Endocrine Abstracts

Patients with glucocorticoid (GC) excess develop insulin resistance and central obesity. We have demonstrated that GCs have tissue-specific effects on insulin sensitivity in humans, causing resistance in skeletal muscle but sensitivity in subcutaneous adipose tissue. The molecular mechanisms that underpin these differences remain poorly understood. Over the last decade small non-coding RNAs (microRNAs–miRNAs) controlling protein expression have been identified, representing an additional regulatory layer to the control of metabolism through the regulated expression of enzymes, transcription factors and signalling components. miRNAs are readily detected in human serum and altered miRNA profiles have been linked to metabolic disease.

In order to identify GC regulated miRNAs blood was extracted from 10 healthy volunteers under four treatment conditions. Volunteers were fasted for 12 h and infused with either saline or hydrocortisone (0.2 mg/kg per h) this was followed by 4 h of insulin infusion (100 mU/m² per min). Samples were taken after fasting (+/− hydrocortisone) and after insulin infusion (+/− hydrocortisone). RNA was extracted and used in miRNA array analysis, providing full coverage of mirBASE17, including 1750 known human miRNAs.

In the fasting state, hydrocortisone treatment significantly altered serum levels of seven miRNAs, including some with predicted metabolic targets. Compared to fasting saline, the combination of hydrocortisone and insulin regulated 16 miRNAs, interestingly increasing miR-195 (associated with hypertension) and miR-144 (inhibition of insulin receptor substrate 1 (IRS1)). Compared to insulin alone, hydrocortisone regulated 25 miRNAs, interestingly increasing miR-637 (involved in adipocyte differentiation) and miR-145 (inhibition of IRS1 and 2). This study has identified novel profiles of GC regulated miRNAs in human serum associated with insulin sensitivity, a number of which have predicted and demonstrated metabolic targets. These data will allow us to investigate the endocrine regulation of miRNAs and their role in metabolic homeostasis and highlights potential miRNA targets that may underpin the tissue-specific effects of GCs on insulin action.