Background and aims: HNF1A-MODY causes monogenic diabetes with a lean, insulin sensitive phenotype. Altered glucocorticoid (GC) metabolism has been implicated in the pathogenesis of type 2 diabetes (T2D) and inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which regenerates active cortisol from inactive cortisone have been trialled as a therapeutic approach. 11β-HSD1 is down-regulated in hepatocytes from Hnf1a knock-out mice but the role of pre-receptor GC metabolism in HNF1A-MODY has not been explored. We hypothesised that those with HNF1A-MODY would have a distinctive pattern of GC metabolism that may underpin aspects of their metabolic phenotype.
Subjects and methods: Urinary steroid metabolites were measured by gas chromatography mass spectrometry in 35 subjects with HNF1A-MODY and compared to 35 individuals with T2D and 35 non-diabetic controls. Groups were age- and BMI-matched. Results were analysed separately for men and women due to gender dimorphism of urinary steroids.
Results: 11β-HSD1 activity, assessed by the ratio of urinary (tetrahydrocortisol+5α-tetrahydrocortisol): tetrahydrocortisone was not different between the groups. However, the activity of 11β-HSD2, which deactivates cortisol and is defined by the ratio of urinary cortisol: cortisone, was reduced in patients with HNF1A-MODY and T2D compared to non-diabetic controls (Kruskal-Wallis: P=0.007 men; P=0.02 women). The reduction in renal 11β-HSD2 activity in HNF1A-MODY and T2D resulted in a significant increase in urinary free cortisol compared to non-diabetic controls (P=8.7×10−5 men; P=0.003 women). We also detected an increase in the activity of 5β-reductase (which inactivates cortisol to 5β-dihydrocortisol decreasing cortisol availability) in HNF1A-MODY compared to T2D subjects (P=0.004 men; P=0.005 women). There was no difference in the activity of 5β-reductase between T2D and non-diabetic controls.
Conclusions: Subjects with HNF1A-MODY have enhanced cortisol clearance through the increased activity of 5β-reductase. This has the potential to decrease local glucocorticoid availability and may result in improved metabolic phenotypes as compared to those with T2D.