11beta-hydroxysteroid dehydrogenase inhibition reduces insulin resistance

Obesity and comorbid type 2 diabetes are two frequent and growing global problems. The insulin resistance syndrome was first described in 1988 and contributes to both conditions and indeed is generally accepted to represent a pathophysiological link between the two. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues. Considerable attention has been paid to the development of molecules able to reduce insulin resistance. LeadDiscovery has recently published a report overviewing the therapeutic potential of one class of molecules that fits this profile, the GSK-3 inhibitors (Click here for access). This class of drug stands to play a major role in the treatment of Alzheimer's disease, stroke and bipolar disorder as well as diabetes. Here we highlight a second strategy for reducing insulin insulin resistance, the inhibition of 11beta-hydroxysteroid dehydrogenases (11beta-HSD)1.

Glucocorticoids play a major role in glucose homeostasis by influencing hepatic gluconeogenesis and glycogen degradation. This process involves the activation nuclear receptors and can be modulated by intracellular enzymes that control glucocorticoid activity. 11beta-HSD1 is widely expressed, particularly so in the liver, and activates glucocorticoid by converting cortisone into cortisol or 11beta-dehydrocorticosterone into corticosterone. In contrast, 11beta-HSD2 catalyzes the inactivation of active glucocorticoid. Genetic deletion of 11beta-HSD1 lowers plasma glucose levels in mice on high-fat diets and attenuates the activation of enzymes involved in hepatic gluconeogenesis suggesting that inhibitors of this enzyme may be of use in various metabolic disorders. Consequently, Biovitrum recently conducted a high-throughput screen of their compound collection followed by a lead optimization process thus developing a series of arylsulfonamidothiazole 11beta-HSD1 inhibitors (see Barf et al, 2002). One lead molecule from this series, BVT.2733, is a selective inhibitor of murine 11beta-HSD1 and has previously been shown to decrease blood glucose levels and gluconeogenic enzymes in hyperglycemic mice (see Alberts et al, 2002).

Recently, Biovitrum researchers have reported that BVT.2733 can also limit insulin resistance. In their 2003 Endocrinology paper, Alberts et al report that oral BVT.2733 reduced plasma glucose levels in three different strains of hyperglycemic mice, but importantly not in normal mice suggesting that the therapeutic use of BVT.2733 may prevent hyperglycemia without causing rebound hypoglycemia. Parallel reductions in insulin levels were also reported. Glucose tolerance was also improved as determined using a standard glucose tolerance test. Although insulin levels were reduced, BVT.2733 increased hepatic insulin sensitivity in hyperglycemic mice.

The improved glucose tolerance and insulin sensitivity seen in response to BVT.2733 has prompted Biovitrum to the further develop 11beta-HSD1 inhibitors as treatments of conditions associated with insulin resistance such as obesity and type 2 diabetes. Consequently BVT.3498 has successfully exited a clinical phase I study of 66 healthy volunteers. Biovitrum is presently performing a Phase IIa study that will be finalized by the end of 2003.

Entry date Monday, November 17, 2003

Adapted from Alberts et al, Endocrinology. 2003 Nov;144(11):4755-62