%0 Journal Article
%T Inhibition of endoplasmic reticulum stress and excessive autophagy by Jiedu Tongluo Tiaogan Formula via a CaMKKβ/AMPK pathway contributes to protect pancreatic β-cells.
%A Zhang Q
%A Jin W
%A Wang H
%A Tang C
%A Zhao X
%A Wang Y
%A Sun L
%A Piao C
%J J Ethnopharmacol
%V 333
%N 0
%D 2024 Oct 28
%M 38885916
%F 5.195
%R 10.1016/j.jep.2024.118440
%X <B>BACKGROUND: </B>Jiedu Tongluo Tiaogan Formula (JTTF), a traditional Chinese herbal decoction, exhibits the potential to treat type 2 diabetes mellitus (T2DM) by inhibiting endoplasmic reticulum stress (ERS) and excessive autophagy, which are the risk factors for the abnormal development and progression of β cells.<BR><B>OBJECTIVE: </B>We aimed to assess the effect of JTTF on pancreatic glucotoxicity by inhibiting ERS and excessive autophagy, for which db/db mice and INS-1 insulinoma cells were used.<BR><B>METHODS: </B>The chemical composition of the JTTF was analyzed by UPLC-Q/TOF-MS. Diabetic (db/db) mice were treated with distilled water or JTTF (2.4 and 7.2 g/kg/day) for 8 weeks. Furthermore, INS-1 cells induced by high glucose (HG) levels were treated with or without JTTF (50, 100, and 200 μg/mL) for 48 h to elucidate the protective mechanism of JTTF on glucose toxicity. The experimental methods included an oral glucose tolerance test, hematoxylin-eosin staining, immunohistochemistry, western blotting, RT-qPCR, and acridine orange staining.<BR><B>RESULTS: </B>28 chemical components of JTTF were identified. Additionally, treatment with JTTF significantly decreased the severity of glycemic symptoms in the db/db mice. Moreover, the treatment partially restored glucose homeostasis in the db/db mice and protected the pancreatic β-cell function. JTTF protected INS-1 cells from HG injury by upregulating GSIS and PDX1, MafA mRNA expression. Further, treatment with JTTF downregulated GRP78 and ATF6 expression, whereas it inhibited Beclin-1 and LC3 activation. The treatment protected the cells from HG-induced ERS and excessive autophagy by downregulating the CaMKKβ/AMPK pathway.<BR><B>CONCLUSIONS: </B>The present study findings show that JTTF may protects β-cells by inhibiting the CaMKKβ/AMPK pathway, which deepens our understanding of the effectiveness of JTTF as a treatment strategy against T2DM.