Chronic exposure to glucocorticoid hormones, resulting from either drug treatment or Cushing's syndrome, results in insulin resistance, central obesity, and symptoms similar to the metabolic syndrome. We hypothesized that the major metabolic effects of corticosteroids are mediated by changes in the key metabolic enzyme adenosine monophosphate-activated protein kinase (AMPK) activity. Activation of AMPK is known to stimulate appetite in the hypothalamus and stimulate catabolic processes in the periphery. We assessed AMPK activity and the expression of several metabolic enzymes in the hypothalamus, liver, adipose tissue, and heart of a rat glucocorticoid-excess model as well as in in vitro studies using primary human adipose and primary rat hypothalamic cell cultures, and a human hepatoma cell line treated with dexamethasone and metformin. Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroid-induced effects on AMPK in human adipocytes and rat hypothalamic neurons. Our data suggest that glucocorticoid-induced changes in AMPK constitute a novel mechanism that could explain the increase in appetite, the deposition of lipids in visceral adipose and hepatic tissue, as well as the cardiac changes that are all characteristic of glucocorticoid excess. Our data suggest that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.

Background: There is an urgent need to limit the metabolic side-effects of glucocorticoid overexposure as these can lead to Cushing's syndrome, associated with high morbidity. We have explored the potential for metformin to ameliorate such effects whilst sparing the anti-inflammatory benefits of glucocorticoids. Methods: In this double-blind, phase 2 proof-of-concept trial, 53 patients without known diabetes established on mid-to-high doses of glucocorticoids, administered as treatment for a chronic inflammatory disease, were randomised to receive 2550mg/day metformin (n=26) or an identical placebo (n=27) for 12 weeks. The primary endpoint was the change in visceral to truncal subcutaneous fat ratio assessed by computed tomography; secondary endpoints involved metabolic, bone, cardiovascular and inflammatory parameters. Findings: Nineteen patients on metformin and 21 on placebo completed the study. The groups received equivalent cumulative dose of glucocorticoids (1860mg (IQR 1060 to 2810) vs. 1770mg (IQR 1020-2356) prednisolone equivalent; p=0.76). There was no change in the visceral-to-subcutaneous fat ratio (0.11 (95%CI-0.02 to 0.24); p=0.09) between the treatment groups but metformin-treated patients lost truncal subcutaneous fat (-3835mm 2 (95%CI-6781 to-888); p=0.01) compared to placebo. Improvements in markers of carbohydrate, lipid, liver and bone metabolism were observed on metformin. Additionally, metformin-treated patients had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters and clinical markers of disease activity. The frequency of pneumonia (1 vs. 7 events; p=0.01), overall rate of moderate-to-severe infections (2 vs. 11; p=0.001), and all-cause hospital admissions due to adverse events (1 vs. 9; p=0.001) were lower in the metformin group compared with placebo. Metformin-treated patients experienced more diarrhoea initially. Interpretation: Metformin administration improved the metabolic profile of glucocorticoid-treated patients with inflammatory disease, favourably modifying cardiovascular risk surrogates, reducing inflammation and hospitalisation.

SummaryAdrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.