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.
Kashiwagi
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Third Department of Medicine, Shiga University of Medical Science, Japan.
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