Diabetes

677

D I A B E T E S . ~

Treatment u~ith Zi~o Prata, mine Ins~din.

By JOSEPH LEWIS.

I N the interval of time which has elapsed since the discovery of insulin the treatment of diabetes has undergone many changes.

At first we witnessed carbohydrate and insulin economy as the rational and considered line of therapy. At a later phase in the evolution of treatment the disadvantages of a low carbohydrate --high fat diet--were pointed out.

I t is now generally accepted that a diabetic diet must be moderately rich in carbohydrate and that an adequate allowance of insulin be given to meet the carbohydrate permitted.

In more recent years we have witnessed an advance in treatment along a new channel, namely, the modification of insulin to control more effectively the metabolism of carbohydrate and thereby enable the diabetic life to approach a more normal existence.

This advance has been made possible by the researches of Hagedorn and Scott. The former introduced protamine insulin, while the latter noticed the relationship of zinc to insulin and subsequently adopted a zinc protamine insulin mixture.

Insulin. Three different types of insulin are now available : - -

1. Original insulin (Banting and Best). 2. Protamine insulin (Hagedorn). 3. Zinc protamine insulin (Scott).

Original Insulin. This preparation, while possessing many advantages, does not

meet the requirements of all diabetics. In addition, it has an outstanding disadvantage. When injected into the subcutaneous tissues it is absorbed rapidly, exerts its action quickly and has expended itself within a few hours of its administration. This rapid action, while of inestimable value in the treatment of hyperglye~emie coma, fails in the majority of severe diabetics to control the blood-sugar level unless repeated. This necessity of injecting insulin twice and sometimes three times daily is a great inconvenience. In addition, eases occur when even with three injections daily it is impossible to maintain a normal blood-sugar and even to avoid aeetonurea.

These insulin-resistant eases present their own problems, and in spite of the loyal co-operation of the patient present many diff- curies in the way of treatment. This difficulty of obtaining normal

* Communication to the Section of Medicine, Royal Academy of Medicine in Ireland, October 8th, 1937.

Face page 679.

CBART I.

20 un i t s zinc p r o t a m i n e insu l in subcutaneously. Note fall in blood sugar 24 hours a f te r a single inject ion.

30 uni t s zinc p ro tamine insul in intr ,nvenously Rena l ~hreshold of 220 re.gins, per cent.

678 IRISH JOURNAL OF MEDICAL SCIENCE

fasting Mood-sugars, together with the inconvenience and discomfort of frequent injections of insulin, constitutes the greatest drawbacks to the treatment of diabetes by original insulin. After many years of research Hagedorn and his collaborators introduced protamine insulin.

Prota~inr Insulin. This is a mixture made by uniting the protamine obtained from

fishes with original insulin. When injected into the subcutaneous tissues, it is absorbed slowly

and maintains its effect for about 10-12 hours. This advance how- eve r was not as satisfactory as was first anticipated; the milder cases of diabetes benefited to some extent, but the severer cases were difficult to control on a single daily injection.

I t had the additional disadvantage in that two bottles were required, one for the buffer reagent of sodium phosphate and the other for the protamine insulin, These were mixed by the patient before use in order to bring the solution to the same hydrogen ion concentration as the blood.

Experimental studies carried out by Scott and his co-workers showed the influence of zinc on the rate of absorption of insulin.

Later it was demonstrated that the removal of zinc from protamine insulin resulted in a preparation which was rapidly absorbed and whose action was no more prolonged than that of the original insulin. On the other hand, however, the addition of minute qualities of zinc to protamine insulin and the suitable adjustment of the hydrogen in concentration resulted in a substance with an action more prolonged than any previously known.

Zinv Prata~inv Insulin. Zinc is a mineral widely distributed in nature and is found in

practically every tissue in animals. It is present in large amounts in those tissues concerned with the metabolism of carbohydrates. Scott has shown that zinc is apparently a constituent of insulin and is not bound to it as an impurity, but is united to it chemically. This, together with other considerations, led him and his co-workers to build a unit containing protamine insulin and zinc in combination in the expectation that a preparation would be evolved with an action more prolonged than that of protamine insulin alone.

This preparation proved successful in experimental animals, which success subsequently led to its clinical application in diabetes. When mixed it is a rather opalescent solution of protamine insulin with zinc in suspension. I t is of the same hydrogen ion concentration as the blood. This factor dispenses with the use of a separate buffer reagent. The quantity of zinc present is extremely minute, amounting to only 1 mgm. per 500 units of insulin. This negligible amount of zinc does not produce any local reaction when injected into the tissues. On allowing the phial to stand a sediment falls to the bottom leaving a clear supernatent watery fluid.

This sediment contains the zinc and must be shaken into solution before use. Since zinc protamine insulin is a protein mixture it

DIABETES 679

has been suggested that the phial be gently and repeatedly inverted instead of being violently agitated to ensure a uniform suspension of the zinc in the insulin.

Ac:tian on Bloo&Sugur. When injected subcutaneously, zinc protamine insulin is slowly

absorbed from the tissues. The time of onset of its action varies, as does the duration of

its action, with the amount injected and the severity of the diabetes. t n the diabetic of average severity the zinc protamine insulin first asserts its action about 8 to 9 hours after injection. I t continues to act for about a further 12 hours, i.e., it is active 21 hours after injection. The action of zinc protamine insulin may, however, start earlier. I have noticed symptoms of hypoglycmmia occur in an ambulant patient 5�89 hours after injection. The blood-sugar may show a hypoglyc~emic level 28 hours after injection. (The gradual lowering effect on the blood-sugar can be seen in Chart I, which shows a hypoglyceemic level reached 27 hours after the injection of zinc protamine insulin.)

The slow absorption and slow sustained action of this preparation on the 'blood-sugar resemble the physiological action of the pancreatic insulin and permit of a more effective control of the: blood-sugar.

The slow absorption of zinc protamine insulin has, however, one outstanding disadvantage. In a moderately severe diabetic the blood-sugar will be seen to rise after the ingestion of carbohydrate, the elevation varying with the severity of the disease, the quantity of carbohydrate consumed and the time at which the meal is ingested. Hyperglyc~emia and glycosuria are not infrequent find- ings after a rich carbohydrate meal, but the blood-sugar is effectively controlled and the urine sugar-free 24 hours after an adequate dose of zinc protamine insulin has been administered. The disadvantage of a temporary hyperglye~emia is negatived by the advantage of a single daily injection of insulin in practically every diabetic and the assurance of a normal blood-sugar level 24 hours after a single injection.

In my experience the difficulty of preventing acetonuria in some diabetics on original insulin, in spite of their willing co-operation, is overcome by the use of zinc protamine insulin. The in tr~venaus administration of zinc protamine insulin failed to produce any untoward effects on my patients. The blood-sugar level was, however, influenced and the lowering effect demonstrated. The rapidity of fall varied with the amount of zinc insulin injected. In one (Chart II) patient a fasting blood-sugar of 340 mgms. per cent. reached 164 mgms. within 7 hours. The onset of action com- menced within an hour after its intravenous injection and was maintained for 7 hours, after which it rose again without the administration of carbohydrate. Given intravenously in another ease, the blood-sugar reached the surprisingly low level of 36 mgms. per cent. without producing symptoms of hypoglyc~emia, after which


it rose spontaneously. The greatest fall appeared in the first hour following the intravenous injection, after which the fall was more gradual. In the cases in which it was used the intravenous action lasted for 7 hours.

I t would appear that the duration of its action by the intravenous route is no more prolonged than that of original insulin.

The rapid rate of onset would suggest its usefulness in the treatment of hyperglyc~emic coma if given by the intravenous route in the absence of original insulin.

Harmful Effe~t$ af Zinc. Scott and Fisher hav~ demonstrated the retarding effect which

zinc has on the action of insulin. The possibility of zinc inhibiting the action of endogenous insulin as it does injected insulin must be borne in mind.

It has been shown that the increased intake of zinc is followed by an increased elimination, primarily through the fmces, but also through the urine. Heller and Bourke noted the effects of zinc in animals. I t failed to produce any harmful effects on growth, reproduction and function when administered in their meals. In men exposed to the fumes of zinc for over 25 years there was no illness noticed ascribable to their occupation. In none of these men was glycosuria to be found. On this latter evidence it is unlikely that zinc inhibits endogenous insulin.

Glycosuria. The slow action of zinc protamine fails to control the immediate

rise in the blood-sugar and the consequent glycosuria following a rich carbohydrate meal.

I f a specimen of urine be examined about one hour after ,.he ingestion of (say) 30 ~mns. of carbohydrate in a moderately severe diabetic, glycosuria will probably be found. This should not be a disconcerting finding, and is due to the difficulty in spacing the carbohydrate in amounts small enough to prevent the escape of glucose.

While the presence of glycosuria indicates hyperglyc~emia and wastage of sugar, there is nevertheless a total clearance of urinary sugar and a normal blood-sugar established 24 hours after a single injection of zinc protamine insulin.

The temporary rise in the bloed-sugar and consequent glycosuria could be prevented by a corresponding reduction in the carbohydrate allowance, but this is unnecessary if a normal blood-sugar and urinary clearance is obtainable once in 24 hours.

This temporary giycosuria has been overcome by the addition of original insulin to the zinc protamine insulin. Laurence and Archer have found that these can be given in the same syringe without affecting the action of either. This method could be use- fully employed at the breakfast meal, the original insulin checking the immediate rise in the blood-sugar and the zinc protamine insulin acting on the carbohydrate consumed later in the day.

DIABETES 681

Some patients find it difficult to avoid mixing the insulins when extracting some from the second phial, especially if a negative pressure exists in the second bottle.

I do not now advise the use of both original and zinc protamine insulin in the same patient, as I fail to see any grave objection to a temporary blood-sugar elevation or temporary glyeosuria. There is, of course, a transitory wastage of sugar which does not appear to be of any great significance.

Rabinowitch does not employ original and zinc protamine insulin in the same patient; he suggests the use of separate syringes and separate sites of injection to prevent contamination of the zinc protamine insulin with the original insulin in view of the dependence of the effectiveness of this mixture on an accurately adjusted /~H.

I failed to observe any immediate or remote, general or local effects from th6 use of both insulins in the same syringe. Each insulin exerted its own individual action.

Diet.

The low carbohydrate diet originally utilised with the consequent employment of a minimum amount of insulin resulted in a badly balanced diet disproportionately rich in fats. This rich fat dietary was not without its ultimate dangers and became replaced by a more rational diet containing the basic essentials in the necessary. proportions. The more liberal allowance of carbohydrate is now fully, appreciated, and in view of the properties of zinc protamine insulin a return to physiological requirements can be allowed.

The actual amount of carbohydrate permitted must be left to the discretion of the physician, but it should be remembered that added carbohydrate does not necessarily require a proportionate increase in insulin ; in fact, a very small increase is not infrequently required, amounting to but a few additional units.

With zinc protamine insulin the addition of a few extra units permits of a considerable increase in carbohydrate allowance.

In the past unnecessary carbohydrate starvation was only too often seen. The emaciation resulting from a badly balanced, inadequate diet was recently observed in the case of a woman aged 53 years. She had lost 8 stone 9 lbs. in 3 years and required 3 injections of original insulin daily (15-10-10). On this dosage of insulin and on a diet containing 30 gins. of carbohydrate, 130 gins. protein and 100 gins. fat, hyperglyc~emia and acetonuria were present. She is now stabilised and sugar-free on a single daily injection of zinc protamine insulin (50 units) and a carbohydrate allowance of 180 gms. She increased her weight by 6 lbs. in 4 days, and has continued to increase steadily.

As with original insulin, the diet must be calculated for the individual's requirements and the insulin adjusted to meet the carbohydrate allowance. I t is advisable to permit not less than 100 gms. daily; much more may be allowed, but less should be avoided if possible.


I t is advisable to initiate treatment with less than 100 gzns, e.g., 6tart with 60 gins. and gradually increase the carbohydrate by 10 gms. daily. The ladder increase in diet permits of greater immediate tolerance of carbohydrate and is to be preferred to the basal method.

The carbohydrate permitted is divided into small portions and distributed throughout the day a t intervals in such amounts as would permit of little glycosuria after each meal, e.g., 100 gms. of carbohydrate would be given as follows : - -

B'fast. Lunch. Tea, 9 p.m. 11 p.m. 15 gms. 15 gms. 25 gins. 25 gms. 20 gins.

The smallest quantities of carbohydrate are given before lunch, the larger amounts in the evening, when the zinc protamine insulin manifests its greatest action.

I t is important to give the last meal before bedtime (11 p.m.) in order to obviate the possibility of hypoglyc~emic symptoms during sleep.

At the outset of treatment the urine is examined 3 hours after each meal. I f sugar is absent in any specimen the quantity of carbohydrate is increased for the previous meal.

By utilising the ladder increase in diet I have found it possible to raise the amount of carbohydrate considerably and concurrently to reduce the quantity of insulin.

Chart IV shows the increasing carbohydrate tolerance and the reduced insulin requirements.

Blood-Sugar an~ Urinary Analysis. I have not found blood-sugar tests absolutely essential, but ~ e y

are extremely helpful in determining the amount of increase in carbohydrate or the increase or reduction in insulin.

In Chart IV it is seen that the urine is sugar-free practically all the time. In spite of the increasing carbohydrate there is a progressive fall in the blood-sugar. Th6 blood-sugar level acts as an insulin control, but I believe nevertheless that standardisation of most diabetics is possible from urinary analysis alone.

I t has been stated that if the 24-hour specimen of urin~ is sugar- free it may be taken that the blood-sugar of that day was normal or nearly so. This statement would not include those cases of hyperglyc~emia without glycosuria known to occur in diabetes of old standing.

With zinc protamine insulin the absence of urinary sugar does not necessarily indicate a normal ~or nearly normal blood-sugar; indeed it may be very much below normal.

In the regulation of the diet and its control by zinc protamine insulin I am of the opinion that fasting blood-sugar estimations should be performed every few days in addition to the examination of fasting specimens of urine each morning.

In examining the morning specimen of urine it is very important to collect it accurately.

The urine should be passed about one hour before breakfast and

DIABETES 683

discarded, as this urine may contain sugar from the last meal. Immediately before breakfast a second specimen is collected and examined.

Method oS Treatment. It is highly advisable to staadardise diabetics with zinc protamine

insulin under institutional observation. I t is inadvisable to use this preparation in an ambulant patient. This was pointedly demonstrated in the case of a young man who, contrary to advice, left his home to visit a cinema. During the performance symptoms ef hypoglycmmia developed which were promptly relieved by eating a bar of chocolate. The carbohydrate allowance having been estimated and divided into amounts as suggested above, zinc protamine insulin is injected at breakfast hour. I commence with 20 units. I f the fasting blood-sugar shows a hyperglyc~emic level in the presence of glycosuria the insulin is increased by 10 units until the urine is sugar-free and the fasting blood-sugar within normal limits. If, on the other hand, the fasting urine is sugar- free and the blood-sugar hypoglyc~emic the a~nount of carbohydrate at the last meal is increased or the quantity of insulin reduced by 5 units until a faint reaction appears in the fasting urine or/and the blood-sugar reaches a normal level.

I f blood-sugar estimation is not available sufficient carbohydrate should be given at bedtime (11 p.m.) to bring about a slight reduction with Benedict's or Fehling's reagents.

i have not found it necessary to resort to more than one injection daily of zinc protamine insulin in any of my cases. Laurence and Archer in their series of patients had only one case in which two injections were found necessary.

Some difference of opinion exists as to the best time at which the insulin should be injected. Some advise at breakfast time, others recommend the evening. The evening suggestion is based on the view that hypoglyc~emia, if it occurs, will develop during the following day when the patient is awake. The danger of hypoglyc~emic coma is remote and will not arise if the patient is properly standardised and the necessary instructions as to diet and exercise are followed.

Unlike original insulin, it is unnecessary to give the injection 20 minutes before breakfast (unless combined with original insulin). I t may be injected immediately before or immediately after breakfast.

I t is advisable that weekly fasting blood-sugar tests be performed for a short period. I t has been found that the patient's sensitivity to the insulin increases for a period, as evidenced by a gradual fall in the blood-sugar. This might necessitate a reduction in the insulin or permit of an increase in the carbohydrate.

Mrs. C., an elderly diabetic, had been receiving three injections daily of original insulin. Her diet was increased to 105 gms. of carbohydrate daily. She was stabilised on 50 units of zinc protamine insulin once daily. A fasting blood-sugar of 170 mgms. per cent. fell to l~t5 mgms. per cent. ten days later, and four days later still had roached 111 mgms. per cent.


This reduction in the blood-sugar may conceivably be due to an increase in the carbohydrate tolerance rather than due to an increased sensitivity brought about by the zinc.

This feature has been observed in other cases and may lvsult in hypoglyc~emic symptoms if not checked by periodic blood-sugar tests.

H y p o g l , y c v e m ~ .

This danger from zinc protamine insulin is comparatively uncommon and should not act as a deterrent against its use.

A striking feature about this preparation of insulin is the infrequency of reactions in the presence of the blood-sugar below the hypoglyc~emic level. The absence of symptoms in spite of extremely low blood-sugar readings constitutes one of the unique features of this insulin. The time of onset ot' symptoms varies considerably.

In one case sweating and tremor occurred 5�89 hours after the injection of 20 units. In another case mild symptoms arose 9 hom~ after 20 units, while in another case sweating and tremor occurred 19 hours after a similar dose of zinc protamine insulin. The onset of symptoms of hypoglyc~emia is gTadual and sneaking. The unsuspecting patient may dismiss as " nothing " the early warn- ings. So mild are these early warning- symptoms that they are frequently ignored. Symptoms of tremor, palpitation and sweating rarely progress to more seVous symptoms, and usually disappear spontaneously. They may however, though seldom, become more serious with visual disturbances, hallucinations, complete loss of consciousness and coma. In one case symptoms were left untreated and the patient carefully observed. The blood-sugar fell to 36 mgms. per cent. without the development of any further symptoms, after which it rose spontaneously and the sweating and tremors disappeared.

The blood-sugar may reach surprisingly low levels. In a male with a blood-sugar of 36 mgms. per cent. no symptoms were com- plained of or elicited when carefully questioned. In another male patient a " peculiar smooth feeling " of his tongue was the only symptom elicited with a blood-sugar of 39 mgms. per cent.

Following a misunderstanding in management one patient became unconscious during sleep. Consciousness was regained after the intravenous administration of 30 c.cs. of normal glucose. Unfortunately a blood-sugar estimation was overlooked during the period of coma, but after the glucose injection it was found to be 65 mgms. per cent.

Such extreme symptoms are most unusual with zinc protamine insulin, indeed the mildness of symptoms induced us to attempt to produce symptoms in a few cases.

In three patients blood-sugars were examined hourly. I t was fonnd to rise spontaneously after having reached its lowest level of 36 mgms. per cent. The symptoms were mild and insignificant and disappeared without treatment.

DIABETES 685

This spontaneous rise may be due to some extent at least to the antagonistic action of epinephrin and insulin (Kerr and Best, Canad. Med. Assn. Jo., 1936, 34,400).

I t is possible that the absence of subjective symptoms in spite of th~ reduction of the blood-sugar below the hypoglyc~emic level is not t ruly reflected by the blood-sugar, i,e., the concentration of sugar in the blood does not reflect the concentration of this sugar in the tissues elsewhere. (Rabinowitch, Ca.nad. Meal. Ja., Feb., 1937.)

When the diet and insulin allowance have been regulated symptoms, however mild, should not arise in an intelligent co-operating patient unless the late meal be omitted or violent exercise be indulged in without due allowance.

The presence of a bare trace of sugar in the fasting urine is the best guarantee against hypoglyc~emia. Symptoms, should they arise, are relieved by taking glucose, sugar or chocolate, but a further supply might be necessary to avoid an early recurrence of symptoms.

I have not noticed such symptoms as convulsions or loss of consciousness in any of the cases on whom attempts were made to produce hypoglyc~emia by the injection of zinc protamine insulin. In these cases the maximum dose used was 40 units on a low carbohydrate diet, and the only symptoms observed were palpitation, sweating and tremors. In my series of cases I have found it necessary on two occasions only to exceed 40 units. The usual doses employed varied between 10 and 30 units. On this dosage and adequate carbohydrate hypoglyc~emic symptoms should rarely arise.

Replacement of Origina~ by Zinc Protaznine Insulin. I t would appear that the change over from original to zinc

protamine insulin varies with the age and severity of the disease. In the elderly mild diabetics the replacement is accompanied by little disturbance in the carbohydrate metabolism. These mild cases become sugar-free within a few days of the change over. In young diabetics (usually severe cases) this change over is frequently accompanied by a temporary acute metabolic upset. This may persist for 4 to 10 days or more, during which period the urine contains large quantities of sugar. In such cases it is advisable to maintain the carbohydrate at a low level of about 80 gins daily. In addition soluble insulin should be given in small amounts before the 6 p.m. meal in about 10-unit doses until the blood-sugar and fasting urine are normal. In mild diabetics it is rarely necessary to inject the evening insulin. Curtailment of carbohydrate for a few days is usually sufficient.

Case Reports. CASE I. Hyperglycemia coma, with gangrene o! toes and arteritis.

Mrs. L., a diabetic of old-standing, aged 64 years, two years previously developed gangrene of her toes which necessitated amputation. She was indifferent about her diet and insulin at home, and was admitted to hospital comatose. Urine contained both sugar and acetone. Her past diabetic history showed high fasting blood-sugar of 350 and 380 mgms.


per cent . on di f ferent occasions. Old records of th i s case showed her d i e t ~o be composed of 30 gins. of ca rbohydra t e dai ly and 10 un i t s of o r ig ina l in su l in twice daily.

H e r a r te r ies were h a r d and to r tuous , and he r genera l condi t ion e x t r e m e l y low. H e r c h a r t shows the progress of he r case on zinc p r o t a m i n e insul in.

Or ig ina l insul in was .given in t he following a m o u n t s : 100-60-60-20, a f t e r which consciousness was rega ined .

Date

]2.7. '37 14.7.'37 17.7.'37 29.7.'37 11.7.'37 23.7/37

Carb. in gins.

67 87

107 127 127

Calories

1,074 1,598 1,678 1,758 1,758

C ~ r r IV.

Sugar

X X X X

Fast ing Acetone blood

sugar in m. gms.

X X 380 --- 63 - - 90 --- 142

- - 142 - - 1 3 0

Z.P~ Insul in

30

3 0

3 0

3 0

This c h a r t shows the g r e a t to lerance exhib i ted to c a rbohyd ra t e on zinc p r o t a m i n e insul in. P rev ious blood-sugar cha r t s i nd i ca t e th i s p a t i e n t to be " i n su l i n - r e s i s t an t . " The ca r bohyd r a t e was suppl ied in the fo rm of glucose dr inks . Genera l i m p r o v e m e n t occurred, and the p a t i e n t expressed herself as feel ing b e t t e r t h a n ever before. .She u n f o r t u n a t e l y died unexpectedly and suddenly f rom a h e a r t a t t ack .

C A S E I I . Diabetes and thyrotoxicosis . Mrs. C., aged 53 years , suffered f rom diabetes for four years. She h a d

been on a badly ba lanced d ie t r i ch in fa t s and poor in ca rbohydra te . She was emacia ted, weak, ne rvous and very deb i l i t a t ed w i thou t any energy. She was receiving 15-10-10 un i t s of o r ig ina l in su l in daily. H e r thy ro id g l and showed two large n o d u l a r swellings. H e r h e a r t was r egu la r a t 94 pe r minu te . She weighed 8 s tone 5 lbs. when a d m i t t e d to a n u r s i n g home.

She was .given Lugol ' s solut ion (m. x ) a n d zinc p r o t a m i n e insul in , as seen in t he accompanying cha r t . Before removal of the a d e n o m a t a she was sugar- f ree on 50 un i t s of zinc p r o t a m i n e insul in . A t t he t ime of r e p o r t i n g he r f a s t i ng blood-sugar is 170 mgms. p e r cent . , he r carbo- h y d r a t e i n t ake is 180 gins. da i ly and her insu l in r equ i r emen t s 20 u n i t s once daily.

0 ~ V.)

Date

24.6. '37

26.6. '37 28.6.'37

7.7.'37 10.7.'37 19.7.'37 27.7.'37 28.7.'37

4.8.'37 ]2 .8 /37 17.9.'37

Carb. in gins.

101 lOl lOl

Removal 101 101 120 120 180 180

Sugar

X X X X

X X X X X

of adenom

A c e t o n e

X X

X

under ga

Blood Sugar Z.P.

m. gins.% Insul in

360 re.gins.%

- - 30 - - 30 170 len 50

s and oxyg and eye 125 50 l l l 50 - - 30 - - 2 0

- - 2 0

- - 2 0

Weight

8st 5 lbs.

8st l l l b s . 8st. 13lb.

lopropane.

9st. 61bs 9,qt. l l lb.

10st. llb. l l s t . 2lb.

The influence of t he toxic goi t re is following i ts removal and t he reduced improbab le t h a t the reduced insu l in is t o l e r ance alone.

seen by the fall in the blood-sugar insu l in requ i rements . I t is h ighly due to an mcrease in c a r b o h y d r a t e

DIABETES 687

This p a t i e n t is now res tored to robus t hea l th on a very l ibera l and var ied ca rbohydra t e die t , and requires one dai ly in jec t ion of 20 un i t s of zinc p r o t a m i n e insulin.

CAsH I I I . Mr. J . F . , aged 30 years , had been unde r t r e a t m e n t for d iabetes for four years. He was first seen in a pre-comatose s t a t e and emacia ted . W i t h soluble insul in he r ega ined consciousness. He had been advised previously as to diet and requ i red 20 and 15 un i t s of. o r ig ina l insul in daily. Die te t ic indiscre t ions led to his downfall .

Blood-sugar f indings showed h im to be an " insu l in was t e r . " H e was placed on a ladder d ie t , commencing wi th 60 gms. of ca rbohydra t e and one in jec t ion of 20 un i t s of zinc p r o t a m i n e insu l in daily. I / i s c a rbohydra t e was g radua l ly increased un t i l 105 gins. was reached. On one occasion symptoms of hypoglycmmia occurred in the ear ly morn ing , when his blood-sugar was found to be 36 mgms. pe r cent. This necess i ta ted a f u r t h e r ca rbohydra t e increase. He is now balanced on 120 gms. of carbo- hydra tes and a daily in jec t ion of 20 un i t s of zinc p r o t a m i n e insul in.

His weight has increased ~by ] s tone 6 lbs., and his energy and v i t a l i ty h-~ve been fully restored. He indulges in s t renuous swimming wi thou t ill-effects.

C~ss 1V. A r t e r i o - s c l e r o s i s a n d d i a b e t e s .

A n ehler ly woman, aged 67 years, was re fe r red to me suffer ing f rom diabetes and severe p r u r u t u s vulvm. She had lost energy and a l i t t l e weight. On admiss ion to hosp i ta l she weighed 10 s tone 12 lbs. The following c h a r t shows the progress of he r case.

Date

23.7.'37

27.7.'37 31.7.'37

3.8.'37 6.8.'37 7.8.'37 8.8. '37

10.8.'37

Carb.

50

70 90

100 120 120 120 120

Sugar

CHART VI.'

Acetone Fast ing Blood

Sugar in m.gms.%

166

14;I

149 134 131 137 149

Z.P. Insu l in

20

30 30

30 30 20 15 10

Remarks

Prur i t i s vulvae

No pruritis.

Note t he progressive increase in ca rbohydra t e i n t a k e and g r a d u a l r educ t ion of zinc p r o t a m i n e insul in. W e i g h t increased by 2�89 lbs. in n ine days.

The above cases are a few from the series showing t he inc reas ing carbo- hyd ra t e i n t a k e and " t a i l i ng off " of the insu l in requ i rements .

Results of Treatment. In no instance was it found necessary to give more than one

injection daily. On a stabilised diet and adequate insulin glycosuria could be avoided and a normal fasting blood-sugar restored. The presence of sugar in the urine during the day is of no great significanc~, and is frequently found after a rich carbohydrate meal.

The carbohydrate allowance could be greatly increased at the expense of a few additional units of zinc protamine insulin to a greater extent than with original insulin.

Weight and energy increased in most of the patients, and both old and new cases felt constitutionally improved.

688 I R I S H J O U R N A L OF M E D I C A L S C I E N C E

I f vigorous exercise is to be indulged in it is advisable to eat some sugar or chocolate dur ing or immediately before the game, so as to avoid symptoms of hypoglyca~mia.

In my cases symptoms f rom hypoglyc~emia in spite of extremely low blood-sugar readings did not appear a la rming; on the contrary, the mildness of symptoms was surprising in the presence of such hypoglycmmic blood levels. These symptoms should not occur in a proper ly balanced patient. Trea tment should be carried out in an institution under supervision. I t was noticed that the carbo- hydra te tolerance increased in many cases and it is not surpris ing to find a hypoglyc~emic blood-sugar a short time a f te r a normal las t ing blood-sugar has been reported.

" Insulin-resistant " cases responded extremely well to a single daily injection of zinc protamine insulin.

The effective lowering of the blood-sugar from intravenous injection would suggest its use in hyperglycmmic coma. I failed to observe any ill effects f rom its administrat ion by this i~)ute.

The diabetic of average severity if proper ly stabilised shouht, with the aid of zinc protamine insulin be able to live a more or less normal life free f rom gross dietetic restrictions. There are few articles of diet which he cannot use in moderation. He should be educated to unders tand his disease, to know his carbohydrate l imitations and to be conversant with the variat ions in diet permit ted to him.

ICe]erences. ~.. Rabinowitch, I. M. : Canad. Med. Ass. Jo., Feb., 1937. 2. Scott and Fisher: Biochem. Jo., 1935, 29, 1048. 3. Kerr, Best et. al. : Canad. Med. Ass. Jo., 1936, 34, 400. 4. Rabinowitch, I. M. : Canad. Med. Ass. Jo. (1936b), 35, 239. 5. Laurence and Arch: Brit. Med. Jo., Mar. 6, 1937. 6. ]=Ieller and Bourke: Jo. Biol. Chem., 1927, 74, 85.

Diabetes

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