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*Diabetes
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 285-291
Copyright © 2003 by The Endocrine Society

Original Article

Effects of the 11ß-Hydroxysteroid Dehydrogenase Inhibitor Carbenoxolone on Insulin Sensitivity in Men with Type 2 Diabetes

Robert C. Andrews, Olav Rooyackers and Brian R. Walker

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.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates cortisol from inactive cortisone in liver and adipose tissue. Inhibition of 11ß-HSD1 offers a novel potential therapy to lower intracellular cortisol concentrations and thereby enhance insulin sensitivity and hepatic lipid catabolism in type 2 diabetes, obesity, and hyperlipidemia. We evaluated this approach using the nonselective 11ß-HSD inhibitor, carbenoxolone, in healthy men and lean male patients with type 2 diabetes.

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.

This work was supported by grants from Diabetes UK, the Wellcome Trust (Catalyst Biomedica), and British Heart Foundation.

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.




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