alpha2A-adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice

V Fagerholm, Mika Scheinin, M Haaparanta

Research output: Contribution to journalArticleScientificpeer-review

34 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE: The imidazoline-type alpha2-adrenoceptor antagonists (+/-)-efaroxan and phentolamine increase insulin secretion and reduce blood glucose levels. It is not known whether they act by antagonizing pancreatic beta-cell alpha2-adrenoceptors or by alpha2-adrenoceptor-independent mechanisms. Many imidazolines inhibit the pancreatic beta-cell KATP channel, which is the molecular target of sulphonylurea drugs used in the treatment of type II diabetes. To investigate the mechanisms of action of (+/-)-efaroxan and phentolamine, alpha2A-adrenoceptor knockout (alpha2A-KO) mice were used.

EXPERIMENTAL APPROACH: Effects of (+/-)-efaroxan, 5 mg kg(-1), and phentolamine, 1 mg kg(-1), on blood glucose and insulin levels were compared with those of the non-imidazoline alpha2-adrenoceptor antagonist [8aR,12aS,13aS]-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine (RS79948-197), 1 mg kg(-1), and the sulphonylurea glibenclamide, in alpha2A-KO and control (wild type (WT)) mice.

KEY RESULTS: In fed WT mice, (+/-)-efaroxan, phentolamine and RS79948-197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed alpha2A-KO mice, (+/-)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted alpha2A-KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg(-1)), caused severe hyperinsulinaemia and hypoglycaemia in alpha2A-KO mice. This was mimicked in WT mice by co-administration of RS79948-197 with glibenclamide.

CONCLUSIONS AND IMPLICATIONS: These results suggest that (+/-)-efaroxan and phentolamine increase insulin secretion by inhibition of beta-cell alpha2A-adrenoceptors, and demonstrate a critical role for alpha2A-adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.

Original languageEnglish
Pages (from-to)1287-96
Number of pages10
JournalBritish Journal of Pharmacology
Volume154
Issue number6
DOIs
Publication statusPublished - Jul 2008
MoE publication typeA1 Journal article-refereed

Keywords

  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Antagonists/pharmacology
  • Adrenergic beta-Antagonists/pharmacology
  • Animals
  • Atropine Derivatives/pharmacology
  • Benzofurans/pharmacology
  • Blood Glucose/metabolism
  • Drug Synergism
  • Fasting/physiology
  • Glyburide/pharmacology
  • Hypoglycemic Agents/pharmacology
  • Imidazoles/pharmacology
  • Insulin/blood
  • Insulin Secretion
  • Isoquinolines/pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscarinic Antagonists/pharmacology
  • Naphthyridines/pharmacology
  • Phentolamine/pharmacology
  • Propranolol/pharmacology
  • Receptors, Adrenergic, alpha-2/genetics

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