinetics were measured in the fasted state from 0700–0730 h, during a 3-h euglycemic hyperinsulinemic clamp (including somatostatin infusion and replacement of physiological GH and glucagon levels), and during a 2-h euglycemic hyperinsulinemic clamp with a 4-fold increase in glucagon levels. Data are the mean ± SEM.
Carbenoxolone had the expected effects of raising blood pressure and lowering plasma potassium. Carbenoxolone reduced total cholesterol in healthy subjects (5.25 ± 0.34 vs. 4.78 ± 0.40 mM; P < 0.01), but had no effect on other serum lipids or on cholesterol in diabetic patients. Carbenoxolone did not affect the rate of glucose disposal or the suppression of free fatty acids during hyperinsulinemia. However, carbenoxolone reduced the glucose production rate during hyperglucagonemia in diabetic patients (1.90 ± 0.2 vs. 1.53 ± 0.3 mg/kg·min; P < 0.05). This was attributable to reduced glycogenolysis (1.31 ± 0.2 vs. 1.01 ± 0.2 mg/kg·min; P < 0.005) rather than altered gluconeogenesis.
These observations reinforce the potential metabolic benefits of inhibiting 11ß-HSD1 in the liver of patients with type 2 diabetes. Further studies in obesity and hyperlipidemia are now warranted. However, clinically useful therapeutic effects will probably require selective 11ß-HSD1 inhibitors that lower intraadipose cortisol levels and enhance peripheral glucose uptake.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Relatively nonselective inhibitors of 11ß-HSD1 are available for human use. The principal active constituent of confectionary liquorice, glycyrrhetinic acid, and its hemisuccinate derivative, carbenoxolone, are potent inhibitors of both 11ß-HSD1 and its isoenzyme, 11ß-HSD2 (10). 11ß-HSD2 is expressed principally in the distal nephron, where it inactivates cortisol to cortisone and thereby protects mineralocorticoid receptors from cortisol (11, 12). Inhibition of 11ß-HSD2 with liquorice derivatives results in cortisol-dependent mineralocorticoid excess with hypertension and hypokalemic alkalosis (13, 14). However, in addition carbenoxolone inhibits regeneration of cortisol from cortisone by 11ß-HSD1 in liver (14, 15). In a previous study of healthy men we showed that carbenoxolone increased insulin sensitivity, as measured by an increase in glucose infusion rate during euglycemic hyperinsulinemic clamp (16). There was no effect on peripheral glucose uptake, measured by arterio-venous sampling across the forearm, so it was inferred that carbenoxolone lowers intrahepatic cortisol concentrations and thereby prevents insulin-dependent suppression of hepatic glucose production.
In the present study we aimed to characterize the mechanism of action of carbenoxolone on insulin sensitivity in healthy men and quantify its effects for the first time in patients with type 2 diabetes. The selection of patients most likely to respond to 11ß-HSD1 inhibition was an important consideration. In obese patients there is tissue-specific dysregulation of 11ß-HSD1, resulting in increased regeneration of cortisol in adipose tissue (6, 7, 8) but decreased activity in liver (6, 17). In contrast, in lean patients with type 2 diabetes we found a relatively small decrease in hepatic 11ß-HSD1 activity and no change in the enzyme in adipose tissue (18). It is not established that carbenoxolone effectively inhibits 11ß-HSD1 in adipose tissue, but it does inhibit 11ß-HSD1 in liver (Livingstone, D. E. W., et al., unpublished observations) (14). For these reasons we recruited only lean patients with type 2 diabetes in the current study and aimed principally to study the effects of carbenoxolone in the liver.
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Subjects and Methods |
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We studied six men with type 2 diabetes mellitus (diagnosed <3 yr previously by WHO criteria; DM group) recruited from our clinic and six normal healthy controls recruited by advertisement. Patients were treated with diet alone, without oral hypoglycemic agents or insulin, and were free of retinopathy, nephropathy, and neuropathy at their most recent annual review. Exclusion criteria included body mass index greater than 32 kg/m2, weight loss greater than 5 kg in the previous 3 months, therapy for any other medical conditions, including dyslipidemia and hypertension, blood pressure greater than 160/90 mm Hg, major psychiatric disorder, abnormal renal or thyroid function on biochemical screening, or glucocorticoid therapy by any route in the previous 3 months. Healthy control men were matched for age, weight, height, body mass index, and blood pressure. Local ethical committee approval and written informed consent were obtained.
Protocol
Participants took carbenoxolone (100 mg every 8 h, orally, for 7 d) or placebo in a double-blind, randomized, cross-over trial with phases separated by at least 3 months of washout. This dose of carbenoxolone has been shown previously to inhibit conversion of cortisone to cortisol in man (14, 15). On d 4 of each phase measurements of weight, blood pressure and plasma electrolytes were made to avoid adverse effects of carbenoxolone (hypokalemia and sodium retention), but no subject had to be withdrawn. On the evening of the seventh day of each phase, participants were admitted to the Clinical Research Facility for clamp studies. Compliance with study medication was monitored by tablet counting and by measuring plasma carbenoxolone levels in samples obtained at 0700 h on the eighth day.
Euglycemic clamp protocol
Participants attended the clinical research facility at 1730 h for a standardized meal. Thereafter their only oral intake was water. Cannulas were placed in an antecubital vein for infusions and retrogradely in a contralateral dorsal hand vein; the hand was kept in a hot box for arterialized blood sampling. The clamp was divided into three phases (Fig. 1
).
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Phase 2. From 0730–1030 h, a hyperinsulinemic, normoglucagonemic, normoglycemic clamp was performed with infusions of insulin (0.4 mU/kg·min), somatostatin (0.25 mg/h), glucagon (1.5 ng/kg·min), GH (3 ng/kg·min), and 20% glucose. The 20% glucose infusion rate was varied to maintain arterialized blood glucose at 5.0 mM.
Phase 3. From 1030–1230 h, a hyperinsulinemic, hyperglucagonemic, normoglycemic clamp was performed by increasing the glucagon infusion rate from 1.5 to 6.0 ng/kg·min while maintaining other infusions.
In addition to frequent samples for bedside blood glucose monitoring, blood samples were obtained as indicated in Fig. 1
. Blood was immediately centrifuged, and the plasma was frozen and stored at -80 C until analysis.
Laboratory analyses
Enzyme immunoassays (Eurogenetics Tasah Corp. UK Ltd., Hampton, UK) were used to measure plasma insulin, GH, and C peptide. Electrolytes were measured with a Vitras 950 (Ortho Diagnostics, Raritan, NJ), and glucose was determined on a Cabas Mira Plus (Roche, Mannheim, Germany). Triglycerides, total cholesterol, and high density lipoprotein (HDL) cholesterol were measured using ELISA kits (TG, CHOL, and HDL C-plus, respectively; Roche). Hemoglobin A1c (HbA1c) was measured by ion exchange HPLC (Variant 11, Bio-Rad Laboratories, Inc., Richmond, CA). RIAs were used to measure cortisol (19) and glucagon (20). Free fatty acids were measured by a colorimetric technique (Wako, Neuss, Germany). Carbenoxolone was measured by HPLC with UV detection (at 254 nm) using 18
-glycyrrhetinic acid as an internal standard.
Enrichment of glucose isotopomers was analyzed as its acetylated di-0-isopropylidene derivative (21) using a gas chromatograph quadrupole mass spectrometer (Voyager, Thermoquest, Manchester, UK). Electron impact ionization was used with selective monitoring of masses 287–293. Enrichment of lactate isotopomers was analyzed as its propyl-amideheptafluorobutyric acid using electron impact ionization with selective monitoring of masses 327–330 (22). Measured isotopomer distributions were corrected for natural 13C enrichment at all masses as described previously (23), using software provided by Dr. Henri Brunengraber (Western Reserve University, Cleveland, OH). Coefficients of variation for enrichment measurements for both glucose and lactate were less than 5%, as assessed from quality control samples prepared and analyzed with the samples.
Calculation of glucose kinetic parameters
Rates of glucose appearance (Ra) and peripheral glucose disposal (Rd) were calculated from steady state enrichment of the plasma glucose pool with [13C6]glucose, using mean data obtained in the basal state (0700–0730 h), during hyperinsulinemia (1000–1030 h), and with the addition of hyperglucagonemia (1200–1230 h). All enrichments during these periods were confirmed as steady state by regression coefficients for seven measurements against time not significantly different from zero. Glucose and lactate enrichments achieved in plasma at plateau were similar to those reported by Tayek and Katz (24). The glucose production rate was calculated by subtracting the glucose infusion rate from Ra. Gluconeogenesis rates were calculated at the same intervals according to the steady state formulas described by Tayek and Katz (24). Glycogenolysis was calculated as (glucose production rate) - (gluconeogenesis rate).
Statistics
Data are expressed as the mean ± SEM. The effects of carbenoxolone within groups were examined by paired t tests. Differences between patient groups were tested by unpaired t tests. Multiple regression was used to explore whether interindividual differences in the effects of carbenoxolone were attributable to differences in achieved plasma level of carbenoxolone or differences between DM patients and controls (analyzed as 0 or 1).
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Results |
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DM and control men were well matched for age (59 ± 3 vs. 58 ± 3 yr, respectively; P = 0.94), body mass index (29.2 ± 1.3 vs. 29.1 ± 0.9; P = 0.94), and waist/hip circumference ratio (0.95 ± 0.01 vs. 0.92 ± 0.03; P = 0.43). Glycemic control was excellent in all DM patients, so that HbA1c was only marginally higher than in controls (6.8 ± 0.4% vs. 6.0 ± 0.1%; P = 0.06). HDL cholesterol was lower in DM patients (Table 1).
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Tablet count and plasma carbenoxolone levels confirmed good compliance with study medication (Table 1). Carbenoxolone levels tended to be higher in DM than controls (P = 0.09). Carbenoxolone had the expected effects to raise blood pressure and lower plasma potassium in both groups, although the effect on plasma potassium was only statistically significant in the DM patients. In contrast, in the control group carbenoxolone decreased fasting plasma cholesterol and tended to increase HDL cholesterol; these effects were not observed in DM patients.
Effects of carbenoxolone on glucose kinetic parameters
The technical success of the clamps is shown in Fig. 2. Plasma glucose was maintained similarly close to 5.0 mM throughout in both groups with and without carbenoxolone (Fig. 2b). To achieve this insulin was infused at low doses overnight in five of the DM patients and three of the control subjects (controls after placebo, 0.3 ± 0.1 U/h; controls after carbenoxolone, 0.4 ± 0.2 U/h; DM after placebo, 1.0 ± 0.6 U/h; DM after carbenoxolone, 1.3 ± 0.3 U/h). The resulting plasma insulin levels at 0700–0730 h tended to be higher in DM patients regardless of carbenoxolone therapy (Fig. 2c). Thereafter, the anticipated degree of hyperinsulinemia was achieved by infusion of 0.4 mU/kg·min insulin, but resulting insulin concentrations were higher in DM subjects after placebo than in other groups. C Peptide levels were similar at baseline and were suppressed in all subjects during hyperinsulinemia (Fig. 2d). GH levels were similar at baseline and were clamped successfully in all participants except one DM patient after carbenoxolone whose GH level rose to more than 15 mU/liter from 1200–1230 h (Fig. 2g). Plasma glucagon levels were not different at baseline and were clamped, as intended, to physiological levels by infusion of 1.5 ng/kg·min and to high levels by infusion of 6.0 ng/kg·min (Fig. 2f). Plasma cortisol followed the normal diurnal rhythm in all groups (Fig. 2h).
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). There was a nonsignificant trend for higher absolute infusion rates in healthy controls after carbenoxolone consistent with increased whole body insulin sensitivity as previously reported (16). This was not attributable to differences in peripheral insulin sensitivity. Free fatty acid levels were not different at baseline and were suppressed similarly during hyperinsulinemia (Fig. 2e). Rd (Fig. 3a) was stimulated, as expected, by insulin and rose further with the addition of hyperglucagonemia, especially in control subjects, but was unaffected by carbenoxolone in either group.
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). These changes in glucose production during the clamp were associated with the expected changes in gluconeogenesis (Fig. 3c) and glycogenolysis (Fig. 3d), both of which were suppressed by hyperinsulinemia and stimulated by hyperglucagonemia. By contrast with the lack of effect on peripheral glucose uptake, carbenoxolone prevented the increase in the glucose production rate during hyperglucagonemia in DM subjects only. This was attributable to reduced glycogenolysis, with no significant difference in gluconeogenesis. The influence of interindividual variations in plasma carbenoxolone concentrations was investigated for each of the variables that were significantly different between carbenoxolone and placebo phases in either group. In Pearson simple correlations, plasma levels of carbenoxolone were not significantly associated with the difference between measurements during carbenoxolone and placebo phases. Multiple regression was employed to explore whether differences in the effects of carbenoxolone between DM and controls could be accounted for by differences in plasma carbenoxolone levels. Explanatory variables were plasma carbenoxolone concentration and diagnosis (DM or control, coded as 0 and 1). These models did not show any independent effect of plasma carbenoxolone concentration.
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Discussion |
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An important consideration in designing this study to test the utility of 11ß-HSD1 inhibition in metabolic disease was raised by observations that there are tissue-specific alterations in enzyme activity in obesity. Thus, 11ß-HSD1 is increased in adipose tissue, but decreased in liver in obesity (6, 7, 8, 17, 27). In contrast, lean patients with type 2 diabetes have normal adipose 11ß-HSD1 and less marked down-regulation of hepatic conversion of cortisone to cortisol (18, 28). To avoid the potential confounding effects of obesity and to exclude any unknown effects of oral hypoglycemic or antihypertensive agents, we selected nonobese normotensive patients with type 2 diabetes controlled by dietary therapy alone. The result was that patients in this study were not typical of type 2 diabetes. Indeed, they had near-normal blood glucose and HbA1c levels, a small requirement for overnight insulin infusion to obtain fasting euglycemia, and only minor differences in plasma lipids. After overnight euglycemia with insulin infusion as required, glucose production, free fatty acids, and glucagon levels were not elevated in these diabetic patients, and glucose disposal was not measurably impaired. Nonetheless, the effects of carbenoxolone differed between healthy controls and diabetic patients; an effect on cholesterol was only evident in healthy controls, and measurable effects on glucose production were only evident in diabetic patients.
In a previous study we showed that the same regime of carbenoxolone administration to healthy men resulted in enhanced insulin sensitivity, as measured by increased glucose infusion rate during a hyperinsulinemic clamp (16). A key difference, however, is that the previous study was performed with a higher insulin infusion rate and achieved higher concentrations (
70 mU/liter compared with 30 mU/liter here) designed to examine effects on insulin-stimulated glucose uptake rather than glucose production (29). Also, GH and glucagon levels were not clamped previously, and the participants were younger. In the current study there was a trend for a similar magnitude of increase in glucose infusion rate in healthy controls (means differed by 7% previously and by 17% here), but it did not reach statistical significance. Glucose production was marginally, but not significantly, lower in healthy men after carbenoxolone treatment in the current study. This contrasts with the statistically significant effects of carbenoxolone on glucose kinetics in diabetic patients. By analogy with other insulin-sensitizing therapies it might be anticipated that the effects of carbenoxolone would be smaller in healthy controls than in diabetic patients, because, for example, troglitazone induced around twice the increase in insulin sensitivity in diabetic patients (30) as it did in healthy men (31). Further, plasma carbenoxolone levels tended to be higher in the diabetic patients than in controls, so that the effect of carbenoxolone could have been underestimated in control subjects. Single measurements of plasma carbenoxolone concentrations were included in this study principally as a qualitative assessment of compliance, and more detailed pharmacokinetic studies would be required to confirm that this difference did not occur by chance. Importantly, however, in multiple regression analysis the variations in carbenoxolone concentrations between individuals did not account for different effects of carbenoxolone in DM patients and controls. Finally, insulin levels during the clamp studies were higher in the diabetic patients during placebo therapy than in all other groups, which may lead to underestimation of the effects of carbenoxolone in the diabetic patients. Against this background, it is unclear whether quantitative or qualitative differences explain the discrepancies between the effects of carbenoxolone in health and diabetes, although we suspect the former.
This is the first report of the effects of carbenoxolone, or any 11ß-HSD inhibitor, in diabetic patients. It shows that carbenoxolone affects glucose production, as inferred indirectly from our previous report (16), but the mechanism of the effect was not expected. In 11ß-HSD1 knockout mice a key feature is impaired up-regulation of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase, on fasting (2). Glucocorticoids are known to oppose the effect of insulin in regulating the expression of gluconeogenic enzymes (32). However, carbenoxolone did not alter gluconeogenesis after overnight fast, during hyperinsulinemia, or during hyperglucagonemia. One consideration in this paradox is that the contribution of the kidney to gluconeogenesis in man remains unquantified. By inhibiting inactivation of cortisol by 11ß-HSD2 in kidney (14) carbenoxolone increases intrarenal cortisol concentrations, which might enhance renal gluconeogenesis in compensation. To resolve this will require studies either with selective 11ß-HSD1 inhibitors or with cannulation of hepatic and/or renal vein. The kidney is not, however, a major site of glycogen storage. Glucocorticoids have complex effects on glycogenic and glycogenolytic enzymes, which predict increased turnover and amplification of the effect of other signals (32, 33). Thus, the observation that carbenoxolone attenuated net glucagon-induced glycogenolysis is consistent with lowering of intrahepatic cortisol concentrations.
A more recently recognized consequence of changes in intrahepatic glucocorticoid concentrations is the effect on lipid metabolism (3). The effects of carbenoxolone in the liver are the most likely explanation for the decrease in total cholesterol observed in healthy controls. In 11ß-HSD1 knockout mice hepatic lipid catabolism is markedly increased, while synthesis is apparently normal, resulting in reduced serum triglycerides and total cholesterol (3). In addition, altered apolipoprotein A1 expression in these animals may account for higher HDL cholesterol (3). However, the importance of enhanced lipid catabolism in man and comparison of effects in healthy controls and diabetic patients should be reassessed with a longer duration of carbenoxolone administration, because plasma lipids take several weeks to reequilibrate after the introduction of conventional lipid-lowering therapy.
Liquorice derivatives, such as carbenoxolone and glycyrrhetinic acid, are potent inhibitors of both isozymes of 11ß-HSD in vitro and in cell culture (10, 34, 35, 36). However, in vivo they have inconsistent effects, probably because of pharmacokinetic differences in access to tissues. Thus, carbenoxolone, but not glycyrrhetinic acid, inhibits hepatic 11ß-HSD1 in vivo in man, as judged by impaired generation of cortisol after an oral dose of cortisone. In animals, in vivo inhibition of 11ß-HSDs with carbenoxolone in other tissues is also inconsistent, for example varying between different regions of the central nervous system (37, 38). Indeed, in Zucker obese rats in vivo administration of carbenoxolone inhibits 11ß-HSD1 in liver, but not in adipose tissue (Livingstone, D. E. W., et al., unpublished observations). In the current study relatively modest hyperinsulinemia was employed to approximate the ED50 for suppression of hepatic glucose production (29). For these reasons the positive effects of carbenoxolone on hepatic carbohydrate and lipid metabolism but lack of effect on peripheral glucose uptake in both the current and previous study (16) do not allow the conclusion that inhibition of 11ß-HSD1 in extrahepatic tissues, notably adipose tissue, would not be beneficial. However, the acute effects of carbenoxolone on hepatic insulin sensitivity were of modest magnitude in the lean group of patients studied here. For more substantial effects on glucose tolerance and glycemic control in patients with diabetes, it appears likely that 11ß-HSD1 inhibitors will be required to inhibit glucocorticoid regeneration in adipose tissue as well as liver. Reducing cortisol action in adipose tissue may then provide an increase in peripheral glucose disposal in addition to the reduced glucose production observed with carbenoxolone. Further, given the up-regulation of adipose 11ß-HSD1 in obesity (6, 7, 8), but not in lean patients with type 2 diabetes (18), inhibition of adipose is likely to be of the most benefit in obese patients.
In summary, these studies with a nonselective 11ß-HSD inhibitor illustrate the potential value of inhibition of 11ß-HSD1 in lean hyperglycemic patients. It will now be important to establish whether similar benefits can be obtained in obese patients and patients with dyslipidemia. However, by inhibiting renal 11ß-HSD2, carbenoxolone has unacceptable long-term side-effects, including raising blood pressure, so that exploiting this approach for useful therapy will require either simultaneous blockade of renal mineralocorticoid receptors or the long-awaited development of selective 11ß-HSD1 inhibitors.
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Acknowledgments |
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Footnotes |
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Present address for R.C.A.: University of Bristol, Research Center for Neuroendocrinology, Bristol Royal Infirmary, Bristol, United Kingdom BS2 8HW.
Present address for O.R.: Department of Anesthesiology, KARO, Karolinska Institute, Huddinge Hospital, 14186 Hudinge, Sweden.
Abbreviations: DM, Diabetes mellitus; HbA1c, hemoglobin A1c; HDL, high density lipoprotein; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1; Ra, rate of glucose appearance; Rd, rate of peripheral glucose disposal.
Received July 30, 2002.
Accepted October 1, 2002.
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 R. A. S. Schweizer, M. Zurcher, Z. Balazs, B. Dick, and A. Odermatt Rapid Hepatic Metabolism of 7-Ketocholesterol by 11{beta}-Hydroxysteroid Dehydrogenase Type 1: SPECIES-SPECIFIC DIFFERENCES BETWEEN THE RAT, HUMAN, AND HAMSTER ENZYME J. Biol. Chem., April 30, 2004; 279(18): 18415 - 18424. [Abstract] [Full Text] [PDF]
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 T. C. Sandeep, J. L. W. Yau, A. M. J. MacLullich, J. Noble, I. J. Deary, B. R. Walker, and J. R. Seckl From The Cover: 11{beta}-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics PNAS, April 27, 2004; 101(17): 6734 - 6739. [Abstract] [Full Text] [PDF]
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N. M. Morton, J. M. Paterson, H. Masuzaki, M. C. Holmes, B. Staels, C. Fievet, B. R. Walker, J. S. Flier, J. J. Mullins, and J. R. Seckl Novel Adipose Tissue-Mediated Resistance to Diet-Induced Visceral Obesity in 11{beta}-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice Diabetes, April 1, 2004; 53(4): 931 - 938. [Abstract] [Full Text] [PDF]
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 J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]
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P. Alberts, C. Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norling, G. Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, et al. Selective Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Improves Hepatic Insulin Sensitivity in Hyperglycemic Mice Strains Endocrinology, November 1, 2003; 144(11): 4755 - 4762. [Abstract] [Full Text] [PDF]
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J. Westerbacka, H. Yki-Jarvinen, S. Vehkavaara, A.-M. Hakkinen, R. Andrew, D. J. Wake, J. R. Seckl, and B. R. Walker Body Fat Distribution and Cortisol Metabolism in Healthy Men: Enhanced 5{beta}-Reductase and Lower Cortisol/Cortisone Metabolite Ratios in Men with Fatty Liver J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4924 - 4931. [Abstract] [Full Text] [PDF]
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D. J. Wake, E. Rask, D. E. W. Livingstone, S. Soderberg, T. Olsson, and B. R. Walker Local and Systemic Impact of Transcriptional Up-Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3983 - 3988. [Abstract] [Full Text] [PDF]
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D. S. Weigle Pharmacological Therapy of Obesity: Past, Present, and Future J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2462 - 2469. [Full Text] [PDF]
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D. E. W. Livingstone and B. R. Walker Is 11beta -Hydroxysteroid Dehydrogenase Type 1 a Therapeutic Target? Effects of Carbenoxolone in Lean and Obese Zucker Rats J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 167 - 172. [Abstract] [Full Text]
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and •, Healthy controls; 
and 
, diabetic patients. 
, measurements during hyperinsulinemia and hyperglucagonemia from 1200–1230 h. *, P < 0.05; **, P < 0.01 (between the groups indicated, by paired t tests).