Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1: A novel treatment for the Metabolic Syndrome
Lead Research Organisation:
University of Birmingham
Department Name: Clinical and Experimental Medicine
Abstract
The rates of obesity and diabetes are escalating alarmingly in the UK population. These conditions significantly decrease life expectancy and increase the risk of heart attacks and strokes. We believe that increased steroid (cortisol) production within liver and fat tissue is an important cause of these conditions. Studies using newly developed drugs given to rats and mice with diabetes dramatically improve the condition and lower blood glucose levels to those seen in non-diabetic animals. In addition these drugs appear to reduce blood cholesterol levels and decrease weight. In collaboration with Pfizer inc. we now propose to test the efficacy of these drugs in the first human studies. Using a varriety of techniques we will be able to show that these drugs not only inhibit cortisol production form liver and fat, but that they improve blood glucose levels in patients with type 2 diabetes and decrease circulating cholesterol levels.
Technical Summary
Patients with Cushing?s syndrome inform us of the link between circulating cortisol excess and visceral obesity, type 2 diabetes mellitus and vascular mortality. However, circulating cortisol concentrations are normal in patients with Metabolic Syndrome-Diabetes-Obesity but we have shown that tissue-specific cortisol excess, mediated via 11 beta-hydroxysteroid dehydrogneases (11beta-HSD?s)is implicated in the pathogenesis of hypertension, hepatic glucose output and visceral adipogenesis. 11beta-HSD1, in liver and adipose, acts as an oxo-reductase generating cortisol from inactive cortisone and facilitates glucocorticoid action locally increasing hepatic gluconeogenesis and adipocyte differentiation. Clinical studies have linked 11beta-HSD1 expression to metabolic dysregulation in obesity, diabetes mellitus and polycystic ovary syndrome. Therefore, 11beta-HSD1 inhibition offers a novel therapy to treat patients with the metabolic syndrome by blocking cortisol generation in liver and fat.
In collaboration with Pfizer, we have developed selective 11beta-HSD1 inhibitors, selective in that they inhibit 11beta-HSD1 in human hepatocytes and adipocytes at low nM concentrations (5nM), but not the related 11beta-HSD2 (50 microM). In rodent models of obesity/diabetes they improve insulin sensitivity, reduce blood glucose and body weight.
Clinical studies will define optimal biomarkers of enzyme inhibition. Normal volunteers will be given the non-selective inhibitor carbenoxolone (300mg/day). Urinary cortisol/cortisone metabolites (measured by GC/MS), interconversion of prednisone to prednisolone (HPLC determination), generation of cortisol following oral cortisone acetate, subcutaneous adipose tissue microdialysis (cortisol/cortisone ratios in afferent and efferent catheters) and 11beta-HSD1 expression in adipose tissue biopsies (real-time PCR, primary culture enzyme assays) will be analysed. Studies will then be refined for the investigation of the selective 11beta-HSD1 inhibitor (Pfizer compound 887423). Once effective inhibition of 11beta-HSD1 is confirmed, studies will analyse its effect upon glucose tolerance (OGTT with insulin levels), insulin sensitivity (euglycaemic clamp), hepatic gluconeogenesis (in-house deuterated water assay). Their impact upon fuel metabolism, lipolysis and lipid metabolism will be determined by indirect calorimetry, adipose microdialysis (glycerol release) and adipose biopsy (expression of key enzymes in lipid metabolism). Longer term studies will address their impact upon body composition (DEXA), visceral fat mass (CT quantification) and safety parameters (liver function, biochemistry, haematology, HPA-axis, androgens).
This hypothesis led research has been fuelled by advances in the laboratory in partnership with Pharma. A translational aspect will potentially deliver a novel therapy for a major health hazard directly for patient benefit. It is likely that a successful outcome of this research will see randomised controlled trials of selective 11beta-HSD1 inhibition in obese patients with and without type 2 diabetes mellitus.
In collaboration with Pfizer, we have developed selective 11beta-HSD1 inhibitors, selective in that they inhibit 11beta-HSD1 in human hepatocytes and adipocytes at low nM concentrations (5nM), but not the related 11beta-HSD2 (50 microM). In rodent models of obesity/diabetes they improve insulin sensitivity, reduce blood glucose and body weight.
Clinical studies will define optimal biomarkers of enzyme inhibition. Normal volunteers will be given the non-selective inhibitor carbenoxolone (300mg/day). Urinary cortisol/cortisone metabolites (measured by GC/MS), interconversion of prednisone to prednisolone (HPLC determination), generation of cortisol following oral cortisone acetate, subcutaneous adipose tissue microdialysis (cortisol/cortisone ratios in afferent and efferent catheters) and 11beta-HSD1 expression in adipose tissue biopsies (real-time PCR, primary culture enzyme assays) will be analysed. Studies will then be refined for the investigation of the selective 11beta-HSD1 inhibitor (Pfizer compound 887423). Once effective inhibition of 11beta-HSD1 is confirmed, studies will analyse its effect upon glucose tolerance (OGTT with insulin levels), insulin sensitivity (euglycaemic clamp), hepatic gluconeogenesis (in-house deuterated water assay). Their impact upon fuel metabolism, lipolysis and lipid metabolism will be determined by indirect calorimetry, adipose microdialysis (glycerol release) and adipose biopsy (expression of key enzymes in lipid metabolism). Longer term studies will address their impact upon body composition (DEXA), visceral fat mass (CT quantification) and safety parameters (liver function, biochemistry, haematology, HPA-axis, androgens).
This hypothesis led research has been fuelled by advances in the laboratory in partnership with Pharma. A translational aspect will potentially deliver a novel therapy for a major health hazard directly for patient benefit. It is likely that a successful outcome of this research will see randomised controlled trials of selective 11beta-HSD1 inhibition in obese patients with and without type 2 diabetes mellitus.
