The Anti-apoptosis Effect Of Huang-Gui Solid Dispersion On Islet β-cells And Its Mechanism In Mice With Type2Diabetes

Type2diabetes mellitus (T2DM) is the most common endocrine disease inclinic.Accumulating evidence indicates that progressive β-cell failure is related withreductions in both β-cell mass and secretary function in the pathogenesis of T2DM.So maintenance of β-cell function and mass is the important strategy to prevent orretard development of T2DM.Apoptosis is now considered an important contributor to β-cell mass reduction inT2DM. Beta-cell apoptosis is mediated not only via extrinsic death receptor orintrinsic mitochondrial pathway but also due to endoplasmic reticulum (ER) stress. Arecent observation suggests that ER stress may be responsible for the mechanisms ofpalmitate (PA) contributing to β-cell apoptosis. Reported observations suggest thatGroup VIA phospholipase A2(iPLA2) may sensitize β-cell to apoptosis in ERstress-induced INS-1insulinoma cell. These findings raise the likelihood that iPLA2βparticipates in ER stress-induced apoptosis by activating the intrinsic apoptoticpathway. it maybe a target to preserve β-cell secretion and prolong β-cell survival,thereby to prevent or retard development of T2DM.Berberine（BER），an isoquinoline alkaloid, a major active component of RhizomaCoptidis and its derivatives exhibit pleiotropic pharmacological activities. Recently,BER has received much attention due to its hypoglycemic activity. Both animal andclinical studies have demonstrated that berberine improves insulin resistance,decreases blood glucose levels, and inhibits the progression of diabetes. On the otherside, low oral bioavailability of BER due to poor solubility and membranepermeability limits its clinical use for treatment of diabetes. In this study, wedeveloped an amorphous solid dispersion of berberine with absorption enhancersodium caprate, referred to as Huang-Gui Solid Dispersion (HGSD) preparations withhigh oral bioavailability, and observed the protective effect of HGSD on islet cellapoptosis. Further we investigated the effect of BER on β-cell function impaired by PA and whether or not the underlying molecular mechanism is related to the GroupVIA phospholipase A2(iPLA2) pathway.Main methods: Treatment effects of HGSD on type2diabetic (T2D) mice andpalmitate-induced MIN6β-cells injury were observed. Fasting plasma glucose, insulinlevels, glucose tolerance test were evaluated. Histological examination and insulinimmunostaining were examined in islet. Apoptosis rate was detected in islet andMIN6cells. The glucose stimulated insulin secretion (GSIS) and expression of iPLA2,p38-MAPK/phosphorylated p38MAPK (p-p38MAPK), caspase3were detected inMIN6cells.Key findings: HGSD treatment (150mg/kg) decreased fasting plasma glucose,elevated plasma insulin levels, improved glucose tolerance, preserved pancreaticinsulin content and attenuated β-cell apoptosis in T2D mice. Meanwhile, the effectivecomponents BER of HGSD treatment attenuated the palmitate-induced reduction inMIN6β-cells viability, apoptosis, impaired GSIS and activation of iPLA2,p38-MAPK and caspase3.Significance: These data suggest that HGSD treatment provides a beneficialanti-diabetic effect in mice with T2D and this protective effect may be mediatedthrough prevention of β-cell apoptosis via inhibition of the iPLA2/p38MAPKpathway.