Sleep restriction, the reduction in sleep resulting from insufficient or interrupted sleep, affects a third of adults in the US. It arises from shortened slep periods, environmental disturbances, or disrupted sleep from obstructive sleep apnea, movement disorders, or other pathology. Sleep restriction induces stress, and causes insulin resistance, resulting in development of type 2 diabetes mellitus. Type 2 diabetes mellitus affects 26 million Americans at an estimated cost of $174 billion/year. The mechanisms underlying development of insulin resistance from sleep restriction remain unknown, although hormones involved in the stress response, principally cortisol (F) and testosterone (T), appear to play a major role. Until the mechanisms underlying rising insulin resistance are unveiled, targeted therapies cannot be developed. This proposal aims to establish that increased F and decreased T underlie development of insulin resistance. We will also uncover the processes that cause hypothalamopituitary adrenal (HPA) axis activation and hypothalamopituitary testicular (HPT) deactivation that must be present when F is increased and T is decreased. Interventions to modify release or action of these two hormones is eminently feasible, and will provide a means to alter the formidable increasing incidence of type 2 diabetes in this country, but the role of those hormones must initially be outlined. We will conduct 2 randomized placebo controlled studies that will restrict sleep to 4h/night for 4 nights in groups of 40 and 20 young (22-45y) men. We will show that increased F and decreased T are essential for sleep restriction to induce insulin resistance by comparing effects of sleep restriction on insulin resistance in 40 men under conditions where F and T can change freely with conditions where both are fixed. We will also determine, in 20 additional young men, if sleep restriction increases F through: (a) increasing hypothalamic corticotropin releasing hormone (CRH), evaluated by examining alterations in pituitary ACTH to a submaximal dose of dexamethasone;(b) heightened adrenal gland production of F, in response to the standard low dose i.v. cosyntropin test;and (c) muted negative feedback of pituitary ACTH by F, evaluated by quantifying unleashed ACTH secretory adaptations to blockade of steroidogenesis by ketoconazole. We will then examine if sleep restriction decreases T in these same 20 men by: (a) decreasing hypothalamic gonadotropin releasing hormone (GnRH), tested by examining the pituitary LH response to a submaximal dose of ganirelix;(b) muted Leydig cell production of T in response to rhLH;and (c) heightened negative feedback of pituitary LH by T, tested by quantifying LH secretion to T deprivation with ketoconazole. The goal is to understand how shortened or disturbed sleep results in metabolic ill-health, and to unveil the underpinning hormonal mechanisms. The studies have the potential to exert a major impact on understanding the mechanisms contributing to type 2 diabetes mellitus, which is closely associated with sleep-disordered breathing and other conditions which shorten sleep time, and imposes an exorbitant national health cost.
Insufficient sleep is common, and leads to insulin resistance, a major factor in the development of type 2 diabetes mellitus. This proposal attempts to reveal the hormonal mechanisms underlying the link between insufficient sleep with insulin resistance. The studies have the potential to outline specific interventions to modify the deleterious hormonal changes, and significantly impact the rising incidence of diabetes mellitus.
|Melehan, Kerri L; Hoyos, Camilla M; Hamilton, Garun S et al. (2018) Randomized Trial of CPAP and Vardenafil on Erectile and Arterial Function in Men With Obstructive Sleep Apnea and Erectile Dysfunction. J Clin Endocrinol Metab 103:1601-1611|
|Zhang, Wenyi; Piotrowska, Katarzyna; Chavoshan, Bahman et al. (2018) Sleep Duration Is Associated With Testis Size in Healthy Young Men. J Clin Sleep Med 14:1757-1764|
|Piotrowska, Katarzyna; Wang, Christina; Swerdloff, Ronald S et al. (2017) Male hormonal contraception: hope and promise. Lancet Diabetes Endocrinol 5:214-223|
|James, Stephen M; Honn, Kimberly A; Gaddameedhi, Shobhan et al. (2017) Shift Work: Disrupted Circadian Rhythms and Sleep-Implications for Health and Well-Being. Curr Sleep Med Rep 3:104-112|
|Melehan, K L; Hoyos, C M; Yee, B J et al. (2016) Increased sexual desire with exogenous testosterone administration in men with obstructive sleep apnea: a randomized placebo-controlled study. Andrology 4:55-61|
|Killick, Roo; Hoyos, Camilla M; Melehan, Kerri L et al. (2015) Metabolic and hormonal effects of 'catch-up' sleep in men with chronic, repetitive, lifestyle-driven sleep restriction. Clin Endocrinol (Oxf) 83:498-507|