['To investigate the correlation of hypertriglyceridemia with abnormal glucose metabolism and insulin resistance.', 'Lipid and glucose metabolism, whole-body and tissue-specific insulin sensitivity, genes and proteins related with oxidative stress and endoplasmic reticulum (ER) stress were compared between LPL+/- and control mice at different weeks of age.', '16-50-week LPL+/- mice had increased body weight compared with their respective controls. Fat mass in visceral adipose tissue (VAT) of 16 and 28-week LPL+/- mice were twice more than their control littermates, and 50-week LPL+/- mice showed the same trend of increase. Plasma lipids were higher in 16-50-week LPL+/- mice. 28- and 50-week LPL+/- mice had elevated tissue lipid accumulation (liver, skeletal muscle, pancreas) and impaired glucose tolerance, while 16-week LPL+/- mice showed no differences. Homeostasis model assessment of insulin resistance for 28 and 50-week LPL+/- mice were twofold greater, whereas that for 16-week LPL+/- mice had no change. Insulin-stimulated phosphorylated Akt (Ser473) in VAT of 28-week LPL+/- mice decreased by 80.6% (p\xa0=\xa00.001), and that in liver and skeletal muscle decreased by 62.4% (P\xa0<\xa00.001) and 51.8% (p\xa0=\xa00.005) respectively. Then we found that plasma malondialdehyde and reactive oxygen species levels in liver and skeletal muscle of LPL+/- mice were elevated. Increased ER stress biomarkers were also detected in liver and VAT of 28-week LPL+/- mice.'] Is insulin resistance caused by lipotoxicity related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice?