Small molecule inhibition of protein phosphatase 2A in vivo does not disrupt glucose homeostasis in mice.

Abstract

Identifying new targets for therapeutic intervention that might attenuate cardiovascular complications associated with type 2 diabetes is needed. Earlier we reported that mice treated with a potent and selective small molecule inhibitor (LB1; Lixte Biotechnology Holdings, Inc., East Setauket, NY; 1 mg/kg IP) 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 (Bharath et al, Diabetes, 2015). We concluded that PP2A hyperactivation should be considered further as a therapeutic target for intervention. Results from another laboratory group indicated that 2 mg/kg LB1 IP (3 hours) 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 the two studies we tested the 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. To test the first two hypotheses, 7‐week old male C57BL/6J mice 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. First, glucose and insulin tolerance testing indicated that LB1 treatment does not impair peripheral glucose homeostasis in Con mice or HF mice. Second, 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 h fast, insulin or saline was administered (i.v.) 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.Support or Funding InformationAmerican Diabetes Association (ADA: 1‐12‐BS‐208, ADA 7‐08‐RA‐164) and National Institutes of Health (NIH: 2R15HL091493) to JDSThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.