Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-gamma-deficient mice on a high-fat diet.
Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-gamma activity on beta-cell function, we investigated insulin secretion in PPARgamma(+/-) mice on a high-fat diet. Glucose-induced insulin secretion in PPARgamma(+/-) mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARgamma(+/-) mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-gamma agonist, pioglitazone, reduced the islet TG content in PPARgamma(+/-) mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-gamma protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-gamma agonist can restore impaired insulin secretion under conditions of islet fat accumulation.
Matsui
Junji
J
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Terauchi
Yasuo
Y
Kubota
Naoto
N
Takamoto
Iseki
I
Eto
Kazuhiro
K
Yamashita
Tokuyuki
T
Komeda
Kajuro
K
Yamauchi
Toshimasa
T
Kamon
Junji
J
Kita
Shunbun
S
Noda
Mitsuhiko
M
Kadowaki
Takashi
T
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004041:Dietary Fats; D018149:Glucose Intolerance / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism*
D017931:DNA Primers; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D000077205:Pioglitazone