Effects of Various Natural Organic Substances and Amino Acids on Blood Sugar Level, and Some Experimental Studies on Oral Hypoglycemic Agents

Abstract

Recent extensive studies of oral antidiabetic agents, particularily two kinds of hypoglycemics, sulfonyl ureas and biguanides, greatly attracted our attention because of its high degree of hypoglycemic activity and low toxicity. But these compounds have not been yet satisfactorily recommended as a perfect antidiabetic drug. There remains further elucidation of the mechanism of the hypoglycemic action. The author's purpose of the present studies is to obtain some more information about the hypoglycemic action of certain natural organic substances, amino acids, chlorpropamide as a sulfonyl urea derivative and metformin as a biguanide derivative.The results reported were established in normal male and female, non-pregnant rats (Wistar strain), weighing over 100 g. All blood sugar determinations were performed in a fasting state, according to method of Somogyi and Nelson's blood sugar determination.1) The following natural organic substances and amino acids were orally administered in normal rats, with doses of 100 mg/kg of cholic acid, 50 mg/kg of desoxycholic acid, 200 mg/kg of hippuric acid, 200 mg/kg of theobromine, 50 mg/kg of caffeine, 100 mg/kg of theophylline, 700 mg/kg of DL-norleucine, 200 mg/kg of L-cystine, 500 mg/kg of tyrosine and 700 mg/kg of DL-creatinine.a) Although cholic acid, desoxycholic acid, caffeine, theophylline and tyrosine disclosed slight hypoglycemic action, a potent prolonged activity of blood sugar lowering effect was recognized in theobromine. Its maximal hypoglycemic reduction ratio of blood sugar level showed 38.6 per cent in 5 hours after the administration and the duration of hypoglycemic action over 6 hours.b) No hypoglycemic effect was observed in hippuric acid, DL-norleucine, L-cys-tine and DL-creatinine.2) In the mean number of β-cell count of the Langerhans' islet of the alloxan diabetic rats, treated orally with doses of 200 mg/kg of theobromine in the 7 to 60 day's duration of diabetic state, the degree of 14.1 counts and more of β-cell per a islet (more than approximately 1/5 of β-cells in a normal islet) revealed relatively marked lowering effect. On the other hand, that of 10.2 counts and less of β-cells per islet (less than 1/6 of β-cells in a normal islet) was not active in hypoglycemic effect.3) The oral administration of theobromine in doses of 200 mg/kg in normal rats for a month showed no histologic change, including Langerhans' islet, except only a mild cardiac hypertrophy.4) The intravenous administration of 300 mg/kg of chlorpropamide in normal rats lowered the blood sugar level in 55.5 per cent at maximum (the post-administrative 4 hours-value on the average of 5 cases) and its action was prolonged for 5 hours and more in duration. In addition, the intravenous administration of metformin, 200 mg/kg, revealed the blood sugar lowering effect in 62.8 per cent at maximum (the post-administrative 2 hours-value on the mean of 5 cases) and maintained for 5 hours and more in its effect.5) In the experiments of the oral administration of theobromine in doses of 200 mg/kg, the intravenous administration of chlorpropamide in doses of 300 mg/kg and metformin in doses of 200 mg/kg in normal rats, the blood sugar levels were measured under our interruptive treatment of blood supply in the pancreas, and the alteration of β-granules in Langerhans' islets was observed after the sacrifice at each hypoglycemic condition. The results obtained were as follows : a) Theobromine caused the degranulation by its direct action on β-cells of Langerhans' islets of the pancreas, resulting in its hypoglycemic activity through the release of insulin. b) Chlorpropamide lowered the blood sugar in the same mechanism as theobromine. c) Metformin, on the contrary, showed its hypoglycemic action, both mainly by extrapancreatic mechanism and partly by pancreatic mechanism, namely by the secretion of insulin.