Fluid compartmental shifts with efficacious pioglitazone therapy in overweight monkeys: implications for peroxisome proliferator-activated receptor–γ agonist use in prediabetes

Abstract 

Pioglitazone is prescribed to improve insulin sensitivity in type 2 diabetes mellitus patients and has been discussed as a therapy for metabolic syndrome. Pioglitazone and other thiazolidinediones are associated with fluid retention and edema that may exacerbate existing or developing congestive heart failure, which is often present in these patients. Using a nonhuman primate model, our aims were to evaluate (1) whether fluid shifts were detectable in normoglycemic monkeys, (2) which fluid compartment changed, and (3) whether fluid retention was dose dependent. Seventeen adult male cynomolgus macaques (Macaca fascicularis) were studied in a Latin square design such that all animals received 0, 1, 2, and 5 mg/kg pioglitazone for 6 weeks with 2 weeks of washout between dosing intervals. Doses approximated human exposures achieved with 30, 45, and 60 mg. At the end of each period, animals were weighed and underwent dual-absorption x-ray absorption scanning for body composition measurements. Fluid volumes were quantitated by Evans blue dilution for plasma volume, equilibration of sodium bromide for extracellular water, and deuterated water for total body water. Significant (P < .05) effects were seen with expansion of PV at both the 2- and 5-mg/kg doses, along with reduced plasma sodium at 5 mg/kg; however, surrogate end points used to indicate fluid retention (body weight, hematocrit, total protein, and albumin) did not change significantly. Significant trends toward increases in interstitial fluid and extracellular water with increasing dose were apparent. Pioglitazone effectively improved metabolic status by significantly decreasing fasting glucose and triglycerides and increasing adiponectin. We conclude that thiazolidinedione-related plasma volume expansion occurs in nondiabetic primates and that fluid retention is detectable when compartments are directly measured.