Abstract
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.
Highlights
Human ovarian follicles largely exist as a quiescent population, of which a small number daily initiate growth throughout reproductive life
This study demonstrates that inhibition of phosphatase and tensin homologue (PTEN) with bpV(HOpic) affects human ovarian follicle development by promoting the initiation of follicle growth and development to the secondary stage, as in rodent species, but severely compromises the survival of isolated secondary follicles
In this study we investigated the ability of bpV(HOpic) a pharmacological inhibitor of PTEN, a major negative regulator of the phosphoinositide 3-kinase (PI3K) pathway, to affect human ovarian follicle activation and development in both tissue fragments and isolated follicles in vitro
Summary
Human ovarian follicles largely exist as a quiescent population, of which a small number daily initiate growth throughout reproductive life. Remaining follicles degenerate either from the dormant state (Tingen et al, 2009) or after growth has been initiated (Kaipia and Hsueh, 1997). Development of growing follicles is controlled by the coordinated actions of multiple complex, integrated signalling pathways regulated by local and systemic hormonal signals (Pangas, 2007; Sobinoff et al, 2013) and reproductive senescence occurs when the quiescent follicle population is exhausted through activation and degeneration. Prior to exhaustion of the follicle pool, the overwhelming majority of human follicles are dormant and can persist in this state for decades. The ability to recruit these dormant follicles into the growing pool and support their complete development in vitro would
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