Introduction

Diabetes mellitus(DM)is a global，high-morbidity，metabolism disorder syndrome，which is characterized by chronic hyperglycemia(Florez，Hirschhorn，& Altshuler，2003).There are three types of diabetes，typeⅠDM，typeⅡDM，and gestational diabetes mellitus(GDM；Kitabchi，Umpierrez，Miles，& Fisher，2009).The diabetic patients always has insulin deficiency actually or relatively，and/or insulin resistance.The pancreatic isletβ-cell plays an important role in diabetes pathology.Glucose toxicity is a well-established entity that has been shown in diabetic models to contribute to development of insulin resistance，impaired insulin secretion，and pancreaticβ-cell failure(Marasco&Linnemann，2018).Apoptosis is probably the main form ofβ-cell death in both types of DM.Autophagy is a conserved intracellular self-protective mechanism which plays an important role in cell death and survival(Mizushima，Levine，Cuervo，& Klionsky，2008).For example，it helps host cells degrades aggregated proteins，damaged mitochondria，and other aging or disordered organelles to produce small molecules such as amino acids to ensure the survival of cells and maintaining cell homeostasis(Booth，Tavallai，Hamed，Cruickshanks，& Dent，2014；Shen et al.，2015；Tu，Fan，Yang，Zhang，& Liang，2013).It also induces cell death，which was regulated by caspase-8(Yu et al.，2004).Autophagy has beenshown to regulate glucose homeostasis，insulin resistance，avertβ-cell dysfunction，improve insulin sensitivity，and protectβ-cells from apoptosis during DM(Barlow &Thomas，2015；Ebato et al.，2008；Li et al.，2018；Lim et al.，2018；Zhang，Cao，Liu，Xie，&Li，2015).Based on the important function of autophagy in the diabetes，upregulation of autophagic activity could be useful therapeutically by preventing DM progression.(https://www.daowen.com)

To date，the focus on pharmacological studies to treat diabetes shifts to employing biological activities from natural sources.The cytoprotection of natural products together with low cost and minimal side effects has been attracted major concern in drug discovery.Gymnema sylvestre is one of such herbs(Ota& Ulrih，2017).Gymnemic acid I(GA I)is a bioactive component extracted from Gymnema sylvestre.It functions in antidiabetic and slimming effects(Sanematsu et al.，2014；Tiwari，Ahmad，& Baig，2017).GA I is a high antisweetness inhibitor via human sweet receptor type 1 receptor 2(T1R2)and T1R3(Sanematsu et al.，2014).It also inhibits secretion of gastric inhibitory peptide(GIP，also known as glucose-dependent insulinotropic peptide)and can be used as a protein synthesis inhibitor(Capolupo et al.，2017；Fushiki，Kojima，Imoto，Inoue，&Sugimoto，1992).Chronic reduction of GIPsecretion or inhibition of GIP receptor signaling alleviates obesity and insulin resistance(Gasbjerg et al.，2018；Joo et al.，2017).However，the molecular mechanism of GA I regarding its clinical therapy in DM is not elucidated and the interaction between autophagy and apoptosis is remaining to be verified in pancreaticβ-cells under high glucose stress.Our current study is to elucidate the mechanism of GA I on diabetes therapy for secondary development of GA I.