A potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models

Oh, Hye Young; Jeong, Ki‐Heon; Han, Hye Young; Son, Hyun Joo; Kim, Su Sung; Lee, Hyun Jung; Kim, Shinae; Ho, Joon; Jun, Hee-Sook; Ryu, Je Ho; Choi, Cheol Soo

doi:10.1016/j.ejphar.2015.10.042

Cited by 14 publications

(22 citation statements)

References 39 publications

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“…Additionally, 11β-HSD1 KO mice are resistant to obesity and MS [12]. In addition, pharmacologic inhibition of endogenous 11β-HSD1 has been shown to reduce weight gain and improve lipid metabolic profile and insulin sensitivity in obese animal models [13,14]. These results support the hypothesis that 11β-HSD1 plays a pathogenic role in the development of obesity and insulin resistance in adipose tissue through elevated active GC levels.…”

Section: Introductionsupporting

confidence: 61%

Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice

Wang

Liu

et al. 2019

Clinical Science

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Excessive glucocorticoid (GC) production in adipose tissue promotes the development of visceral obesity and metabolic syndrome (MS). 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is critical for controlling intracellular GC production, and this process is tightly regulated by hexose-6-phosphate dehydrogenase (H6PDH). To better understand the integrated molecular physiological effects of adipose H6PDH, we created a tissue-specific knockout of the H6PDH gene mouse model in adipocytes (adipocyte-specific conditional knockout of H6PDH (H6PDHAcKO) mice). H6PDHAcKO mice exhibited almost complete absence of H6PDH expression and decreased intra-adipose corticosterone production with a reduction in 11β-HSD1 activity in adipose tissue. These mice also had decreased abdominal fat mass, which was paralleled by decreased adipose lipogenic acetyl-CoA carboxylase (ACC) and ATP-citrate lyase (ACL) gene expression and reduction in their transcription factor C/EBPα mRNA levels. Moreover, H6PDHAcKO mice also had reduced fasting blood glucose levels, increased glucose tolerance, and increased insulin sensitivity. In addition, plasma free fatty acid (FFA) levels were decreased with a concomitant decrease in the expression of lipase adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) in adipose tissue. These results indicate that inactivation of adipocyte H6PDH expression is sufficient to cause intra-adipose GC inactivation that leads to a favorable pattern of metabolic phenotypes. These data suggest that H6PDHAcKO mice may provide a good model for studying the potential contributions of fat-specific H6PDH inhibition to improve the metabolic phenotype in vivo. Our study suggests that suppression or inactivation of H6PDH expression in adipocytes could be an effective intervention for treating obesity and diabetes.

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Section: Introductionsupporting

confidence: 61%

Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice

Wang

Liu

et al. 2019

Clinical Science

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“…Besides, SKI2852 treatment led to a dose-dependent suppression of both PEPCK and G6Pase expression levels, compared with vehicle treatment. These data suggest that 11βHSD1 inhibition by SKI2852 may improve the whole body and hepatic insulin sensitivities and reverse diabetic symptoms by, at least in part, suppression of these gluconeogenic enzyme expression levels in DIO mice [28].…”

Section: In Vivo Preclinical Trialsmentioning

confidence: 78%

“…In almost all in vivo pre-clinical studies included in this review (Table 3), the duration and level of 11β-HSD1 activity inhibition in different tissues (liver and adipose) were evaluated by an ex-vivo 11β-HSD1 inhibition assay [5,17,[27][28][29][30]33]. In addition, despite the multiple results achieved, no preclinical trial refers to safety in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological 11β-HSD1 inhibition with CNX-010-49, KR-67105, Compound 11 and H8 have normalized most of metabolic dysregulations in rodents, including hyperglycemia, glucose intolerance and insulin resistance [27,29,31,33] and therefore may be useful as new therapeutic compounds for T2DM prevention and treatment. The selective and potent enzyme inhibition achieved with SKI2852 makes it a compound with great potential and an important drug candidate for diabetes treatment [28]. KR-67105 and other compounds also show anti-diabetic action by the suppression of diabetes-related gene expressions, such as G6Pase and PEPCK in mice, and therefore may provide a new therapeutic window in T2DM prevention and treatment [29].…”

Section: Discussionmentioning

confidence: 99%

“…In DIO-C57BL/6 mice, compound SKI2852 led to a strong inhibition of cortisonecortisol conversion by 80% in both liver and adipose tissue [28]. In ob/ob mice a 34% decrease in postprandial glycemia values and a 21% decrease in HbA1c values were ob-served.…”

Section: In Vivo Preclinical Trialsmentioning

confidence: 99%

See 2 more Smart Citations

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

2021

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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.

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Comprehensive chemical analysis of Zhenshu Tiaozhi formula and its effect on ameliorating glucolipid metabolic disorders in diabetic rats

Cai

Zhang

et al. 2021

Biomedicine & Pharmacotherapy

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A potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models

Cited by 14 publications

References 39 publications

Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice

Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice

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

Comprehensive chemical analysis of Zhenshu Tiaozhi formula and its effect on ameliorating glucolipid metabolic disorders in diabetic rats

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