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PP-36

Natural diterpenoid kansuinine A protects islet β-cells from ApoC3-Rich low-

density lipoprotein induced apoptosis through LOX-1/IKKβ/NF-κB pathway

inhibition

1
2
1
1
Bo-Yi Pan, Y u -Ting Hsu, Kwun-Wing Cheng, Fang-Yu Chen, Ming-Yi Shen* ,1,3,4

1 Graduate Institute of Biomedical Sciences, China Medical University, 91, Hsueh-Shih Rd.,
Taichung 40402, Taiwan
2 School of Medicine, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402,
Taiwan
3 Department of Medical Research, China Medical University Hospital, 91, Hsueh-Shih Rd.,
Taichung 40402, Taiwan
4 Department of Nursing, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354,
Taiwan
* E-mail: shenmy1124@gmail.com

Abstract
Type 2 diabetes mellitus (T2DM) is often aggravated by dyslipidemia, which accelerates
oxidative stress and apoptosis in pancreatic β-cells. Kansuinine A (KA), a diterpenoid
compound isolated from Euphorbia roots, has demonstrated strong antioxidative and
antiapoptotic properties, making it a promising candidate for metabolic disease intervention. In
this study, we explored the protective role of KA against β-cell damage triggered by
apolipoprotein C3 (ApoC3) rich low-density lipoprotein (AC3RL). In this study, we established
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a pathological model of combined hyperlipidemia and hyperglycemia by feeding ApoE mice
a high-fat diet (HFD), followed by intraperitoneal administration of KA at doses of 20 μg/kg or
60 μg/kg. KA treatment markedly improved glucose tolerance, stabilized insulin secretion,
enhanced antioxidant defense systems, and significantly reduced pancreatic β-cell apoptosis.
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Notably, HFD-fed ApoE mice exhibited a pronounced elevation in plasma AC3RL levels,
highlighting the model’s features of metabolic dysregulation and lipoprotein imbalance. In
vitro, rat β-cell line Rin-m5F was treated with AC3RL isolated from patients with T2DM. KA
(0.1–1μM) effectively attenuated AC3RL-induced oxidative stress and mitochondrial
dysfunction, preserved cell viability, and inhibited apoptosis. Mechanistic studies, integrating
immunoblotting and molecular docking, demonstrated that KA exerts its protective effects both
in vivo and in vitro by suppressing the IKKβ/NF-κB signaling pathway, downregulating LOX-
1 expression, and mitigating β-cell apoptosis. These findings indicate that KA mitigates
dyslipidemia-driven β-cell injury through antioxidative and anti-inflammatory mechanisms,
supporting its potential development as a natural therapeutic for T2DM prevention and
management.

Keywords: Type 2 diabetes mellitus (T2DM); Kansuinine A (KA); Apolipoprotein C3 (ApoC3)
rich low-density lipoprotein (AC3RL)