Deleterious Effects of Supplementation with Dehydroepiandrosterone Sulphate or Dexamethasone on Rat Insulin-Secreting Cells Under In Vitro Culture Condition

Abstract

Dehydroepiandrosterone (DHEA) and glucocorticoids are steroid hormones synthesised in the adrenal cortex. Administration of DHEA, its sulphate derivative, DHEAS, and more controversially dexamethasone (DEX), a synthetic glucocorticoid, have beneficial effects in diabetic animals. Cultivating BRIN-BD11 cells for 3 days with either DHEAS (30 muM) or DEX (100 nM), reduced total cell number and reduced cell viability and cellular insulin content. DHEAS-treated cells had poor glucose responsiveness and regulated insulin release, coupled with reduced basal insulin release. In contrast, DEX-treated cells lacked responsiveness to glucose and membrane depolarisation, and both protein kinase A (PKA) and protein kinase C (PKC) secretory pathways were desensitised. Therefore, we conclude that this steroid hormone and synthetic glucocorticoid are not beneficial to pancreatic beta-cells in vitro.

Functional and Molecular Aspects of Glucocorticoids in the Endocrine Pancreas and Glucose Homeostasis

“…(Ortsäter et al, 2005) Dex 100 nM for 3 d in BRIN-BD 11 cells DEX-treated cells lacked responsiveness to glucose and membrane depolarisation, and both PKA and PKC secretory pathways were desensitised. (Liu et al, 2006) Dex 1 µM concomitant or for 3 h previous culture in rat islets Dex (included in the perifusion solution) has no effect on GSIS. Previous incubation with Dex markedly decrease the 1 st and the 2 nd phases IS under 15 mM glucose.…”

“…Overall, it appears that GCs act at distal sites by diminishing the efficacy of [Ca 2+ ]i on the secretory response by interfering with the amplifying pathway, although we cannot exclude their possible negative effects also in the mechanisms involved in the rapid first phase insulin secretion (Jeong et al, 2001). The interference of GCs in distal sites of the insulin secretory machinery may explain the wide spectrum of non-glucose insulin secretagogues being inhibited by GCs (Lambillotte et al, 1997;Myrsén-Axcrona et al, 1997;Shao et al, 2004;Liu et al, 2006).…”

“…The mechanisms involved in islet hypertrophy were elucidated several years later (Rafacho et al, 2007;Rafacho et al, 2009). Activation of cell cycle progression machinery in normal rats in response to GC treatment is probably associated with the degree of IR that in turn is correlated to dose and/or duration of GC administration (Rafacho et al, 2009;Rafacho et al, 2011) and does not involve direct effects of GCs on -cells, since it is known that steroids inhibit -cell proliferation and promote -cell death in vitro (Weinhaus et al, 2000;Liu et al, 2006;Ranta et al, 2006;Nicoletti-Carvalho et al, 2010). Instead, increased levels of circulating hormones and/or substrates, such as glucose, insulin, insulin-growth factor (IGF)-1, glucagon-like peptide (GLP)-1 and other circulating growth factors, may be responsible for promotion of -cell growth in GC-treated rats [for review see references (Heit et al, 2006) and (Vasavada et al, 2006)].…”

“…Additional effects may contribute to -cell dysfunction; impairment of insulin secretion in response to -ketoisocaproate (KIC), tolbutamide, or high K + concentration after DEX treatment is also observed (Lambillotte et al, 1997;Shao et al, 2004;Liu et al, 2006), suggesting that factors distal to oxidative phosphorylation (KIC) or metabolismindependent signals (tolbutamide, high K + ) may also be involved in the adverse GC effects on the insulin secretory process. DEX may also modulate the inward repolarizing K + currents by upregulating Kv1.5 ion channels as well as Na + /K + ATPase activity, which appear to be mediated through activation of the serum-and GC-inducible kinase (SGK1)-1 (Ullrich et al, 2005;Ullrich et al, 2007).…”

The effect of Dehydroepiandrosterone on insulin resistance in patients with impaired glucose tolerance

“…12 Liu et al demonstrated that DHEA-S deteriorated glucose control and beta-cell function in vitro. 13 Due to the divergent results concerning the effects of DHEA-S on diabetes and especially insulin resistance, we performed a study to assess the effect of DHEA on insulin resistance and consequently on the glycemic control in patients with impaired glucose tolerance.…”