Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 as Potential Drugs for Type 2 Diabetes Mellitus—A Systematic Review of Clinical and In Vivo Preclinical Studies

Abstract

Diabetes mellitus is a pathology with increasing frequency in society, being one of the main causes of death worldwide. For this reason, new therapeutic targets have been studied over the years. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme responsible for reducing cortisone to its active form cortisol, which can lead to metabolic changes such as insulin resistance and hyperglycemia. Therefore, 11β-HSD1 inhibition may offer a new therapeutic approach for type 2 diabetes mellitus. This work intends to systematically review the available scientific evidence on this subject. For this, a search was conducted in three databases and 15 clinical and in vivo preclinical studies were included in this review. Despite the high inhibitory and selectivity levels achieved with several molecules and the demonstrated clinical efficacy in diabetes treatment, no phase III clinical trials have yet been conducted. This is important because the long-term effects of 11β-HSD1 inhibitors including the consequences in hypothalamic–pituitary–adrenal axis must be evaluated. However, this enzyme remains a promising target for drug development, including due to its effectiveness in controlling various factors that constitute the metabolic syndrome and its potential for multiple indications in patients with diabetes, including wound healing and weight loss.

Celastrol attenuates high‐fructose diet‐induced inflammation and insulin resistance via inhibition of 11β‐hydroxysteroid dehydrogenase type 1 activity in rat adipose tissues

“…14 It is evident from various reports that increased activity of intracellular glucocorticoids in metabolically active tissues including adipose tissues contributes to the development of metabolic syndrome, particularly insulin resistance and type 2 diabetes. 10,39,40 11β-HSD1 is a bidirectional NDPH-dependent enzyme responsible to interconvert inactive cortisone to its active form cortisol, which in excess can lead to metabolic dysregulations. Studies have shown that the inhibitions of cortisol action using GR antagonist such as 11β-HSD1 inhibitors exhibited ameliorative properties to protect against type 2 diabetes, obesity and insulin resistance.…”

“…Glucocorticoids such as cortisol are among the ubiquitous hormones that modulate various biological and physiological processes including insulin sensitivity, regulation of energy metabolism, inflammation, stress response, and cardiovascular functions 14 . It is evident from various reports that increased activity of intracellular glucocorticoids in metabolically active tissues including adipose tissues contributes to the development of metabolic syndrome, particularly insulin resistance and type 2 diabetes 10,39,40 . 11β‐HSD1 is a bidirectional NDPH–dependent enzyme responsible to interconvert inactive cortisone to its active form cortisol, which in excess can lead to metabolic dysregulations.…”

“…Recent studies including prospective and cross-sectional studies on humans clearly suggest that visceral obesity and insulin resistance are strongly linked to the prolonged activation of tissue-specific intracellular GR, which represents as a ligand-dependent transcription factor in a manner that is independent of circulating cortisol levels in blood. 10 Increased locally tissue-specific glucocorticoids possess distinct effects to cause an unfavorable redistribution of lipid accumulation in several types of adipose tissues including visceral and subcutaneous white adipose tissue. 10 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular key enzyme acting as an oxidoreductase dependent on the provision of nicotinamide-adenine dinucleotide phosphate (NADPH) as a cofactor to convert inactive cortisone into physiologically active cortisol (corticosterone in rodents) within intact cells.…”

“…Active cortisol acts through activation of glucocorticoids receptor (GR) in several peripheral tissues including liver, kidney, vascular, and adipose tissues to mediate various biological and physiological functions. Recent studies including prospective and cross‐sectional studies on humans clearly suggest that visceral obesity and insulin resistance are strongly linked to the prolonged activation of tissue‐specific intracellular GR, which represents as a ligand‐dependent transcription factor in a manner that is independent of circulating cortisol levels in blood 10 . Increased locally tissue‐specific glucocorticoids possess distinct effects to cause an unfavorable redistribution of lipid accumulation in several types of adipose tissues including visceral and subcutaneous white adipose tissue 10 …”

“…11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is an intracellular key enzyme acting as an oxidoreductase dependent on the provision of nicotinamide‐adenine dinucleotide phosphate (NADPH) as a cofactor to convert inactive cortisone into physiologically active cortisol (corticosterone in rodents) within intact cells 10 . The intracellular cortisol level is tightly regulated by 11β‐HSD activity in endoplasmic reticulum (ER).…”