Background: Abnormalities in glucose metabolism may be the underlying cause of β-cell dysfunction and identity impairment resulting from high glucose exposure. In China, Coptis deltoidea C. Y. Cheng et Hsiao (YL) has demonstrated remarkable hypoglycemic effects.
Hypothesis/purpose: To investigate the hypoglycemic effect of YL and determine the mechanism of YL in treating diabetes.
Methods: A type 2 diabetes mouse model was used to investigate the pharmacodynamics of YL. YL was administrated once daily for 8 weeks. The hypoglycemic effect of YL was assessed by fasting blood glucose, an oral glucose tolerance test, insulin levels, and other indexes. The underlying mechanism of YL was examined by targeting glucose metabolomics, western blotting, and qRT-PCR. Subsequently, the binding capacity between predicted AMP-activated protein kinase (AMPK) and important components of YL (Cop, Ber, and Epi) were validated by molecular docking and surface plasmon resonance. Then, in AMPK knockdown MIN6 cells, the mechanisms of Cop, Ber, and Epi were inversely confirmed through evaluations encompassing glucose-stimulated insulin secretion, markers indicative of β-cell identity, and the examination of glycolytic genes and products.
Results: YL (0.9 g/kg) treatment exerted notable hypoglycemic effects and protected the structural integrity and identity of pancreatic β-cells. Metabolomic analysis revealed that YL inhibited the hyperactivated glycolysis pathway in diabetic mice, thereby regulating the products of the tricarboxylic acid cycle. KEGG enrichment revealed the intimate relationship of this process with the AMPK signaling pathway. Cop, Ber, and Epi in YL displayed high binding affinities for AMPK protein. These compounds played a pivotal role in preserving the identity of pancreatic β-cells and amplifying insulin secretion. The mechanism underlying this process involved inhibition of glucose uptake, lowering intracellular lactate levels, and elevating acetyl coenzyme A and ATP levels through AMPK signaling. The use of a glycolytic inhibitor corroborated that attenuation of glycolysis restored β-cell identity and function.
Conclusion: YL demonstrates significant hypoglycemic efficacy. We elucidated the potential mechanisms underlying the protective effects of YL and its active constituents on β-cell function and identity by observing glucose metabolism processes in pancreatic tissue and cells. In this intricate process, AMPK plays a pivotal regulatory role.
Keywords: AMPK signaling; Coptis deltoidea C. Y. Cheng et Hsiao; Diabetes; Glucose metabolism; β-cell identity.
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