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 oral agent, pioglitazone, on VLDL-triglyceride (TG) turnover were studied in genetically obese Wistar fatty rats characterized by hyperinsulinemia (7,488 +/- 954 pmol/l), hyperglycemia, (22.5 +/- 1.4 mmol/l), and hypertriglyceridemia (4.39 +/- 0.54 mmol/l). They had an increased hepatic TG production (16.2 +/- 0.1 micromol/min; lean rats, 5.4 +/- 0.3 micromol/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 than that from lean donors (4.80 +/- 0.56 vs. 3.14 +/- 0.23 min). Although feeding fructose into fatty rats did not change plasma glucose and insulin 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 production to 27.5 +/- 1.2 micromol/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 in lean recipients (4.46 +/- 0.76 min). Daily administration of pioglitazone (3 mg/kg body weight) in fructose-fed fatty rats ameliorated glycemia 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 improvement of an impairment in the ability of fructose-fed fatty rats to remove lean VLDL-TG (half-fife: 2.6 +/- 0.6 min). Pioglitazone, however, produced no change in TG production (25.9 +/- 2.7 micromol/min), the half-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 lipase in postheparin plasma. We conclude that in Wistar fatty rats 1) hypertriglyceridemia is attributed to TG overproduction and impaired TG catabolism, and the latter is due to changes in both VLDL, such that they are less able to be removed, and changes in the nature of Wistar fatty rats, such that they are less able to remove VLDL-TG; 2) fructose further increases hepatic TG production with a resultant deterioration in hypertriglyceridemia; 3) pioglitazone normalizes TG levels by altering the physiology of the Wistar fatty rats in a manner that increases their ability to remove VLDL-TG from the circulation.
Kazumi
T
T
Department of Medicine, Hyogo Medical Center for Adults, Japan.
Hirano
T
T
Odaka
H
H
Ebara
T
T
Amano
N
N
Hozumi
T
T
Ishida
Y
Y
Yoshino
G
G
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D004040:Dietary Carbohydrates; D004195:Disease Models, Animal; D002149:Energy Intake; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005632:Fructose / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008049:Lipase / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000187:drug effects; D008099:Liver / Q000201:enzymology; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013851:Thinness / Q000097:blood / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood*
D004040:Dietary Carbohydrates; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D008079:Lipoproteins, VLDL; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D005632:Fructose; D002784:Cholesterol; D008049:Lipase; D008071:Lipoprotein Lipase; D000077205:Pioglitazone