Effect of the fatty acid oxidation inhibitor methyl palmoxirate (methyl 2-tetradecylglycidate) on recovery from insulin-induced hypoglycemia in diabetic dogs.
Methyl palmoxirate, an effective hypoglycemic agent administered p.o., has been shown to decrease hepatic glucose production secondary to inhibition of mitochondrial fatty acid oxidation. Because the ability to increase hepatic glucose production is an important counter-regulatory defense against hypoglycemia, we compared the ability of streptozotocin/alloxan-induced diabetic dogs treated p.o. with vehicle or methyl palmoxirate (2.5 mg/kg/day X 7 days) to recover from insulin-induced hypoglycemia. Hepatic glucose production and glucose utilization were determined by isotope dilution before and after acute reduction of plasma glucose by i.v. insulin injection (0.10 or 0.13 U/kg). Diabetic dogs treated with methyl palmoxirate for 6 days had lower overnight fasting plasma glucose levels than vehicle-treated animals (158 +/- 7 vs. 171 +/- 11, respectively, P less than .05). Plasma glucose at 4 hr after the last dose of drug decreased to 115 +/- 5 mg/dl, whereas glucose in the vehicle-treated dogs was unchanged (172 +/- 8 mg/dl). Recovery from insulin-induced hypoglycemia (nadirs of 58 +/- 5 and 42 +/- 4 mg/dl in the vehicle- and methyl palmoxirate-treated groups, respectively) was not significantly different between the two groups of dogs. Restoration of plasma glucose was primarily due to increased hepatic glucose production in both treatment groups, as glucose utilization did not fall significantly below baseline levels. Plasma glucagon levels increased in both vehicle- and methyl palmoxirate-treated dogs in response to hypoglycemia, indicating that release of an important counter-regulatory hormone was not compromised by drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Tuman
R W
RW
Department of Biological Research, McNeil Pharmaceutical, Spring House, Pennsylvania.
Bowden
C R
CR
Inman
M
M
Altszuler
N
N
Tutwiler
G F
GF
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004285:Dogs; D004852:Epoxy Compounds / Q000627:therapeutic use*; D004988:Ethers, Cyclic / Q000627:therapeutic use*; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000188:drug therapy*; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D011422:Propionates / Q000627:therapeutic use*
D001786:Blood Glucose; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D007328:Insulin; D011422:Propionates; D005934:Glucagon; D005947:Glucose; C017522:methyl 2-tetradecylglycidate