The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice

To determine the relationship between hypoglycemic activity and body weight gain induced by insulin sensitizers, we compared the effects of thiazolidi nedione analogs (troglitazone and pioglitazone) and the oxadiazolidinedione analog (Z)-1,4-bis vertical bar 4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)met hyl]phenoxy\but-2-ene (YM440) in diabetic db/db mice. Oral treatment with Y M440 (100 mg/kg) for 28 days decreased the blood glucose concentration (con trol vYW1440, 418 +/- 12 v 243 +/- 44 mg/dL). The hypoglycemic activity of this agent was comparable to that of troglitazone (300 mg/kg) and pioglitaz one (100 mg/kg). There were no changes in food intake among the groups. Tro glitazone and pioglitazone, but not YM440, significantly increased body wei ght gain during treatment (control, 7.2 +/- 0.5 g; YM440, 7.5 +/- 0.8 g; tr oglitazone, 10.9 +/- 0.8 g; and pioglitazone, 14.5 +/- 1.1 g), To further a ssess whether the increase in body weight by troglitazone or pioglitazone w as 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 treatmen t (3.53 +/- 0.23 and 3.60 +/- 0.16 g). In contrast, troglitazone and piogli tazone 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 (PPAR gamma), a nuclear receptor responsible for adipogenesis. Troglitazone and pioglitazone activated PPAR gamma and increa sed triglyceride accumulation and mRNA expression of fatty acid-binding pro tein (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 thiazolidinedione s. YM440 ameliorates hyperglycemia without changing PPAR gamma activity, ad ipocyte differentiation, or fat weight. Thus, YM440 could be a useful hypog lycemic agent for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) without affecting body weight. Copyright (C) 2000 by W.B. Saunders Company.