Hirsutine ameliorates hepatic and cardiac insulin resistance in high-fat diet-induced diabetic mice and in vitro models. (March 2022)

• Record Type: Journal Article
• Authors: Hu, Wei; Li, Meng; Sun, Wuyi; Li, Qixiu; Xi, Haiyan; Qiu, Yuanye; Wang, Ran; Ding, Qian; Wang, Zhou; Yu, Yue; Lei, Heping; Mao, Yicheng; Zhu, Yi Zhun
• Is Part Of: Pharmacological research. Volume 177(2022)
• Publication Date: 2022-03
• Subjects: IR Insulin resistance -- T2DM type 2 diabetes mellitus -- HFD high-fat diet -- HGHI high-glucose and high-insulin -- FBG fasting blood glucose -- DMSO Dimethyl Sulfoxide -- PI3K phosphatidylinositol-3-kinase -- Akt protein kinase B -- AMPK AMP-activated protein kinase -- ACC acetyl-CoA carboxylase -- Akt protein kinase B, FoxO1, forkhead transcription factor1 -- G6Pase glucose-6-phosphatase -- PEPCK phosphoenolpyruvate carboxykinase -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1α -- OGTT oral glucose tolerance test -- ITT insulin tolerance test -- HbA1c glycated hemoglobin -- 2-NBDG 2- Deoxy − 2-[(7-nitro-2, 1, 3- benzoxadiazol-4-yl) amino]- D- glucose -- GLUT glucose transporter -- met metformin -- FCCP Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone -- IRS insulin receptor substrate -- ERK Ras/ extracellular signal-related kinase -- MAPK mitogen-activated protein kinase -- PKM2 pyruvate kinase M2 -- OCR oxygen consumption rate -- ECAR extracellular acidification rate; Hirsutine -- HFD -- Glucose metabolism -- T2DM -- Insulin resistance -- PI3K/Akt signaling; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105917
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Closely associated with type 2 diabetes mellitus (T2DM), hepatic steatosis and cardiac hypertrophy resulting from chronic excess intake can exacerbate insulin resistance (IR). The current study aims to investigate the pharmacological effects of hirsutine, one indole alkaloid isolated from Uncaria rhynchophylla, on improving hepatic and cardiac IR, and elucidate the underlying mechanism. T2DM and IR in vivo were established by high-fat diet (HFD) feeding for 3 months in C57BL/6 J mice. In vitro IR models were induced by high-glucose and high-insulin (HGHI) incubation in HepG2 and H9c2 cells. Hirsutine administration for 8 weeks improved HFD-induced peripheral hyperglycemia, glucose tolerance and IR by OGTT and ITT assays, and simultaneously attenuated hepatic steatosis and cardiac hypertrophy by pathological observation. The impaired p-Akt expression was activated by hirsutine in liver and heart tissues of HFD mice, and also in the models in vitro . Hirsutine exhibited the effects on enhancing glucose consumption and uptake in IR cell models via activating phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which was blocked by PI3K inhibitor LY294002. Moreover, the effect of hirsutine on promoting glucose uptake and GLUT4 expression in HGHI H9c2 cells was also prevented by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Enhancement of glycolysis might be another factor of hirsutine showing its effects on glycemic control. Collectively, it was uncovered that hirsutine might exert beneficial effects on regulating glucose homeostasis, thus improving hepatic and cardiac IR, and could be a promising compound for treating diet-induced T2DM. Graphical Abstract: ga1