Because the renin-angiotensin-aldosterone system influences
glucose homeostasis, the
mineralocorticoid receptor (MR) signal in pancreatic islets may regulate
insulin response upon
glucose load.
Glucagon-like peptide-1 (GLP-1) production is stimulated by
interleukin-6 (IL-6) in pancreatic α-cells. To determine how
glucose homeostasis is regulated by interactions of MR,
IL-6 and
GLP-1 in islets, we performed
glucose tolerance and histological analysis of islets in primary
aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active
GLP-1 concentration in primary
aldosteronism (PA) patients before and after the administration of MR antagonist
eplerenone. In PA model rodents,
aldosterone decreased insulin-secretion and the islet/pancreas area ratio and
eplerenone added on
aldosterone (E+A) restored those with induction of
IL-6 in α-cells. In α-cells treated with E+A,
IL-6 and
GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and
IL-6 mRNA and these upregulations were blunted by MR silencing using
small interfering RNA (
siRNA). Transcriptional activation of the
IL-6 gene promoter by E+A-treatment required an intact MR binding
element in the promoter. Active
GLP-1 concentration was significantly increased in PA patients after
eplerenone treatment. MR signal in α-cells may stimulate
IL-6 production and increase
GLP-1 secretion, thus protecting pancreatic β-cells and improving
glucose homeostasis.