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    • In vivo CA mediate hypoxic nutritional and neurologic

    2023-12-12

    In vivo CA mediate hypoxic, nutritional, and neurologic stress responses. Stimulation of ADRα2A by these hormones to reduce β-cell metabolism has an obvious role in suppressing insulin secretion (Arun, 2004). Since β-cell metabolism and insulin secretion are linked, mechanisms that inhibit metabolism also reduce insulin secretion. Suppression of β-cell metabolism may protect against longer bouts of hypoxia or stress. β-cells are susceptible to hypoxia because they rely on quantitative production of ATP by oxidative metabolism to secrete insulin (Cantley et al., 2010). Signals that suppress oxidative metabolism independent of nutrient sensing may benefit β-cells during hypoxia, in order to prevent depletion of oxidative pathways and increase redox status. Especially given prolonged elevations of CA are seen in pathologies such as fetal growth restriction, which is characterized by low plasma oxygen, as well as in individuals undergoing intense exercise training or frequent hypoxia bouts (Macko et al., 2016, Davy et al., 1995, Silverman and Mazzeo, 1996, Barnholt et al., 2006). Whether this acute mechanism to suppress metabolism ultimately prevents damage to β-cells under chronic stress (high CA) conditions long term has yet to be determined, but the co-occurrence of hypoxia and CA in vivo provide a compelling basis for CA regulation of islet and β-cell metabolism.
    Conclusion
    Funding This work was supported by National Institutes of HealthR01 DK084842 (S.W.L. Principal Investigator).
    Disclosure
    Acknowledgements
    Introduction Stress involves activation of the hypothalamus-pituitary-adrenal axis, leading to elevated levels of glucocorticoids and to the activation of the sympathetic nervous system (Chrousos, 2009). Human adrenal medullary pitavastatin produce and release epinephrine (80%) and norepinephrine (20%) into the bloodstream (Gerra et al., 2001, Scanzano and Cosentino, 2015, Schoder et al., 2000). Normally, catecholamine blood levels are reported in the low nanomolar range (Goldstein et al., 2003) but during stress they reach 0.53–1 nM (epinephrine) and 3.60–10 nM (norepinephrine) (Clutter and Cryer, 1980, Paran et al., 1992, Sofuoglu et al., 2001). Corresponding concentrations in different organs are not well established. While Campos et al. (1990) described catecholamine levels in different rodent testicular compartments, and Mayerhofer et al. (1996) reported on norepinephrine in rhesus monkey testes, to our knowledge, human testicular concentrations are not known. Several testicular cells possess adrenergic receptors and thus are potential targets of catecholamines (Patrao et al., 2008). For example, alpha adrenergic receptors (α-ADRs) and beta adrenergic receptors (β-ADRs) were described in Leydig cells, Sertoli cells, early spermatocytes and myoid cells of the seminiferous tubules of different species (Huo et al., 2012, Jacobus et al., 2005, Mayerhofer et al., 1991, Mayerhofer et al., 1993, Miyake et al., 1986, Skinner and Heindel, 1990, Stojkov et al., 2014). In vitro studies mainly performed in animal testicular tissues or isolated cells with selective adrenergic agonists or antagonists, indicated that α-ADRs and β-ADRs regulate for example androgen production in Leydig cells (Frungieri et al., 2000, Frungieri et al., 2002a, Huo et al., 2012, Mayerhofer et al., 1989, Mayerhofer et al., 1993, Mayerhofer et al., 1996, Mayerhofer et al., 1999, Mhaouty-Kodja et al., 2007, Stojkov et al., 2012). Little is known about human testicular ADRs and their roles, but there is evidence that the cells forming the wall of the human seminiferous tubule, express α- and β-ADRs. These peritubular (“myoid”) cells, have characteristics of smooth muscle cells (Maekawa et al., 1996, Mayerhofer, 2013). Miyake et al. (1986) monitored the intra-tubular pressure changes in vitro and concluded that isolated human seminiferous tubules are capable of undergoing contractions specifically after norepinephrine stimulation. In the testis, peritubular cells are in close proximity to sympathetic nerve fibers and microvessels, i.e. the sources of norepinephrine and epinephrine. These catecholamines therefore are likely physiological regulators of contractions and sperm transport.