Effects of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome

Feig, Peter U.; Shah, Sukrut; Hermanowski‐Vosatka, Anne; Plotkin, D.; Springer, Martin S.; Donahue, Steven; Thach, Chau; Klein, E.; Lai, Eseng; Kaufman, Keith D.

doi:10.1111/j.1463-1326.2011.01375.x

Cited by 150 publications

(179 citation statements)

References 20 publications

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“…An additional study has also demonstrated increased 5bR activity with increasing hepatic fat (78). Although selective 11b-HSD1 inhibitors have not been studied in the context of hepatic steatosis, in patients with diabetes, they caused modest improvement in glycaemic control and weight loss and improved lipid profiles (79,80).…”

Section: Glucocorticoidsmentioning

confidence: 99%

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

Hazlehurst

Tomlinson

2013

European Journal of Endocrinology

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Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease spanning from simple benign steatosis to steatohepatitis with fibrosis and scarring that can eventually lead to cirrhosis. Its prevalence is rising rapidly and is developing into the leading indication for liver transplantation worldwide. Abnormalities in endocrine axes have been associated with NALFD, including hypogonadism, hypothyroidism, GH deficiency and hypercortisolaemia. In some instances, correction of the endocrine defects has been shown to have a beneficial impact. While in patients with type 2 diabetes the association with NAFLD is well established and recognised, there is a more limited appreciation of the condition among common endocrine diseases presenting with hormonal excess or deficiency. In this review, we examine the published data that have suggested a mechanistic link between endocrine abnormalities and NAFLD and summarise the clinical data endorsing these observations.

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Section: Glucocorticoidsmentioning

confidence: 99%

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

Hazlehurst

Tomlinson

2013

European Journal of Endocrinology

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“…There were also reductions in weight (−1.8 kg) and blood pressure (systolic −7.9 mmHg and diastolic −5.4 mmHg). In patients without statin treatment, MK-0916 increased total cholesterol and LDL-cholesterol by about 10% [89]. In similarly overweight/obese volunteers with metformin-treated type 2 diabetes, 200 mg daily of INCB-13739 for 12 weeks lowered HbA 1c (−0.6%), FPG (−0.64 mmol/l), HOMA-IR (−24%), body weight (≈ −1 kg) and total cholesterol (−3%).…”

Section: βHsd1 Inhibitorsmentioning

confidence: 99%

“…This requires careful consideration and more data even though no serious adverse events have been reported in short-term (3 month) clinical trials published to date [88][89][90][91].…”

Section: Outstanding Challengesmentioning

confidence: 99%

“…A number of selective 11βHSD1 inhibitors have been tested in humans, and data from phase II clinical trials have been published to date on four of them (MK-0916, MK-0736, INCB-13739 and ABT-384) [88][89][90][91]; for a summary on metabolic outcomes see Table 1. In obese patients with type 2 diabetes, 6 mg MK-0916 daily for 12 weeks lowered HbA 1c by 0.3% but there was no effect on fasting plasma glucose (FPG, the primary endpoint).…”

Section: βHsd1 Inhibitorsmentioning

confidence: 99%

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Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

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Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissuespecific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

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“…A plazmaglükózértékben nem volt szignifi káns különbség a gyógyszert és a placebót szedők között, de a hypertonia előfordulása, a HbA 1c és a testsúly szignifi kánsan csök-kent a gyógyszert szedők körében [47].…”

Section: Klinikai Vizsgálatokban Kipróbált 11-β-hsd-1-gátlókunclassified

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

et al. 2013

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A glükokortikoidok szabályozzák a szénhidrát-és aminosav-anyagcserét, modulálják az immunrendszer működé-sét és a stresszre adott válaszreakciókat. Elégtelen, illetve fokozott szekréciójuk jellegzetes kórképeket okoz. A szervezet glükokortikoidhormon-ellátottsága mellett az utóbbi évtizedben előtérbe került az adott szövetekben loká-lisan képződő glükokortikoidok patofi ziológiai szerepének kutatása. A lokális glükokortikoidellátottság egyik kulcsenzime a sejtek endoplazmatikus reticulumában elhelyezkedő 11-β-hidroxi-szteroid-dehidrogenáz enzim 1-es és 2-es típusa, amelyek az inaktív kortizon és az aktív kortizol közötti kétirányú átalakulást katalizálják. Az 1-es tí-pusú enzim elsősorban a kortizon aktiválásában játszik szerepet és főként a májban, gonádokban, zsírszövetben, agyban és csontban a biológiailag aktív kortizol lokális képződéséért felelős. Az enzimet kódoló gén az 1-es kromoszómán található. A szerzők jelen munkájukban összefoglalják a 11-β-hidroxi-szteroid-dehidrogenáz enzim 1-es típusának működésével kapcsolatba hozható klinikai és (kór)élettani folyamatokat. Összefoglalójukban áttekintik az enzimaktivitás gátlásában szerepet játszó genetikai variánsokkal kapcsolatos legfontosabb ismereteket és az enzimaktivitást gátló vegyületekkel szerzett tapasztalatokat. Az eredmények összegzéséből kitűnik, hogy bár ismereteink sok területen még hiányosak, az 1-es típusú enzim működésének és/vagy termelődésének gyógyszeres befolyásolása ígéretes terápiás lehetőséget jelenthet elhízásban, csontritkulásban vagy akár cukorbetegségben szenvedő betegek kezelésében. Orv. Hetil., 2013, 154, 283-293. Kulcsszavak: kortizol, kortizon, szövetspecifi kus glükokortikoidhatás, 11-β-hidroxi-szteroid-dehidrogenáz 1-es típus Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disordersGlucocorticoids play an important role in the regulation of carbohydrate and amino acid metabolism, they modulate the function of the immune system, and contribute to stress response. Increased and decreased production of glucocorticoids causes specifi c diseases. In addition to systemic hypo-or hypercortisolism, alteration of local synthesis and metabolism of cortisol may result in tissue-specifi c hypo-or hypercortisolism. One of the key enzymes participating in the local synthesis and metabolism of cortisol is the 11β-hydroxysteroid dehydrogenase enzyme. Two isoforms, type 1 and type 2 enzymes are located in the endoplasmic reticulum and catalyze the interconversion of hormonally active cortisol and inactive cortisone. The type 1 enzyme mainly works as an activator, and it is responsible for the generation of cortisol from cortisone in liver, adipose tissue, brain and bone. The gene encoding this enzyme is located on chromosome 1. The authors review the physiological and pathophysiological processes related to the function of the type 1 11β-hydroxysteroid dehydrogenase enzyme. They summarize the potential signifi cance of polymorphic variants of the enzyme in clinical diseases as well as knowledge related to inhibitors of...

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Effects of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome

Abstract: Inhibition of HSD1 with MK-0916 was generally well tolerated in patients with T2DM and MetS. Although no significant improvement in FPG was observed with MK-0916 compared to placebo, modest improvements in A1C, body weight and blood pressure were observed.

Cited by 150 publications

References 20 publications

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

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