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Keywords:

  • Zucker rats;
  • insulin resistance;
  • hyperglycemia;
  • body weight;
  • plant sterols;
  • cholesterol absorption

Abstract

The purpose of this investigation was to determine the effects of Phytostanol Phosphoryl Ascorbate (FM-VP4) on insulin resistance, hyperglycemia, plasma lipid levels, body weight, and gastrointestinal absorption of exogenous cholesterol in Zucker (fa/fa) fatty and lean rats. A group of 12 age-matched male obese (n = 6) and lean (n = 6) Zucker rats were administered 250 mg/kg twice a day (as 2% FM-VP4 in drinking water) for 30 consecutive days. Fasted blood samples prior to and following treatment were taken from all rats for glucose, lipid, insulin, and leptin determination. An oral glucose tolerance test was also carried out at the end of the treatment protocol. In addition, male obese (n = 7) and lean (n = 8) Zucker rats were coadministered a single oral gavage of [3H]cholesterol plus cold cholesterol with or without FM-VP4 (20 mg/kg) dissolved in Intralipid and the plasma concentration of the radiolabel was determined 10 h following the dose. FM-VP4 30-day treatment did not alter body weight, morning glucose, insulin, lipids, and leptin concentrations. There was no alteration in glucose tolerance in the nondiabetic, normoglycemic lean group; however, there was a highly significant improvement in glucose tolerance in the fatty group following FM-VP4 treatment. In addition, the insulin response to oral glucose showed no significant change in nondiabetic lean rats, whereas there was a change in the insulin secretory profile in the fatty group following FM-VP4 treatment. Furthermore, following a single oral gavage of FM-VP4 resulted in a significant decrease in the percentage of radiolabeled cholesterol absorbed. These findings suggest that FM-VP4 treatment to fatty Zucker rats could result in increased glucose responsiveness of the insulin secreting pancreatic β cells. Furthermore, our findings suggest that FM-VP4 may only be effective presystemically. Systemic administration of FM-VP4 is warranted to determine the therapeutic potential of this effect. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:281–288, 2003