RATIONALE AND HURDLES OF INHIBITORS OF HEPATIC GLUCONEOGENESIS IN TREATMENT OF DIABETES-MELLITUS

A typical clinical feature of patients with fasting hyperglycemia in d iabetes is well correlated with accelerated hepatic glucose production which is determined by elevated FFA-induced gluconeogenesis. Therefor e, to treat fasting hyperglycemia, inhibition of both FFA release and fatty acid oxidation in the liver may be efficient modalities of treat ment. (1) Inhibitor of FFA release: a novel selective adenosine Al ago nist, SDZ WAG 994 is a potent inhibitor of adenosine deaminase-induced lipolysis. Twenty-three-week old, male GK rats showing glucose intole rance were treated with WAG 994 (1000 mu g/kg body weight) for 16 days . Plasma glucose level at 0 time in WAG group was significantly (P < 0 .01) less than that of the control. Both plasma FFA and triglyceride c oncentrations also decreased by 54% and 74%, respectively (vs. control GK rats). (2) Inhibition of hepatic fatty acid oxidation: beta-aminob etaine (emeriamine) is a water-soluble carnitine analog and inhibition of CPT-1 in isolated hepatocytes is 100 times more sensitive than tha t in isolated cardiocytes and it suppresses both gluconeogenesis and k etogenesis by 60-80%. However, it may be possible that this drug may i nduce fat deposition in the liver. An inhibitor of elevated fatty acid release from adipose tissue in concomitant with liver-specific and re versible inhibition of fatty acid oxidation may be an effective agent with hypoglycemic and hypolipidemic action for the treatment of diabet es mellitus.