ABSTRACT
Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Propionates/chemical synthesis , Propionates/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Animals , Blood Glucose/metabolism , Cholesterol, HDL/blood , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Mice , Mice, Inbred Strains , Receptors, Cytoplasmic and Nuclear/genetics , Transcription Factors/genetics , Triglycerides/bloodABSTRACT
Blood chemistry profiles (glucose, insulin, and triglycerides) and indirect calorimetry were performed on male Zucker diabetic fatty (ZDF) rats in a longitudinal fashion (starting at 7 weeks of age) to assess the nature and timing of specific events in the transition to overt diabetes. Peripheral (skeletal muscle) insulin resistance was clearly present at 7 weeks of age in ZDF rats, yet circulating glucose was only slightly above normal as a result of compensatory hyperinsulinemia. At a crucial stage from 7 to 8 weeks, a reduction in insulin levels instigated several deleterious changes resulting in reduced whole-body carbohydrate utilization and increased glycemia. In subsequent weeks, an inability to sustain peripheral glucose disposal as a consequence of a continuous decline in insulin levels further reduced carbohydrate utilization (increased lipid utilization) and enhanced the overt hyperglycemia. These observations document in a systematic fashion the alterations that define diabetic progression in ZDF rats.
