Experimental Studies on Production and Progress of Diabetes Mellitus by Zinc Reagents

Abstract

1. Acting upon the idea on occurrence of diabetes published previously by Okamoto, we conducted our studies with 87 sorts of chemicals selected mainly from zinc-affine reagents and also from substances similar to these in structural formulae and closely related chemically to these and have arrived at the following results:(1) We have discovered 17 new substances effective in producing diabetes in rabbits, namely, 8-hydroxyquinaldine, 2, 4-dimethyl-8-hydroxyquinoline, 13 substances with phenylazo bases (phenylazo, tolylazo, hydroxyphenylazo, dimethylaminophenylazo, acetaminophenylazo and aminophenylazo bases) in the position 5 of oxine and 8-hydroxyquinaldine, diphenylthiocarbazide (which, however, apparently changed into dithizone while preparing the injection solution) and nicotine. Except nicotine, all these compounds being insoluble in water, were used dissolved in alkaline solvents or hydrochloric acid under room temperature or by applying heat.(2) The minimum dosis required for inducing diabetes has been estimated to range from 5mg./kg. in the smallest to 45mg./kg. in the highest for quinoline compounds, from several mg./kg. to 10mg./kg. for nicotine and for diphenylthiocarbazide 10-20cc./kg. of saturated solution in saturated aqueous solution of lithium carbonate.(3) These substances injured the β-cells of Langerhans islets and induced permanent diabetes by one single intravenous injections except nicotine which gradually cause severe lesions to β-cells upon 3 or 4 administrations at 5-15 days' intervals in doses of several mg./kg. and finally induces diabetes. In the cases of severe diabetization, the β-cells of the Langerhans islets were reduced to below 12 (below 1/3 of the normal), and in most cases to below 8 (below 1/5 of the normal) in number per islet.(4) At the earliest stage of administration of a reagent, excepting nicotine, a marked fluctuation was seen in blood sugar content. There are 3 major types of this fluctuation.(a) In the majority of cases, the blood sugar content temporarily rose at first (about 3, 6 or 21 hours after administration), then dropped widely (about 3-10, 6-12 or 12-24 hours after administration), rose to permanent high glycemia thereafter and passed over into diabetes. Most of the reagents cause such a type of fluctuation of blood sugar content.(b) Some reagents do not cause the temporary heightening of blood sugar content, but a strong fall of it in 1-4 hours after the administration and then the permanent high glycemia soon sets in. Diabetes is induced in a short time in these cases. 5-(p-hydroxyphenylazo)-8-hydroxyquinoline, 5-(p-dimethylaminophenylazo)-8-hydroxyquinoline and 5-(p-acetaminophenylazo)-8-hydroxyquinoline belong to this type of reagents.(c) The three phases of fluctuation is indeed complete following administration of a few other reagents, but the stage of low blood sugar content is not so distinct here.When the drop of blood sugar content was marked, the following diabetes was also severe. The rise and fall of blood sugar content runs abreast with the lesion of β-cells, the time of abnormal drop of blood sugar content just coinciding with the time of widest necrosis of β-cells. This seems to prove that this drop of blood sugar content is attributable to a sudden release of insulin.(5) 5-methyl-8-hydroxyquinoline, 8-hydroxy-2-(a-methyl) quinoline-methanole, 4-methylthiouracil, diphenylcarbazide, sodium diethyldithiocarbamate and guanidine carbonate are toxic against the β-cells but the toxicity does not reach threshold of diabetization. That is, the reduction of the number of β-cells due to the injury is limited to the extent of dropping to 2/3-1/3 of the normal count and this is not sufficient to cause diabetes.