VLDL TRIGLYCERIDE KINETICS IN WISTAR FATTY RATS, AN ANIMAL-MODEL OF NIDDM - EFFECTS OF DIETARY FRUCTOSE ALONE OR IN COMBINATION WITH PIOGLITAZONE

The effects of dietary fructose alone or in combination with a new ora l agent, pioglitazone, on VLDL-triglyceride (TG) turnover were studied in genetically obese Wistar fatty rats characterized by hyperinsuline mia (7,488 +/- 954 pmol/l), hyperglycemia (22.5 +/- 1.4 mmol/l), and h ypertriglyceridemia (4.39 +/- 0.54 mmol/l), They had an increased hepa tic TG production (16.2 +/- 0.1 mu mol/min; lean rats, 5.4 +/- 0.3 mu mol/min) as well as a longer half-life of VLDL-TG from lean donors (8. 8 +/- 1.4 min, lean recipients; 2.3 +/- 0.9 min), In addition, in lean recipients, the half-life of VLDL-TG from fatty donors was longer tha n that from lean donors (4.80 +/- 0.56 vs, 3.14 +/- 0.23 min), Althoug h feeding fructose into fatty rats did not change plasma glucose and i nsulin levels, it produced a twofold increase in TG levels (8.74 +/- 1 .15 mmol/l), This was associated with a 1.7-fold increase in TG produc tion to 27.5 +/- 1.2 mu mol/min, while no significant change was found in the half-life of lean VLDL-TG in fructose-fed fatty recipients (10 .9 +/- 2.4 min) or in that of VLDL-TG from fructose-fed fatty donors i n lean recipients (4.46 +/- 0.76 min), Daily administration of pioglit azone (3 mg/kg body weight) in fructose-fed fatty rats ameliorated gly cemia and triglyceridemia to the level of lean rats (8.1 +/- 0.7 and 1 .18 +/- 0.05 mmol/l, respectively) and insulinemia to a lesser extent (2,712 +/- 78 pmol/l), A fall in TG levels was associated with improve ment of an impairment in the ability of fructose-fed fatty rats to rem ove lean VLDL-TG (half-life: 2.6 +/- 0.6 min), Pioglitazone, however, produced no change in TG production (25.9 +/- 2.7 mu mol/min), the hal f-life of VLDL-TG from fructose-fed fatty donors in lean recipients (4 .17 +/- 0.38 min), or the activity of lipoprotein Lipase and hepatic L ipase in postheparin plasma, mie conclude that in Wistar fatty rats I) hypertriglyceridemia is attributed to TG overproduction and impaired TG catabolism, and the latter is due to changes in both VLDL, such tha t they are less able to be removed, and changes in the nature of Wista r fatty rats, such that they are less able to remove VLDL-TG; 2) fruct ose further increases hepatic TG production with a resultant deteriora tion in hypertriglyceridemia; 3) pioglitazone normalizes TG levels by altering the physiology of the Wistar fatty rats in a manner that incr eases their ability to remove VLDL-TG from the circulation.