A selective eukaryotic elongation factor 2 kinase inhibitor, A484954 lowered blood glucose in Zucker fatty diabetes mellitus rat

Eukaryotic elongation factor 2 kinase (eEF2K) is a protein kinase, regulating peptide translation. Zucker fatty diabetes mellitus (ZFDM) rat is a recently developed obesity and type 2 diabetes animal model with a missense mutation (fa) in leptin receptor gene (Lepr). ZFDM-Lepr^fa/fa rats (Homo) develop obesity and type 2 diabetes, while ZFDM-Lepr^fa/+ rats (Hetero) are normal. The aim of this study was to determine effects of A484954 on glucose metabolism in ZFDM rats. A484954 (2.5 mg/kg) or carboxymethyl cellulose (CMC; 0.5 %), a vehicle was injected intraperitoneally for 15 days in 17-19-week-old rats. Compared with Hetero CMC, in Homo CMC; 1) blood and urine glucose levels were significantly elevated, 2) Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was significantly elevated, 3) mRNA expression of sodium-glucose cotransporter (SGLT)2 in kidney tended to be elevated, while that of glucose transporter (GLUT)4 in vastus lateralis muscle decreased. Compared with Homo CMC, in Homo A484954; 1) blood glucose was significantly reduced, while urine glucose did not change, 2) HOMA-IR tended to decrease, 3) mRNA expression of SGLT2 in the kidney and GLUT4 in the muscle did not change. This study demonstrates for the first time that A484954 induces hypoglycemic effects in Homo partly via preventing insulin resistance.