Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoproteins and plays an important role in glucose metabolism. To examine the hypothesis that increased LPL activity may alter insulin sensitivity, we investigated glucose metabolism and insulin sensitivity in transgenic (Tg) rabbits expressing the human LPL gene under the control of a I(2) -actin promoter. An intravenous glucose tolerance test showed that the plasma glucose clearance rate was not significantly different between Tg and non-Tg rabbits; however, the area under the curve for insulin and free fatty acids in Tg rabbits was significantly reduced compared with that of non-Tg rabbits (P < .05). Using the intravenous insulin tolerance test, we found that the area of under the curve of glucose of Tg rabbits was also significantly reduced (P < .01). Furthermore, euglycemic-hyperinsulinemic clamp test revealed that the mean glucose infusion rate in Tg rabbits was significantly higher than in non-Tg rabbits (P < .05). These results demonstrate that systemic overexpression of LPL increases whole-body insulin sensitivity and genetic manipulation of LPL genes may be a potential target for the treatment of diabetic patients.