title: Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine islets.
abstract: OBJECTIVE
  Aldosterone concentrations increase in obesity and predict the onset of diabetes. We investigated the effects of aldosterone on glucose homeostasis and insulin secretion in vivo and in vitro.
  
  
  METHODS
  We assessed insulin sensitivity and insulin secretion in aldosterone synthase-deficient (As [also known as Cyp11b2](-/-)) and wild-type mice using euglycaemic-hyperinsulinaemic and hyperglycaemic clamps, respectively. We also conducted studies during high sodium intake to normalise renin activity and potassium concentration in As (-/-) mice. We subsequently assessed the effect of aldosterone on insulin secretion in vitro in the presence or absence of mineralocorticoid receptor antagonists in isolated C57BL/6J islets and in the MIN6 beta cell line.
  
  
  RESULTS
  Fasting glucose concentrations were reduced in As (-/-) mice compared with wild-type. During hyperglycaemic clamps, insulin and C-peptide concentrations increased to a greater extent in As (-/-) than in wild-type mice. This was not attributable to differences in potassium or angiotensin II, as glucose-stimulated insulin secretion was enhanced in As (-/-) mice even during high sodium intake. There was no difference in insulin sensitivity between As (-/-) and wild-type mice in euglycaemic-hyperinsulinaemic clamp studies. In islet and MIN6 beta cell studies, aldosterone inhibited glucose- and isobutylmethylxanthine-stimulated insulin secretion, an effect that was not blocked by mineralocorticoid receptor antagonism, but was prevented by the superoxide dismutase mimetic tempol.
  
  
  CONCLUSIONS
  We demonstrated that aldosterone deficiency or excess modulates insulin secretion in vivo and in vitro via reactive oxygen species and in a manner that is independent of mineralocorticoid receptors. These findings provide insight into the mechanism of glucose intolerance in conditions of relative aldosterone excess.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 2200 Pierce Ave, 560 RRB, Nashville, TN 37232-6602, USA. James.Luther@Vanderbilt.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Luther
authors.forename: P
authors.initials: P
authors.lastname: Luo
authors.forename: M T
authors.initials: MT
authors.lastname: Kreger
authors.forename: M
authors.initials: M
authors.lastname: Brissova
authors.forename: C
authors.initials: C
authors.lastname: Dai
authors.forename: T T
authors.initials: TT
authors.lastname: Whitfield
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: D H
authors.initials: DH
authors.lastname: Wasserman
authors.forename: A C
authors.initials: AC
authors.lastname: Powers
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000172:deficiency / Q000235:genetics; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D001786:Blood Glucose; D007328:Insulin; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D005947:Glucose