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)