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Insulinotropic Effects of Novel I1‐Imidazoline Agonist S43126
Author(s) -
Edwards Lincoln Paul,
Tesfai Jerusalem,
Crane Louis,
Baziard-Mouysset Genevieve
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.842.15
Subject(s) - imidazoline receptor , moxonidine , endocrinology , medicine , agonist , insulin , chemistry , blood pressure , basal (medicine) , insulin resistance , receptor , nifedipine , pharmacology , calcium
The I1‐imidazoline receptor is a novel drug target for hypertension and insulin resistance associated with Type II diabetes. We hypothesize that the novel I1‐imidazoline agonist S43126, act centrally to lower blood pressure and enhance glucose uptake by causing insulin release and phosphorylation of protein kinase B (PKB). Blood pressure measurements were made following cumulative injection of S43126 (5 nmol) and moxonidine (5nmol) into the brain of SHR. ELISA was used to measure insulin release from Min 6 cells under conditions of high (16.8mM), or low (2.8mM) glucose, following treatment with varying doses of S43126 [10‐8M to 10‐5M], for various times (5–60mins), in the presence or absence of inhibitors. Our results showed that both S43126 and moxonidine lowered arterial pressure by 20 mmHg and 45 mmHg respectively. S43126 [10‐5M] stimulated insulin secretion under elevated glucose concentration compared to basal. In addition, insulin secretion and Ca2+ influx mediated by S43126 [10‐5M] were decreased by efaroxan and nifedipine. Furthermore, S43126 [10‐5M] increased [Ca2+]i and 45Ca2+ uptake in a time and dose‐dependent manner. S43126 also caused increased protein expression of Imidazoline Receptor Antisera‐Selected (IRAS) protein, as well as increased phosphorylation of both ERK1/2 and PKB, in a dose‐dependent manner. These data indicate that S43126 may be useful in treating metabolic diseases.