| Description |
As the identification of new targets for therapeutic intervention that might attenuate cardiovascular complications associated with type 2 diabetes are needed, our lab conducted a prior study to address that need. We reported at that time that mice treated with a potent and selective small molecule inhibitor (LB1; Lixte Biotechnology Holdings, Inc., East Setauket, NY; 1 mg/kg IP; intraperitoneal) of protein phosphatase 2A (PP2A) for the last 14 days of an obesogenic diet (12 weeks of fat-feeding) did not display vascular PP2A hyperactivation, endothelial dysfunction, or hypertension that otherwise developed in fat-fed mice treated with vehicle. We concluded that PP2A hyperactivation should be considered further as a therapeutic target for intervention. While our investigation was in progress, results from another study indicated that 2 -mg/kg LB1 IP (3 hr) evoked hyperglycemia, glucose intolerance, and hepatic glycogen depletion in chow-fed and fat-fed (3 days) rats. The authors concluded that targeting PP2A hyperactivation should not be considered as a therapeutic intervention. Based on the incongruent conclusions from these two studies, we conducted a new research study, testing the following hypotheses-that LB1 treatment for 14-days impairs: (i) peripheral; glucose homeostasis; (ii) hepatic glycogen content; and (iii) insulin-mediated signal; transduction in the liver. The first two hypotheses were tested using 7-week old male C57BL/6J mice who consumed standard (Con) or high fat (HF) chow for 12 weeks. Subgroups of Con and HF mice received 1 mg/kg LB1 or saline (Veh) IP for the last 14 days of testing. Glucose and insulin tolerance testing indicated that LB1 treatment does not impair peripheral glucose homeostasis in Con mice or HF mice, denying the first hypothesis. Regarding second hypothesis, LB1 treatment did not lower hepatic glycogen content, p-Akt2S474 / Akt2, p-Gsk3ɑS21 / Gsk3ɑβ, or p-GSS641 / GS, in lean or obese mice under basal, random-fed conditions. To test the third hypothesis, age-matched male mice that consumed standard chow were treated with LB1 or Veh for 14 days. On day 15, after a 6-hr fast, insulin or saline was administered (i.v. intravenous) to anesthetized mice, and segments of liver were collected to assess p-Akt2S474 / Akt2, p-GSK3ɑS21 / GSK3ɑ, and p-GSS641 / GS. Insulin-mediated signal transduction in the liver was similar regardless of LB1 treatment. We conclude that LB1 treatment in mice for 14-days does not impair: (i) peripheral glucose homeostasis; (ii) hepatic glycogen content; or (iii) insulin-mediated; signal transduction in the liver. |
