Arhalofenate

Male ZDF rats at 8 wk of age are used in the assay. ZDF rats are single housed and allowed access ad libitum to tap water and chow. ZDF rats are screened into three groups with similar mean plasma glucose levels. ZDF rats are cannulated in the jugular vein and the carotid artery and are allowed to recover at least for 2 d. Rats are dosed with either vehicle or Arhalofenate (MBX 102) (100 mg/kg) by oral gavage for 4-7 d. On the day of the clamp experiment, rats are dosed and food is withdrawn 1 h later. After rats are fasted for 4 h, blood samples are taken from the carotid catheter to measure basal glucose and insulin levels. Experiments are initiated with a priming injection (0.5 mL/rat of 5 μCi/mL of d-[3-³H] glucose) and initiation of a constant infusion of d-[3-³H] glucose tracer (8 μCi/mL) at a rate of 10 μL/min for 60 min. After the 1-h tracer-equilibration period, a post-tracer blood sample is collected for glucose, insulin and d-[3-³H] glucose specific activity (SA) measurements. Infusion of tracer glucose is then discontinued, and insulin infusion is initiated (10 μL/min equivalent to 40 mU/kg/min) along with glucose infusion. The glucose infusion rate is adjusted empirically to achieve plasma glucose level at 150 mg/dL ± 5% within the next 1.5-2 h. To facilitate this process, blood samples are collected at 10-min intervals for immediate plasma glucose measurements using a glucometer until the end of the study. Clamp is defined by three consecutive glucose measurements that are within the above defined range. Samples (300-400 μL) at the three time points (10-min interval) are collected for glucose, insulin, and d-[3-³H] glucose SA measurements.

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