A V-type starch-lycopene complex with enhanced cis-lycopene content alleviates hyperglycemia and glycogen fragility in type 2 diabetic db/db mice via gut microbiota.

Type 2 diabetes mellitus (T2DM) is a major global health challenge. Resistant starch type 5 (RS5), formed by complexing starch with guest components into V-type crystalline structures, represents a promising approach for glycemia control. Native lycopene has anti-diabetic potential but limited bioactivity. Here we developed a V-type corn starch-lycopene RS5 complex (CS-LYC) and evaluated its effects in T2DM db/db mice, focusing on glycemic control and gut microbiota-liver glycogen connection. CS-LYC contained 26.07% resistant starch and 11.8 mg/g lycopene, with complexation promoting isomerization to the more bioactive (13Z)-isomer and increasing lycopene accumulation in both plasma and liver in vivo. In db/db mice, CS-LYC improved insulin sensitivity and glucose homeostasis by remodeling gut microbiota (enriching Akkermansia and Alistipes) and increasing metabolites (short-chain fatty acids and indole derivatives), subsequently maintaining intestinal barrier function and stimulating GLP-1 secretion. Through the gut-liver axis, this GLP-1 activated the hepatic PI3K/AKT pathway and increased the proportion of stable glycogen α particles, thereby reducing glycogen fragility, with fecal microbiota transplantation further confirming that these effects were mediated by gut microbiota. Collectively, CS-LYC alleviates T2DM via the gut-liver GLP-1/PI3K-AKT axis, offering a new dietary strategy for diabetes management.