Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways.
Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFalpha and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.
Kubota
Naoto
N
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655.
Terauchi
Yasuo
Y
Kubota
Tetsuya
T
Kumagai
Hiroki
H
Itoh
Shinsuke
S
Satoh
Hidemi
H
Yano
Wataru
W
Ogata
Hitomi
H
Tokuyama
Kumpei
K
Takamoto
Iseki
I
Mineyama
Tomoka
T
Ishikawa
Michiro
M
Moroi
Masao
M
Sugi
Kaoru
K
Yamauchi
Toshimasa
T
Ueki
Kohjiro
K
Tobe
Kazuyuki
K
Noda
Tetsuo
T
Nagai
Ryozo
R
Kadowaki
Takashi
T
D052242:Adiponectin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003433:Crosses, Genetic; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000096:biosynthesis; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D052242:Adiponectin; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D014280:Triglycerides; D005947:Glucose; D000077205:Pioglitazone