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11β-HSD1 inhibitors

This enzyme is responsible for the regeneration of cortisol from its inert
form, cortisone (Figure 3). Inhibitors of 11β-HSD1 have reached Phase
IIb clinical trials for the treatment of T2DM. These compounds act by
decreasing the cortisol generated in liver and adipose tissue, thereby
reducing tissue-specific gluconeogenesis and fatty acid metabolism. 76

11β-HSD1 inhibitors are predicted to be at least weight neutral, if not
leading to some weight loss. In addition, they should improve glycae-
mia without inducing hypoglycaemia. The concern of physiologists is
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that if you artificially reduce the level of circulating cortisol by means of
the 11β-HSD1 pathway, you run the risk of adrenal gland compensation
and activation of the hypothalamic-pituitary-adrenal (HPA) axis,
resulting in the production of more cortisol. In this scenario, the
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adrenal glands might also simultaneously produce excess adrenal
androgens, which, at high concentrations are associated with numerous
negative effects.

To date, these fears have not been borne out in animal studies where
the complete deletion of the 11β-HSD1 gene in mice had, overall, in-
conclusively minimal effects on adrenal action. Harno and White
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(2010) conclude that 11β-HSD1 inhibition represent a compelling treat-
ment strategy for T2DM. Table 6 presents a ‘SWOT’ analysis of the
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11β-HSD1 inhibitors.

Figure 3. 11β-HSD1 and regeneration of cortisol. (a) Inactive cortisone is converted to
(b) active cortisol by the enzyme 11β-HSD1. 76

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