Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease defined by persistent hyperglycemia, primarily caused by insulin (INS) resistance and β-cell dysfunction. However, current pharmacological therapies are limited by adverse effects, highlighting the need for safe adjunctive strategies. Plant polysaccharides and their fermentation-derived degradation products exhibit multiple bioactivities and may be promising nutraceutical candidates. This study used degradation products of a water-soluble polysaccharide of finger citron from Guangdong Province (FCP-2-1) by gut micro biota fermentation (DFPG) as the research subject to investigate its hypoglycemic effects and underlying mechanisms in mice with T2DM. The findings indicated that degradation products of FCP-2-1 by gut micro biota fermentation after 8 h (DFPG-8) attenuated body weight loss, polydipsia, polyphagia, high fasting blood glucose, impaired oral glucose tolerance (OGT), and the elevated serum INS and glycated serum protein (GSP) in T2DM mice. In addition, DFPG-8 ameliorated lipid metabolism and attenuated pancreatic islet injury. Mechanistically, DFPG-8 activated colonic cyclic adenosine monophosphate (cAMP) /Protein Kinase A (PKA) and cAMP/Epac by cAMP signaling, up regulated cAMP response element-binding protein (CREB) and caudal type homeobox 2 (Cdx-2), enhanced glucagon gene (GCG) transcription, and promoted glucagon-like peptide-1 (GLP-1) synthesis. It also restored hypothalamic GLP-1 receptor (GLP-1R) expression, thereby modulating appetite and energy balance, reducing food intake, and increasing GLP-1 responsiveness, contributing to improved glycemic homeostasis. Collectively, these findings demonstrate that DFPG-8 may exert hypoglycemic effects by regulating the cAMP/PKA/Epac/GCG/GLP-1/GLP-1R signaling pathway, thereby improving glucose and lipid metabolism as well as appetite regulation, and support its potential development as a functional dietary supplement for the adjunctive management of T2DM.
