Adaptive Responses to High-fructose Corn Syrup Intake Under Energy Restriction in Early Middle-aged Female Mice

Background/Aim: The global prevalence of type 2 diabetes (T2D) continues to rise, with non-obese phenotypes particularly common in East Asian populations. Our previous study in male mice demonstrated that the intake of excessive high-fructose corn syrup (HFCS) under energy restriction impairs glucose tolerance without inducing obesity. This study aimed to elucidate female-specific mechanisms underlying glucose regulation under similar dietary conditions. Materials and Methods: Early middle-aged female ICR mice were randomly assigned to either the HFCS group or the control group. In the HFCS group, mice were given free access to HFCS water, and the energy intake was adjusted to be the same as that in the control group using a standard rodent diet. After 16 weeks, glucose tolerance and insulin sensitivity were assessed via the oral glucose tolerance and insulin tolerance tests, respectively. Pancreatic morphology, gene expression, and serum biochemical and hormonal parameters were analyzed. Results: Glucose tolerance and islet size distribution were comparable between the HFCS and control groups. The HFCS group, however, exhibited lower insulin secretion and reduced pancreatic weight relative to controls. mRNA levels of insulin II, pancreatic and duodenal homeobox 1, glucose transporter 2, and glucokinase were similar between groups, whereas ketohexokinase mRNA tended to be elevated in the HFCS group. In addition, the mRNA levels of glutaminase and glutamate dehydrogenase 1 were higher than those in controls. Serum leptin and insulin-like growth factor I showed upward trends in the HFCS group, and glucagon-like peptide-1 levels were significantly increased compared with controls. Conclusion: Excessive HFCS intake under energy restriction diminished insulin secretion but preserved glucose tolerance in female mice, which might be attributable to extrapancreatic hormonal compensation and adaptive metabolic responses.