In male Wistar rats, a high-fructose diet produces metabolic effects including glucose intolerance, insulin resistance, and endoplasmic reticulum stress that are comparable in magnitude and pattern to those produced by a high-fat diet, indicating that fructose contributes to metabolic disease through pathways similar to those of dietary fat.

When rats consume large amounts of fructose or fat, their liver and insulin-producing cells become overwhelmed with nutrients. This overload causes a buildup of incorrectly folded proteins in a cellular compartment called the endoplasmic reticulum. The cell responds by activating a stress pathway that blocks insulin signals and turns on genes that kill the insulin-producing cells. As a result, the body cannot control blood sugar properly, leading to insulin resistance and glucose intolerance.