Rationale and hurdles of inhibitors of hepatic gluconeogenesis in treatment of diabetes mellitus.
A typical clinical feature of patients with fasting hyperglycemia in diabetes is well correlated with accelerated hepatic glucose production which is determined by elevated FFA-induced gluconeogenesis. Therefore, to treat fasting hyperglycemia, inhibition of both FFA release and fatty acid oxidation in the liver may be efficient modalities of treatment. (1) Inhibitor of FFA release: a novel selective adenosine A1 agonist, SDZ WAG 994 is a potent inhibitor of adenosine deaminase-induced lipolysis. Twenty-three-week old, male GK rats showing glucose intolerance were treated with WAG 994 (1000 micrograms/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 concentrations also decreased by 54% and 74%, respectively (vs. control GK rats). (2) Inhibition of hepatic fatty acid oxidation: beta-aminobetaine (emeriamine) is a water-soluble carnitine analog and inhibition of CPT-1 in isolated hepatocytes is 100 times more sensitive than that in isolated cardiocytes and it suppresses both gluconeogenesis and ketogenesis by 60-80%. However, it may be possible that this drug may induce fat deposition in the liver. An inhibitor of elevated fatty acid release from adipose tissue in concomitant with liver-specific and reversible inhibition of fatty acid oxidation may be an effective agent with hypoglycemic and hypolipidemic action for the treatment of diabetes mellitus.
Third Department of Medicine, Shiga University of Medical Science, Japan.
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Kashiwagi
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; C090949:N(6)-cyclohexyl-2-O-methyladenosine; D000241:Adenosine