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11 β ‐Hydroxysteroid dehydrogenase type 1 inhibition in type 2 diabetes mellitus
Author(s) -
Hollis G.,
Huber R.
Publication year - 2011
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2010.01305.x
Subject(s) - 11β hydroxysteroid dehydrogenase type 1 , endocrinology , medicine , type 2 diabetes mellitus , adipose tissue , metformin , obesity , body mass index , metabolic syndrome , overweight , type 2 diabetes , cortisone , diabetes mellitus , dehydrogenase , enzyme , biology , biochemistry
11 β ‐Hydroxysteroid dehydrogenase type 1 (11 β ‐HSD1) catalyses the intracellular conversion of inert cortisone to physiologically active cortisol, functioning to enhance local cortisol action beyond what would be predicted based on simple plasma exposures. Adipose tissue overexpression of 11 β ‐HSD1 in rodents to levels observed in human obesity can lead to a near complete metabolic syndrome phenotype, and inhibition of 11 β ‐HSD1 has been proposed to be of potential therapeutic benefit to patients with type 2 diabetes mellitus (T2DM). Recently published clinical results with the selective 11 β ‐HSD1 inhibitor, INCB13739, have, for the first time, provided evidence substantiating this hypothesis, and suggest that 11 β ‐HSD1 activity may be important in regulating glycaemia and cardiometabolic risk. In patients with T2DM failing metformin monotherapy, INCB13739 treatment achieves significant reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), and when present improves hyperlipidaemia and hypertriglyceridaemia. Interestingly, these positive effects are observed primarily in subjects categorized as obese (body mass index, BMI > 30 kg/m 2 ) and not in subjects categorized as overweight (BMI ≤ 30 kg/m 2 ), underscoring the likely importance of adipose tissue 11 β ‐HSD1 activity to the cardiometabolic sequelae of obesity. This review summarizes the therapeutic rationale for 11 β ‐HSD1 inhibition, and describes in detail the metabolic and endocrinologic changes observed in patients with T2DM treated with INCB13739.