Akiko Suzuki, Toru Yasuno, Hitoshi Kojo*, Jiro Hirosumi, Seitaro Mutoh
and Yoshitada Notsu
Molecular Biological Research Laboratory and Exploratory Research Laboratories,
Fujisawa Pharmaceutical Co., Ltd.,
5-2-3 Tokodai, Tsukuba, Ibaraki 300-2698, Japan
*Corresponding author.ﾊﾊFAX:+81-298-47-1536
E-mail: hitoshiﾊ_
Abstract: We studied the effect of pioglitazone on the transcription
of 42ﾊgenes associated with diabetes to examine the relationship between
the antidiabetic action of thiazolidinediones (TZDs) and their ability to
modulate transcription through their peroxisome proliferater-activated receptor
(PPAR)-agonistic activity. Diabetic (db/db) mice were orally administered
with pioglitazone for two weeks. Total RNA was prepared from liver, muscle
and adipocytes and the quantity of mRNA was determined by comparative RT-PCR.
The expression of diabetes-related genes was compared between lean and untreated
db/db mice and between untreated and drug-treated db/db mice.
The onset of diabetes was associated with a considerable alteration in the
expression of a large number of diabetes-related genes. Treatment of db/db
mice with pioglitazone modulated the expression of genes involved in the
metabolism of glucose, lipids and lipoproteins. This included genes for
phosphoenolpyruvate carboxykinase, b-oxidation
enzymes, lipoprotein lipase, apolipoproteinﾊAI and uncoupling proteins.
Most of the genes responsible for insulin signaling were unaffected. Administration
of pioglitazone was also shown to induce PPARg
expression in liver and muscle. It is therefore possible to hypothesize
that TZDs may ameliorate diabetes through a mechanism of action involving
a direct decrease in plasma glucose and triglyceride levels and improvements
in free fatty acid-induced insulin resistance.
Keywords: Thiazolidinedione, Pioglitazone, Diabetes, Expression profile,
db/db mouse
Copyrightｩ The Japanese Pharmacological Society 2000
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