Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

Tesfai, Jerusalem; Crane, Louis; Baziard-Mouysset, G; Wentsworth, Kennedy; Lincoln, PaulaM.

doi:10.1016/s1734-1140(11)70708-3

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…Recent work revealed that ligand activation of the imidazoline receptor (I1R) enhances insulin action in PC12 cells. 23 The novel I1R agonist S43126 (2-[4′-methoxyphenyl]-4,5-dihydro-1 H -imidazole) and the known antihypertensive and I1R agonist moxonidine are both capable of engaging this phenomenon. Moreover, moxonidine normalizes plasma insulin levels in an animal model and improves glucose uptake in peripheral cells.…”

Section: Discussionmentioning

confidence: 99%

Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans

Kinsky

Hargraves

Anumol

et al. 2016

Chem. Res. Toxicol.

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Methylglyoxal (MG) is a highly reactive dicarbonyl compound involved in the formation of advanced glycation endproducts (AGE). Levels of MG are elevated in patients with type-2 diabetes mellitus (T2DM), and AGE have been implicated in the progression of diabetic complications. The antihyperglycemic drug metformin (MF) has been suggested to be a scavenger of MG. The present work examined and characterized unequivocally the resulting scavenged product from the metformin–MG reaction. The primary product was characterized by 1H, 13C, 2D-HSQC, and HMBC NMR and tandem mass spectrometry. X-ray diffraction analysis determined the structure of the metformin and MG-derived imidazolinone compound as (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yI)guanidine (IMZ). A LC-MS/MS multiple reaction monitoring method was developed to detect and quantify the presence of IMZ in metformin-treated T2DM patients. Urine from >90 MF-treated T2DM patients was analyzed, with increased levels of MF directly correlating with elevations in IMZ. Urinary MF was detected in the range of 0.17 μM to 23.0 mM, and simultaneous measurement of IMZ concentrations were in the range of 18.8 nM to 4.3 μM. Since plasma concentrations of MG range from 40 nM to 4.5 μM, the level of IMZ production may be of therapeutic significance. Thus, in addition to lowering hepatic gluconeogenesis, metformin also scavenges the highly reactive MG in vivo, thereby reducing potentially detrimental MG protein adducts, with subsequent reductions in diabetic complications.

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Section: Discussionmentioning

confidence: 99%

Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans

Kinsky

Hargraves

Anumol

et al. 2016

Chem. Res. Toxicol.

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“…In conclusion, S43126 is a novel compound that activated I 1 -imidazoline receptors but not α-adrenoceptors [ 23 , 38 ]. We have shown that S43126 induced insulin secretion in a dose and time dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Novel I1-Imidazoline Agonist S43126 Augment Insulin Secretion in Min6 Cells

Tesfai

Crane²,

Baziard-Mouysset³

et al. 2012

J Diabetes Metab

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The I1-imidazoline receptor is a novel drug target for hypertension and insulin resistance which are major disorders associated with Type II diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126 on calcium fluxes and insulin secretion from Min6 β-cells. We also examined the effects of S43126 on the induction of IRAS, and phosphorylation of components in the I1-imidazoline signaling pathways, namely ERK and PKB. Min6 β-cells were treated with varying doses of S43126 [10−8M to 10−5M] for various time (5–60mins). S43126 at higher dose [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 following co-treatment with efaroxan (I1-antagonist) and nifedipine (L-type voltage-gated Ca2+-channel blocker) at various times (5–60mins). Furthermore, S43126 at [10−5M] increased Ca2+ oscillation, [Ca2+] and 45Ca2+ uptake in a time and dose-dependent manner. Moreover, Western blot analysis of treated samples showed that S43126 caused an increased protein expression of IRAS as well as phosphorylation of both ERK1/2 and PKB in a concentration-dependent manner. We conclude that S43126 exerts its insulinotropic effect in a glucose dependent manner by a mechanism involving L-type calcium channels and imidazoline I1-receptors.

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