AJl the experiments of the following series were done on rabbits. THE secretion of glucose is considered to depend on a " threshold " value

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1 THE INFLUENCE OF DIURETICS ON THE EXCRETION OF SUGAR. BYE. J. CONWAY. (From the Physiological Department, University College, Dublin.) THE secretion of glucose is considered to depend on a " threshold " value for the blood sugar beyond which it appears in quantity in the urine. Various interpretations are given as to the manner in which the threshold value operates, according to the view entertained of kidney secretion. The following eperiments were primarily undertaken to -consider the effect on the sugar ecretion in a glycosuria of an increased metabolism in the kidney cells, such as takes place on the injection of sodium sulphate (1) isosmotic with the blood as contrasted with the effect produced by the injection of equal quantities of normal saline-a question which does not seem to have been adequately investigated. Loewi (2) had found that in pancreatic diabetes and also in glycosuria in the rabbit from sugar administered by the alimentary canal that diuresis caused an increase, but in phloridzin diabetes, no increase in the total quantity of sugar ecreted. Loewi used sodium chloride as a diuretic. Weber(3) using theophylline in phloridzin diabetes found that there was an increase of sugar ecreted in diuresis. In the eperiments of Loewi and Weber the blood sugar was not estimated. Cushny (4) states that if sugar is present in the urine from hyperglycaemia, diuresis reduces the percentage and raises the total amount escaping. Recently H. Elias and St Weiss(5) have stated that intravenous injection of sodium phosphate usually lowers the sugar content of the blood in diabetic and alimentary hyperglyseamia while the sugar content of normal blood is unaltered; the effect is accompanied by a decreased ecretion of sugar in the urine and is stated to be due to the phosphate ion. K. Mori (6) has shown that calcium chloride arrests the ecretion of sugar in the urine which has been caused by the injection of sodium chloride or sugar but not in phloridzin or adrenalin glycosuria. AJl the eperiments of the following series were done on rabbits. Urethane was used as anaesthetic in doses of 1-5 gram per kilo. Before collection of the urine (from one ureter only), usually about 30 c.c. of 5 p.c. glucose solution were injected through a jugular cannula. Seven minutes were taken at first for the injection-later reduced to about

2 SUGAR IN URINE. two minutes. Although a glycosuria is almost invariably present from the start of the eperiment the injection had the advantage of securing a suitable flow of urine and keeping the blood sugar content steadier than would otherwise be the case. The urine was collected in small weighed glass tubes. An average of about 1 c.c. of urine was collected in these tubes, the time of collection being noted. The quantities of urine were determined by weighing. When a number of tubes had been collected 30 c.c. of physiological saline or of an isotonic sulphate, phosphate or other solution, were injected through the jugular cannula. The time of injection was 24 mins., generally 2 mins. Two minutes the injection the urine was again collected in a similar fashion. During the collection of the urine blood was taken for analysis, about 1 c.c. at a time. The blood was allowed to clot, and analysis of the sera and urines were done on the following day. The Maclean method (7) was used in the analysis of the blood and urine. Occasionally, owing to the small quantities of urine dealt with, only a few milligrams of glucose were present for analysis and a micro-method was essential. Three different eperiments were performed to see if there were an appreciable glycolysis in the serum 24 hours. Two samples of blood of about 4 c.c. each were taken at the same time an intravenous injection of 30 c.c. 5 p.c. glucose. To one sample was added some oalate and two drops of formalin (8). It was then centrifuged. The other was allowed to clot without the addition of any substance, at room temperature. After 24 hours estimations were made of the glucose in the plasma and serum. No appreciable glycolysis was found to take place in the serum. P.c. glucose in plasma (formalin and oalate) P.c. glucose in serum I. *86 *84 JI. *71 *73 III. *66 * In the course of the eperiments the influence of the following intravenous injections was eamined-normal saline, sodium sulphate, sodium phosphate (ph = 7.4), sodium iodide, urea (in normal saline), and sodium bicarbonate in isosmotic solutions. In addition, a few eperiments were done with stronger sodium chloride solution (1.7 p.c.). Occasionally a second injection of the same solution was given. The following table gives by way of illustration the relative alterations produced by sodium sulphate, normal saline, and by urea in the rate of urine flow, the urinary and the blood sugar. The relative alterations were based on the values immediately before and the injections.

3 236 Rates of urine before Second injections 2-2 Second l injections Second injections I E. J. CONWAY. SodiUm 8ulphate. Glucose Total concs. in ecretion of urine glucose befor( 3 before Normal 8aiine Urea (in normal 8aline) Glucose concs. of serum before Actual Actual p.c. rates of concs. of urine before glucose in injection in urine before c.c. per min. injection The contrast between the effect of the normal saline and isosmotic sulphate is marked. Fig. 1 illustrates the third sulphate eperiment. There is in all the sulphate eperiments (ecept the two second injections) a large fall in the concentration of the glucose in the urine, and generally a pronounced fall in the total output of glucose. On the other hand in the normal saline eperiments-with comparable rates of flow-there is only a slight change in the concentration of glucose in the urine, and the total output of glucose rises in proportion to the diuresis. In the case of the two second injections with sulphate the urinary glucose had not returned to the initial value when the injection was given. Phosphate (6 eps.), urea (4 eps.), strong sodium chloride (6 eps.) behaved similar to sulphate first injections. Of 15 injections of sodium iodide all but three behaved like sulphate and among four bicarbonate eperiments all but one. If the relative alterations of urinary sugar concentration be graphed against the relative alterations in the rate of flow the results appear to fall into three groups (Fig. 2). The upper group contains the eperiments of the normal saline type, while the others are divided between the other two groups. The lower two groups, as seen from Fig. 3, seem to fit in

4 SUGAR IN URINE ~I ~~~~~~ 10~~~~~~~~~~~~~~ LO JO0 IZO,4o 4N~~~~~~~~~~~~~~~~~~~~~~~~~4 Dotted line, rate of flow of urine. VI j d' -q * X AVZ~r Of M 01 Ulr(~M (7da&t1 dhwya4.$ t 6 jxx I X a *a' XZ~~~~~ XX 2.3 X I X > A~~,X. 3 Xs X 4~~~~&tc cf Lat ci wvn rv &''6~ J X 3 ''+ 4 -t * Fig. 2. The observations enclosed in circles are from normal saline injections.

5 238 E. J. CONWAY. with an empirical formula C VR = K and 2K, where C is the relative alteration in sugar concentration and R the relative diuresis. 44 X; q X Xl 8 X. q tx *KXI~~~~~X Is X - X, XX 8s '4, XX X WA-0L 7a& Of4 a 6 Va *4 Fig. 3. For the same relative diuresis there is a much greater fall in the glucose concentration in the urine with substances of the sulphate class than with the chloride class. In regard to the total output of glucose there is in general a fall in the output of glucose in the sulphate group when the diuresis is not marked. If the rate of urine flow remains unchanged by the injection (cf. Fig. 3) the output would in the sulphate group fall to one-third or two-thirds of previous value. The fact that the marked glucose reduction is caused by so many substances seems to rule out a purely membrane effect(9), for it is difficult to see how urea could influence such permeability. If we consider the urinary glucose to come out through the glomerulus the absorption of an optimal fluid of constant composition will afford no eplanation of the reduction in output. The blood sugar is influenced but slightly either as a small increase or small depression (there is often a continuous slow rise in blood sugar subsequent to the injection), but the reduction in glucose in the urine occurs independently of these small variations which are similar in the chloride and sulphate group.

6 SUGAR IN URINE. Physiological saline, which does not cause any pronounced alteration in the concentration of glucose in the urine, was the only fluid in the series eamined at all comparable in composition to blood plasma. It seems legitimate therefore to assume that the alterations in the urinary sugar caused by other injections are due to a removal of sugar that would otherwise be ecreted. The glucose concentration as a rule returns to its initial value about half an hour the injection; before, consequently, the injected material has been completely removed. The reduction in sugar may be due to some initial utilisation of glucose in the ecretion of the foreign substance. That the results obtained with these substances fall into two groups, one indicating twice the activity of the other, might conceivably be due to independent activity of the proimal and distal portions of the convoluted tubules. SUMMARY. Eperiments on the influence of diuretics on the secretion of glucose by rabbits under anaesthesia show that: 1. Physiological saline has but little influence on the sugar concentration in the urine. 2. Sodium sulphate, phosphate, bicarbonate, iodide and urea, injected in solutions isosmotic with blood and in the same quantity (30 c.c.) as the physiological saline caused a marked fall in the glucose conc'entration in the urine and generally a fall in total output of glucose. Occasionally an iodide or bicarbonate injection behaved like the normal saline. Strong sodium chloride solutions behaved like sulphate, etc. 3. This fall of concentration in glucose increases according to the degree of diuresis, and its relation to the change in flow of urine follows a simple empirical law. REFERENCES. (1) Barcroft and Straub. This Journ. 41. p (2) Loewi. Arch. f. ep. Path. u. Pharm. 48. p (3) Weber. Ibid. 54. p (4) Cushny. Secretion of urine, p (5) Elias u. Weiss. Wien. Arch. inn. Med. p (6) Mori. Kyoto Med. Soc. p (7) Maclean. Modem Methods in Diagnosis of Diabetes, etc. p. 59. (8) Anrep and Cannan. This Journ. 56. p (9) Hamburger. Biochem. Zeitsch p PH. LVIII. 16