Triglyceride-rich lipoprotein (TRL) production was studied in ZDF rats, a model of insulin- resistant type 2 diabetes progression. TRL production was measured in vivo by blocking catabolism with Triton WR 1339. Ten-week ZDF rats are hyperinsulinemic with increased TRL production (both triglyceride and apo B). Twenty-week ZDF rats are insulinopenic and TRL production is similar to lean controls. Insulin infusion suppresses glucose and free fatty acids in 10- and 20-week ZDF rats. Increased TRL production is not reduced by insulin in 10-week rats, however, at 20 weeks, TRL production is suppressed by insulin. In vitro studies with hepatocytes derived from 10-week ZDF rats showed minimal insulin dose effects on apoB secretion compared with the response and sensitivity of hepatocytes derived from 20-week ZDF and control lean rats. Hepatic SREBP-1c mRNA levels are increased at 10 weeks, but return to control levels at 20 weeks. Apo B mRNA levels are similar to lean controls at 10 and 20 weeks. Two mechanisms for hypertriglyceridemia associated with hyperinsulinemia are suggested: increased TRL synthesis, and loss of TRL suppression. Increased triglyceride production in hyperinsulinemic rats likely relates to increased expression of SREBP-1c, while increased apo B production involves post-transcriptional processes.