<p>Blood glucose level is hormonally regulated by insulin and glucagon, secreted by pancreatic β-cells and α-cells, respectively. In this article, we present our hypothesis that how glucose and fructose metabolism regulate insulin secretion, and that fructose 1-phosphate–induced futile cycle affects β-cell function and contributes to metabolic diseases. We hypothesize that glucose and fructose differentially regulate insulin secretion through distinct metabolic pathways. Glucose uptake via GLUT1 and its subsequent metabolism increase the ATP/ADP ratio, leading to K_ATP channel closure, membrane depolarization, Ca²⁺ influx, and insulin vesicle exocytosis. Concurrent tau phosphorylation promotes microtubule disassembly, facilitating insulin release. In contrast, fructose uptake through GLUT2, its phosphorylation by fructokinase to fructose 1-phosphate (F1P), and subsequent activation of glucokinase (GK) and fructose 1,6-bisphosphatase-1 (FBPase-1) induce a futile cycle characterized by continuous interconversion between fructose 6-phosphate and fructose 1,6-bisphosphate. This cycle lowers the ATP/ADP ratio, impairs tau phosphorylation and glucose-stimulated insulin secretion, and diverts intermediates toward lipogenesis. Thus, while glucose maintains insulin secretion via regulated glycolysis and energy production, fructose metabolism disrupts this balance through F1P-driven futile cycle, reducing ATP availability, impairing insulin release, and promoting lipid synthesis. Understanding this mechanism provides insight into the adverse effects of dietary fructose on β-cell function.</p>