Several lines of evidence implicate elevated 11p-HSD1 activity in the etiology and/ or maintenance of type 2 diabetes and metabolic syndrome. There is a higher level of 11p-HSD1 mRNA and activity in adipose tissue of obese humans [11,12,14,39] and rodents . Chronic high-fat feeding decreases 11 |b-HSD1 activity and mRNA in fat of C57Bl/6J mice, suggesting that this serves as an adaptive mechanism attempting to protect against the adverse metabolic consequence of high-fat feeding . Interestingly, A/J mice chronically fed a high-fat diet become obese but are less hyperinsulinemic than C57Bl/6J mice, and this is associated with lower basal adipose tissue 11 p-HSD 1 activity and mRNA and a more pronounced decrease in activity with high-fat feeding . This suggests that lower local synthesis of active glucocorticoid in A/J mice confers protection from dysregulated glucose homeo-stasis due to high-fat feeding. Transgenic overexpression of 11p-HSD1 in adipose tissue of mice produces intra-abdominal obesity, insulin resistance, dyslipidemia, and hypertension [42,43] in the absence of elevated corticosterone.
In contrast, mice with targeted disruption of the 11p-HSD1 gene are resistant to diet-induced obesity , have improved glucose tolerance  and an improved lipid profile . Additionally, mice with adipose tissue-specific overexpression of 11 p-HSD2, the enzyme that catalyzes the conversion of active glucocorticoid in to the inactive form, resist diet-induced obesity, have increased energy expenditure, improved glucose tolerance, and insulin sensitivity .
All these data suggest that pharmacological inhibition of 11p-HSD1 activity, particularly in adipose tissue, will reduce intracellular glucocorticoid signaling and improve aspects of metabolic syndrome. Indeed, experimental evidence exists that supports this hypothesis. In monogenic murine models of obesity and type 2 diabetes (Lepob/ob, KKAy), oral administration (200mg/kg bid for 4d) of a selective 11p-HSD1 inhibitor, BVT-2733 (vide infra), significantly reduced plasma glucose levels and improved glucose tolerance . Treatment also produced a modest inhibition of food intake, and a decrease in hepatic glucose production with an accompanying decrease in the level of liver phosphoenolpyruvate carboxykinase mRNA . Consistent with these findings in rodents, treatment of type 2 diabetic humans with the non-selective inhibitor carbenoxolone has been shown to improve hepatic insulin sensitivity [48,49].
A recent study reported that oral administration of a selective 11 p-HSD1 inhibitor to DIO (diet-induced obese) mice (20mg/kg bid for 11d) reduced food intake, body weight and adiposity, fasting glucose and insulin levels . Administration of the same compound to high-fat-fed streptozotocin-treated mice (30 mg/kg bid for 9d) failed to affect feeding or body weight and adiposity, but reduced fasting and postprandial glucose and insulin and improved glucose tolerance. Lastly, treatment of apoE knockout mice with the selective 11p-HSD1 inhibitor (10mg/kg/d for 8 weeks in diet) significantly attenuated the deposition of aortic plaque and cholesterol ester. This was accompanied by a decrease in circulating monocyte chemoattractant protein-1, suggesting that 11p-HSD1 inhibition has a direct anti-inflammatory effect at the blood-vessel wall.
Elevated glucocorticoids have been shown to have negative effects on hippo-campal neurochemistry and function, and it has been proposed that exposure of the hippocampus to high levels of glucocorticoids contributes to aging-related cognitive impairment . 11p-HSD1 is expressed throughout the brain, including the hippocampus , and studies with 11p-HSD1 knockout mice demonstrate that removal of glucocorticoid regeneration within the CNS has a protective effect against age-related cognitive impairment . Indeed, a recent study in elderly men and type 2 diabetics reported that oral administration of carbenoxolone (100 mg tid for 4 weeks) improved verbal fluency in healthy men and verbal memory in type 2 diabetics . These results suggest that 11p-HSD-1 inhibition may be effective in preventing or attenuating the decline of cognitive function with aging.
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