To determine the relationship between
hypoglycemic activity and
body weight gain induced by
insulin sensitizers, we compared the effects of
thiazolidinedione analogs (
troglitazone and
pioglitazone) and the oxadiazolidinedione analog (Z)-1,4-bis4[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phen oxy¿but-2-ene (
YM440) in diabetic db/db mice. Oral treatment with
YM440(100 mg/kg) for 28 days decreased the
blood glucose concentration (control v
YM440, 418 +/- 12 v243 +/- 44 mg/dL). The
hypoglycemic activity of this agent was comparable to that of
troglitazone (300 mg/kg) and
pioglitazone (100 mg/kg). There were no changes in food intake among the groups.
Troglitazone and
pioglitazone, but not
YM440, significantly increased
body weight gain during treatment (control, 7.2 +/- 0.5 g;
YM440, 7.5 +/- 0.8 g;
troglitazone, 10.9 +/- 0.8 g; and
pioglitazone, 14.5 +/- 1.1 g). To further assess whether the increase in
body weight by
troglitazone or
pioglitazone was due to adipogenesis, the weight of intraabdominal fat tissue (epididymal, retroperitoneal, and perirenal) was determined. There were no differences in the total weight of visceral fat between the control and
YM440 treatment (3.53 +/- 0.23 and 3.60 +/- 0.16 g). In contrast,
troglitazone and
pioglitazone significantly increased the fat weight (4.31 +/- 0.13 and 4.66 +/- 0.19 g).
Thiazolidinediones are known as
ligands for
peroxisome proliferator-activated receptor gamma (
PPARgamma), a
nuclear receptor responsible for adipogenesis.
Troglitazone and
pioglitazone activated
PPARgamma and increased
triglyceride accumulation and
mRNA expression of
fatty acid-binding protein (FABP) in 3T3-L1 cells. However,
YM440 had no effect on these indices for adipocyte differentiation. These results suggest that the mechanism is different for the
hypoglycemic action of
YM440 versus the
thiazolidinediones.
YM440 ameliorates
hyperglycemia without changing
PPARgamma activity, adipocyte differentiation, or fat weight. Thus,
YM440 could be a useful
hypoglycemic agent for the treatment of
non-insulin-dependent diabetes mellitus (
NIDDM) without affecting
body weight.