AIMS/HYPOTHESIS: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells. METHODS: Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1 RESULTS: We observed a significant positive association between human serum LRG1 levels and both age and BMI, with elevated levels observed in individuals with vs without type 2 diabetes. In mice fed a high-fat diet, LRG1 upregulation in serum was associated with hyperinsulinaemia. Lrg1 knockout protected mice from diet-induced islet hyperplasia and the loss of beta cell mass. Furthermore, neutralising LRG1 activity prevented the onset of diet-induced hyperinsulinaemia and preserved glucose tolerance. Mechanistically, LRG1 induces inositol triphosphate (IP CONCLUSIONS/INTERPRETATION: In summary, this study identifies LRG1 as a significant contributor to hyperinsulinaemia and beta cell dysfunction. Targeting LRG1 activity emerges as a promising therapeutic approach for addressing diet-induced beta cell dysfunction and managing type 2 diabetes.