Experimental Studies on the Mechanism of Therapeutic Effect of Antidiabetic Sulfonyl-urea

Abstract

The exact mechanism of therapeutic effect of antidiabetic sulfonylurea has been a disputed subject.
The author has attempted to clarify the situation by means of in vitro and in vivo experiments.
For in vitro experiments, Wistar strain of rats were used, while for in vivo experiments, dogs were used.
As sulfonylurea products, IBTD, BZ55 and B860 were employed, though for later experiments D860 was used exclusively. For the experimental technique in vitro, the diaphragm and liver slices of normal and alloxan diabetic rats were incubated with Warburg's apparatus.
The sulfonylurea was added to the incubation medium but it was also administered to the rat prior to excision of tissues. In vivo experiments, insulin-like activity (after Shimazu's method) and glucagon-like activity (after Shinko's method) of blood were examined with simultaneous foollow-ups of arterial and venous blood sugar levels.
The drug was injected intravenously in the carotid or portal vein. In one type of experiment, the injection was made into the arteria pancreaticoduodenale.
In the latter case, endocrine activity of pancreas was determined with blood drawn from the vena pancreaticus.
The results are summarized as follows :
1) In vitro experiments with the diaphragm, a marked inhibition of glycogenolysis and output of glucose were observed in the incubation medium, containing 10μg/ml D860. With Krebs-Ringer-glucose medium glucose uptake and glycogen synthesis showed a 30 per cent increase.
2) With the liver slices, a similar phenomenon was observed within 10 to 100μg/ml concentration of sulfonylurea. D860 was most effective and IBTD with concentration of 10 to 100μgml also showed strong inhibition of glycogenolysis. With Buchanan-Hastings-Nesbett solution, the author observed acceleration of glucose uptake and glucogensynthesis with sulfonyl-urea concentration of 10μg/ml.
3) Sulfonylurea in concentration over 300μg/dl caused increased glycogenolysis and glucose output of the diaphragm and liver slices, particularly of the latter.
4) Experiments with the liver slices under glycogenetic conditions, i.e. Buchanan-Hastings-Nesbett solution with 1000mg/dl glucose showed no apparent change in glycogen synthesis but in the environment without glucose D860 showed inhibition of glycogenolysis, thus indicating the glycostatic effect.
5) Investigation of insulin-like activity and glucagon-like activity of blood drawn from the vena pancreaticus revealed a pattern of response upon injection of D860, which was quite similar to that observed following glucose injection, i.e. there was an increase of insulin-like activity 2-3 hours after injection of glucose or D860.
6) From the investigations above mentioned the author reached the conclusion, that sulfonyl-urea exerts it's first phase effect through the accelerated consumption of endogenous insulin thus inviting initial hypoglycemia and initial decrease of insulin-like activity of plasma. The second phase effect observed, was the increase of insulin secretion, inhibition of glucose output from liver, increase of glucose uptake in the peripheral tissues and consequent retardation of restoration of hypoglycemic blood sugar level.
7) The present day concepts upon the mechanism of antidiabetic sulfonylurea was discussed from the results of our own experiments and references.