In female rats, dietary fructose and glucose impair insulin signaling in the liver and aorta by reducing IRS-2 expression and hepatic p-Akt levels, with fructose producing a significantly greater reduction than glucose, independent of caloric intake.

Fructose is processed in the liver in a way that causes insulin levels to rise, which triggers the liver to make more fat and blocks the breakdown of existing fat. This leads to fat buildup in the liver and signals that disrupt insulin's ability to work. Insulin signaling weakens because a key protein called IRS-2 drops in both the liver and blood vessels, which stops Akt from becoming active. Without active Akt, cells cannot respond to insulin properly, leading to high blood sugar and stiff blood vessels. Fructose also creates harmful molecules that damage blood vessels and blocks another pathway that helps blood vessels relax, making the problem worse.