Effects of antihyperlipidemic agents on hepatic insulin sensitivity in perfused Goto-Kakizaki rat liver.
BACKGROUND
We previously reported that the Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes, has hepatic insulin resistance using a perfused rat liver model. Pioglitazone, eicosapentaenoic acid (EPA), and fenofibrate are antihyperlipidemic agents and improve glucose tolerance. There have been few studies showing that these agents directly improve hepatic insulin sensitivity in type 2 diabetes mellitus. The aim of this study was to explore the effects of these agents on hepatic insulin sensitivity directly using a perfused GK rat liver model.


METHODS
GK rats were treated with oral pioglitazone (6 or 10 mg/kg body weight), EPA (1 or 2 g/kg body weight), or fenofibrate (30 mg/kg body weight) for 2 weeks. Livers were perfused in situ with glucagon or with glucagon and insulin, and hepatic glucose outputs were measured.


RESULTS
In the pioglitazone-treated GK rats, blood glucose levels were significantly decreased. In the pioglitazone- and EPA-treated GK rats, insulin infusion significantly attenuated hepatic glucose output stimulated by glucagon. In the fenofibrate-treated GK rats, fat deposits in the hepatocytes were decreased, and glucose output elicited by glucagon was significantly decreased compared with that in the untreated GK rats, whereas insulin infusion did not affect glucose output by glucagon.


CONCLUSIONS
These findings suggest that pioglitazone and EPA may improve glucose tolerance by directly increasing hepatic insulin sensitivity, while fenofibrate may improve glucose tolerance by improving hepatic glycogen metabolism in the GK rats. We previously reported that the Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes, has hepatic insulin resistance using a perfused rat liver model. Pioglitazone, eicosapentaenoic acid (EPA), and fenofibrate are antihyperlipidemic agents and improve glucose tolerance. There have been few studies showing that these agents directly improve hepatic insulin sensitivity in type 2 diabetes mellitus. The aim of this study was to explore the effects of these agents on hepatic insulin sensitivity directly using a perfused GK rat liver model.
Matsuura
Bunzo
B
Third Department of Internal Medicine, Ehime University School of Medicine, Shitsukawa, Shigenobu, Ehime 791-0295, Japan.
Kanno
Sakiko
S
Minami
Hisaka
H
Tsubouchi
Eiji
E
Iwai
Masaru
M
Matsui
Hidetaka
H
Horiike
Norio
N
Onji
Morikazu
M
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D011345:Fenofibrate / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D010477:Perfusion / Q000379:methods; D000077205:Pioglitazone; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D045162:Thiazolidinediones; D006003:Glycogen; D015118:Eicosapentaenoic Acid; D011345:Fenofibrate; D000077205:Pioglitazone