Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver.
To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m⁻² ·min⁻¹) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.
['Macfarlane|D P|DP|', 'Raubenheimer|P J|PJ|', 'Preston|T|T|', 'Gray|C D|CD|', 'Bastin|M E|ME|', 'Marshall|I|I|', 'Iredale|J P|JP|', 'Andrew|R|R|', 'Walker|B R|BR|']
D001786:Blood Glucose D018592:Cross-Over Studies D003924:Diabetes Mellitus, Type 2 D004311:Double-Blind Method D004734:Energy Metabolism D004791:Enzyme Inhibitors D005230:Fatty Acids, Nonesterified D005990:Glycerol D006727:Hormone Antagonists D006801:Humans D006854:Hydrocortisone D007201:Indicator Dilution Techniques D007328:Insulin D008099:Liver D009682:Magnetic Resonance Spectroscopy D008297:Male D008797:Metyrapone D008875:Middle Aged D015735:Mifepristone D065626:Non-alcoholic Fatty Liver Disease D011965:Receptors, Glucocorticoid D012606:Scotland D013252:Steroid 11-beta-Hydroxylase D013997:Time Factors D016896:Treatment Outcome
glucocorticoids Type 2 diabetes fatty acid metabolism nonalcoholic fatty liver disease