PMID- 28687198 OWN - NLM STAT- MEDLINE DCOM- 20180515 LR - 20180515 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 812 DP - 2017 Oct 5 TI - Neu-P11, a novel MT1/MT2 agonist, reverses diabetes by suppressing the hypothalamic-pituitary-adrenal axis in rats. PG - 225-233 LID - S0014-2999(17)30446-6 [pii] LID - 10.1016/j.ejphar.2017.07.001 [doi] AB - Excessive glucocorticoid (GC) in type 2 diabetes mellitus (T2DM) reduces insulin sensitivity, impairs beta-cell function, increases gluconeogenesis and glycogenolysis, impairs glucose uptake and metabolism, and reduces the insulinotropic effects of glucagon-like peptide 1. Melatonin, which serves as a physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis, has been suggested to have anti-diabetic effects. The objective of the present study was to investigate the effect of the MT1/MT2 melatonin agonist Neu-P11 on glucose and lipid metabolism in T2DM rats induced by a high fat diet combined with low doses of streptozotocin. T2DM rats were intragastrically administered melatonin (20mg/kg), Neu-P11 (20, 10, 5mg/kg), or a vehicle for 4 weeks. The results showed that the increased food intake, water consumption, hyperglycemia, glucose intolerance, and insulin resistance in T2DM rats were all improved by Neu-P11 treatment. Neu-P11 increased GC receptor expression and suppressed 11beta-hydroxysteroid dehydrogenase 1 activity in the hippocampus by enhancing GC sensitivity and HPA feedback, thus decreasing the high GC levels. Transcript levels of the glucose metabolism-related genes peroxisome proliferator-activated receptor-gamma, glucose transporter type-4, and adiponectin in adipose tissue were significantly increased after Neu-P11 treatment, while leptin mRNA was significantly decreased. Furthermore, MT1 and MT2 protein levels were enhanced by Neu-P11. These data suggest that normalization of the hyperactivated HPA axis by melatonin and Neu-P11 in T2DM regulates metabolic profiles and insulin sensitivity, which may attenuate insulin resistance and glucose homeostasis. Because Neu-P11 has superior pharmacokinetics and a longer half-life than melatonin, it might be beneficial in treating obesity and T2DM. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Zhou, Jun AU - Zhou J AD - College of Pharmacy, LanZhou university, Lanzhou 730000, PR China; Department of Pharmacy, Lanzhou General Hospital of PLA, Lanzhou 730050, PR China. FAU - Zhang, Jin AU - Zhang J AD - Department of Pharmacy, The TCM University of Gansu Province, Lanzhou 730000, PR China. FAU - Luo, XiaoHong AU - Luo X AD - Department of Endocrinology, Lanzhou General Hospital of PLA, Lanzhou 730050, PR China. FAU - Li, MaoXing AU - Li M AD - College of Pharmacy, LanZhou university, Lanzhou 730000, PR China; Department of Pharmacy, Lanzhou General Hospital of PLA, Lanzhou 730050, PR China. FAU - Yue, Ying AU - Yue Y AD - College of Pharmacy, LanZhou university, Lanzhou 730000, PR China. FAU - Laudon, Moshe AU - Laudon M AD - Drug Discovery, Neurim Pharmaceuticals Ltd., Tel-Aviv, Israel. FAU - Jia, ZhengPing AU - Jia Z AD - College of Pharmacy, LanZhou university, Lanzhou 730000, PR China; Department of Pharmacy, Lanzhou General Hospital of PLA, Lanzhou 730050, PR China. Electronic address: 121189539@qq.com. FAU - Zhang, RuXue AU - Zhang R AD - College of Pharmacy, LanZhou university, Lanzhou 730000, PR China; Department of Pharmacy, Lanzhou General Hospital of PLA, Lanzhou 730050, PR China. Electronic address: zhoujunh2016@126.com. LA - eng PT - Journal Article DEP - 20170704 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Adiponectin) RN - 0 (Blood Glucose) RN - 0 (Glucose Transporter Type 4) RN - 0 (Indoles) RN - 0 (Leptin) RN - 0 (PPAR gamma) RN - 0 (Pyrans) RN - 0 (RNA, Messenger) RN - 0 (Receptor, Melatonin, MT1) RN - 0 (Receptor, Melatonin, MT2) RN - EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 1) RN - S3UN2146K9 (N-(2-(5-methoxy-indol-3-yl)-ethyl)-4-oxo-4H-pyran-2-carboxamide) RN - W980KJ009P (Corticosterone) SB - IM MH - 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics MH - Adiponectin/genetics MH - Adipose Tissue/drug effects/metabolism MH - Animals MH - Blood Glucose/metabolism MH - Body Weight/drug effects MH - Corticosterone/blood MH - Diabetes Mellitus, Type 2/*drug therapy/genetics/metabolism/physiopathology MH - Drinking/drug effects MH - Fasting/blood MH - Female MH - Gene Expression Regulation, Enzymologic/drug effects MH - Glucose Transporter Type 4/genetics MH - Hippocampus/drug effects/metabolism MH - Hypothalamus/*drug effects MH - Indoles/*pharmacology/therapeutic use MH - Insulin Resistance MH - Leptin/genetics MH - PPAR gamma/genetics MH - Pituitary-Adrenal System/*drug effects MH - Pyrans/*pharmacology/therapeutic use MH - RNA, Messenger/genetics/metabolism MH - Rats MH - Rats, Wistar MH - Receptor, Melatonin, MT1/*agonists MH - Receptor, Melatonin, MT2/*agonists OTO - NOTNLM OT - Glucose and lipid metabolism OT - HPA axis OT - Melatonin OT - Neu-P11 OT - Type 2 diabetes mellitus EDAT- 2017/07/09 06:00 MHDA- 2018/05/16 06:00 CRDT- 2017/07/09 06:00 PHST- 2016/11/29 00:00 [received] PHST- 2017/06/19 00:00 [revised] PHST- 2017/07/03 00:00 [accepted] PHST- 2017/07/09 06:00 [pubmed] PHST- 2018/05/16 06:00 [medline] PHST- 2017/07/09 06:00 [entrez] AID - S0014-2999(17)30446-6 [pii] AID - 10.1016/j.ejphar.2017.07.001 [doi] PST - ppublish SO - Eur J Pharmacol. 2017 Oct 5;812:225-233. doi: 10.1016/j.ejphar.2017.07.001. Epub 2017 Jul 4.