Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

摘要: The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic (9cRA), activates retinoic receptors (RARs) and retinoid X (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for other nuclear that regulate metabolism. Physiological function has not been determined 9cRA, because it detected serum or tissues with analytically validated assays. Here, we identify 9cRA mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), show decreases feeding after glucose dosing varies inversely insulin. reduces glucose-stimulated insulin secretion (GSIS) islets the rat β-cell line 832/13 within 15 min reducing transporter type 2 (Glut2) glucokinase (GK) activities. also Pdx-1 HNF4α mRNA expression, ∼8- 80-fold, respectively: defects cause maturity onset diabetes of young (MODY4 1, respectively), does a defective GK gene (MODY2). Pancreas β-cells generate models reduced number, heterozygous Akita mice, streptozotocin-treated mice have 9cRA. is abnormally high glucose-intolerant which hypertropy, including diet-induced obesity (DIO) ob/ob db/db mice. These data establish pancreas-specific autacoid mechanisms action provide unique insight into GSIS.