The treatment of diabetes mellitus with a single daily dose of protamine zinc insulin

T H E IRISH J O U R N A L MEDICAL SCIENCE

THE OFFICIAL JOURNAL OF THE ROYAL ACADEMY OF MEDICINE IN .IRELAND

OF

8 I x ~ 8 ~ m s . No. 151. JULY, 1938.

THE TREATMENT OF DIABETES MELLITUS WITH A SINGLE DALLY DOSE OF PROTA-

MINE ZINC INSULIN.

By HENRY MOORE and M. A. MoR~TY. (From thee M~fer Mise~icord{ce Hospitul, D~bli~.)

S INCE the recent introduction of protamine zinc insulin for the treatment of diabetes mellitus a number of articles (i. 3, s, 6, 5,) have appeared explaining its genesis and its

employment; consequently, this communication will be confined to a narration of personal experience in i t s clinical use. We were unable to obtain this product through the usual commercial channels in this country until April, 1937, as its importation was apparently prohibited; it was possible for us, however, to start using it in Febraary, 1937, owing to the fact that Professor Elliott P. Joslin of Boston most kindly presented one of us (H. M.) with 24,000 units of protamine zinc insulin (prepared by Eli Lilly and Co.) for use with free hospital patients; we desire to record our grateful thanks to Professor Joslin. After the first supply was exhausted we used the preparations available on the British market with equally good results.

Protamine zinc insulin is more slowly absorbed from the tissues than solu~ble insulin and causes little lowering of the blood sugar for three to six hours after the injection of a single dose. I t exerts its hypoglycmmic action over a longer period of time than solubl~ insulin i therefore it possesses the advantage over soluble insulin that, with adequate dosage, less frequent injections of it a r e u s u a l l y necessary in Order to keep the blood sugar within reasonably normal limits for the whole 24 hours. In many cases, indeed, one injection of protamine zinc insulin may be found sufficient, whereas two Or three of ordinary soluble insulin may be found necessary for the same purpose ; naturally, the diminution in the number of injections is highly appreciated by the patient. With a single moderate dose of protamine zinc insulin, say about 20 to 30 units, there is a slow, steady absorption of insulin over a period of about 18 t o 26 hours, compared with the much more rapid absorption of soluble insulin; this slow absorption more nearly imitates the gradual mobilisation of l insulin in the non- diabetic organism from the islands of Langerhans, and, therefore, it facilitates in a more natural and efficient way the control of

294 IRISH JOURNAL OF MEDICAL SCIENCE

hyperglyesemia when the dosage is adequate. However, as protamine zinc insulin must be deposited in the subcutaneous tissues by a hypodermic syringe, it is obviously not possible to secure from this store the increased insulin mobilisation, with its delicate regulation, that comes from the normal pancreas in response to the rising blood sugar whicE ordinarily follows a meal rich in carbohydrate; yet the slow, continuous absorption of insulin which has been set free from the store at the injection site approaches the ideal more closely than the more rapid absorption that occurs for a ~shorter period when soluble insulin is used. One of the main advantages of protamine zinc insulin depends upon the relative slowness with which insulin is set free from the store of this compound deposited in the subcutaneous tissues. Our experience seems to indicate that, if the islands of Langerhans can still respond in a certain degree to the stimulus of a rising blood-sugar following the ingestion of carbohydrate, a single adequate dose of protamine zinc insulin may suffice in many cases of diabetes to keep the blood-sugar within the normal range for as long as 24 hours without hypoglyc~emic reactions, i f there is adequate dietetic regulation.

Since insulin was introduced in 1922, the senior writer (H. lV[.) has treated with soluble insulin 510 patients suffering from diabetes mellitus. Of these, 19 patients were admitted 27 times in coma, and there were seven deaths in the hospital from coma--a coma mortality of 1.37 per cent. amongst 510 diabetics, and a coma mortality of 25.9 per cent. in 27 attacks of coma. Of the seven deaths from coma, two were admitted moribund and died within 3 hours, two were admitted with gangrene of one or both feet and one with Graves' disease; one died on his second admission with coma, and one died 6 hours after the first admission. We have not had a single case of coma in the last 4 years.

In our method of treatment of uncomplicated diabetes meIlitus with soluble insulin we have used for the last 8 years a moderately high carbohydrate diet, that is about 150 to 180 grms. of carbohydrate (average about 170 grins.) for adults, and as a rule about 80 to 100 grms. of fat and about 90 grins, of protein; recently we have ,been inclined to be a little less liberal with fat. Shortly after insulin became available we were enabled thereby, in 1923, to increase our previously low daily carbohydrate ration to about 70 to 90 grins, for adults; in 1927 we further advanced it to about 110 grms. and since then we gradually increased it until in 1928 it reached about 140 grins, and in 1930 it rose to about 170 grins. We have not for many years used starvation, or so-called " diabetic," low-carbohydrate-content bread. Up to the time when we began to use protamine zinc insulin we were accustomed to put the patient with uncomplicated diabetes on a moderately liberal initial diet and we usually got the fasting blood-sugar down to a practically normal figure with soluble insulin within a few days (3 to 8) after admission; when this was accomplished the diet and insulin requirements were adjusted to the patient's needs over a

THE TREATMENT OF DIABETES 295

period of some weeks in the usual way; with very mild cases it was sometimes eventually possible to omit insulin, at least for a time. With this system we generally were able to discharge the average uncomplicated ease with a normal fasting blood-sugar in about 3 to 4 weeks after admission. This method saves time, trouble and expense and it is very satisfactory to physician and patient. Appropriate measures are, of course, taken for ketosis (low fat intake, etc.) and all patients are instructed tO report for blood-sugar tests, and readjustment if necessary, every 3 to 6 months, or oftener if advisable. The total caloric intake must eventually be sufficient for the work done by the individual patient, bug we aim at keeping the body weight about 5 to 10 pounds below the standard weight for the height, age and sex.

Up to a few months ago we have never started new patients with protamine zinc insulin on admission, as we believed that a normal fasting blood-sugar would be more quickly attained at first with soluble insulin according to the plan outlined above and with which we were familiar: When the blood-sugar has been brought to normal with soluble insulin (this usually, except in severe cases, takes 3 to 8 days--average about 6), we now, generally, change to protamine zinc insulin. This change does not involve any complicated rules if it is made a day or ~wo before the fasting blood-sugar is due to become normal; for example, if the patient's fasting venous blood-sugar has been brought down on a given day to say 138 rags. per 100 c.c. on 20 units of soluble insulin before the first and last chief meals, one may give the last 20 units of soluble insulin before the evening meal as usual; the next morning one may give about 30 to 34 units of protamine zinc insulin about an hour before breakfast as the full dose for the next 24 hours. Naturally, the dosage of protamine zinc insulin in ~the early stages must be worked out in relation to the diet by trial and error over several days by blood-sugar and glycosuria tests; for the first few days, at any rate, it is well to make the single dose ~bout 20 per cent. less than the total daily dose of soluble insulin previously required to bring the fasting blood-sugar to approximately normal under the conditions specified; this is because of the " cumulative" effect over several days of protamine zinc insulin. Recently we have s tar ted treatment at once with protamine zinc insulin in several eases with quite as rapid and satisfactory results, and this is our usual procedure at present.

The best time for giving a single daily dose of protamine zinc insulin can only be decided after a certain amount of experience with each patient; as our familiarity with this product grows, we feel that in the majority of cases the most suitable time for the single injection of protamine zinc insulin is about one hour before breakfast. In a minority of our patients, however, in whom a single morning dose allowed hyperglyc~emia towards evening, a single bedtime dose often abolished this evening hyperglyc~emia and gave more consistently normal blood-sugar levels (two cases of Series I and four of Series II) ; these cases apparently absorb insulin


rather slowly from the protamine zinc combination deposited in the subcutaneous tissue.

I t would seem that giving the single dose at bedtime might in some cases lead to hypoglycemia in t he early hours of the morning, whereas the morning injection plus the small " carry over " from the preceding day's morning dose frequently ensures an adequate supply of insulin during most of the hours of food absorption when insulin is most required. The decision as to time of injection, however, is largely a matter of trial and error. Sometimes those getting the single morning dose show transient hyperglyc~emia about 6 p.m. ; with adequate insulin dosage and proper spacing and division of the carbohydrate rations this can usually be prevented, but, if it does occur, the blood-sugar generally drops to normal in the early hours of the morning owing to the influence of the night fast, during which some insulin is being absorbed from the injection site. We have, in the early part of this study, for a time given a few patients soluble insulin in addition to, but separately from, protamine zinc insulin, but we have been able to stabilize the majority of our patients on one injection of protamine zinc insulin per day.

On theoretical grounds we have, for the purposes of the present study, been opposed to mixing soluble insulin with protamine ' zinc in the same syringe and injecting the mixture; the p i t of ordinary soluble insulin solution is between 3 and 4, whereas that of protamine zinc insulin suspension is about 7, and the slow absorption of insulin from the latter suspension is largely dependent on the pH being as high as 7. When bott~ types of insulin are mixed, the pH of the mixture is changed and some of the protamine zinc insulin is converted into soluble insulin; it is, therefore, difficult to predict the rate of absorption after mixing, and confusion in the clinical effects may occur. Practically, however, it is probable that certain cases of diabetes may respond satisfactorily to one injection of a mixture of the two types of insulin, esPecially when the response to protamine zinc insulin is too slow and when it is desirable to avoid multiple doses of soluble insulin, but we are not concerned with this aspect of the question in the present communication; we have, however, treated satisfactorily in this manner some patients with whom the single dose of protamine zinc insulin gave unsatis- factory results.

Protamine zinc insulin is cumulative, and its full effect may not be evident for three, four or five days. Therefore, the dosage should not be changed too abruptly unless hypoglyc~emic reactions occur; otherwise four or five days ought to be allowed for observation before final judgment is made as to the resulting effect of the single daily dose on the blood-sugar level or glycosuria.

In this study the cases were as far as possible consecutive and unselected. Since February, 1937, all cases of diabetes presenting themselves to the Senior writer were invited to enter the hospital for treatment with protamine zinc insulin and almost all consented and entered the wards or the private hospital; all the cases of


Series I had been taking at least two injections of soluble insulin per day for a considerable time previously. Taking all the cases together they represent a series of average diabetic intensity and only a very small proportion could be classified as mild cases of diabetes. The age incidence in our seventy patients is as follows : - -

D e c a d e . . . . . . . . . . . . i 2 3 4 5 6 7 8 T o t a l

N o . S e r i e s I . . . . . . . . . i 2 5 6 3 6 i i i 35

N o . S e r i e s I I . . . . . . . . . o 2 6 4 3 4 I 5 I 35

T h e y o u n g e s t p a t i e n t w a s a l m o s t n i n e a n d a h a l f y e a r s of a g e , a n d t h e o l d e s t w a s a l m o s t s e v e n t y - s i x y e a r s .

One of our main objects was to discover in what proportion of diabetics we could keep the blood-sugar levels within reasonably normal limits throughout the day with a single dose of protamine zinc insulin; it seems important to obtain this information, because one of the advantages of protamine zinc insulin as compared with soluble insulin is that fewer daily doses of the former are frequently adequate. How successful we have been in obtaining this information can be judged from Tables I, I I and IV. The blood-sugars were determined in venous blood using the Folin-Wu method; the blood was withdrawn in as many Cases as possible at approximately (1) just before breakfast (about 8 a.m.), (2) 2 hours after breakfast (about 10 a.m.), (3) just before the mid-day meal (about 1 p.m.), and (4) at 6 p.m. Sometimes additional tests were done to determine the blood-sugar levels in relation to hypeglyc~emic reactions.

In the early stages of the work the patients were on our usual diabetic diets, averaging for adults from 160 to 170 grams in carbohydrate content per twenty-four hours. After some exper i - ence with protamine zinc insulin, however, we found that, in order to avoid hypoglyc~emic reactions i t became advisable to give five meals instead of the usual three or four, and we soon increased the average total daily carbohydrate allowance for adults to about 190 or 200 grams. These five meals ar~ given in the hospital as a rule at 8 to 8.30 a.m., 11 a.m., 1.30 p.m., 6 p.m., and 10.30 to 11 p.m. When the meals are thus spaced and the carbohydrate suitably divided between the individual meals, the results with the single dose of protamine zinc insulin are frequently very gratifying; the time and size of the dose of protamine zinc insulin and the spacing and size of the individual carbohydrate rations are based upon the results shown by the four spaced blood-sugar tests described ~'bove. The last meal should be near bedtime in order to avoid nocturnal hypoglyc~emic reactions owing to prolonged action of the morning dose of protamine zinc insulin or to the night fast in conjunction with the bedtime dose. In the average adult


case we usually distribute the carbohydrate approximately as follows, with slight variations to suit the individual patient : - -

eoo grams of carbohydrate ...

8to:3o/iiA 1 i . 3 o P.M.

42

I I0.3o to 6 P.M. I I P.M.

4~ I 36 As a routine we test for sugar a specimen of urine passed before

each of the three chief meals and at bedtime (Benedict's quanta- tire test). Although important information is usually thus obtained, we do not feel that we could entirely rely on glycosuria tests alone in forming a judgment on the efficiency of control of diabetes mellitus by the single dose of protamine zinc insulin, as we wished to do in this s tudy; on several occasions we have noted dis- r results in sugar tests of blood and urine; when both specimens were almost simultaneously obtained the blood-sugar was not infrequently below normal when glycosuria was present, and occasionally glycosuria was absent when the blood-sugar was about 170 or 180 rag. per 100 c.c. Usually, however, there was reason- able agreement. Nevertheless, this discrepancy is too frequent to permit, in critical work, of complete reliance on qualitative glycosuria tests alone unless occasionally checked by blood-sugar determinations; it is probably in part dependent upon instability of the " renal threshold "' for glucose.

Patients treated with soluble insulin will often show a blood-sugar level of about 280 to 200 rag. per 100 c.c. for some hours out of the 24 even though the fasting blood-sugar be normal; this may not always be avoidable, even with multiple doses, but hyperglyc~emia lasting for more than a few hours out of the 24 is certainly most undesirable and should be avoided if at all possible. An adequate single dose of protamine zinc insulin seems to be often more efficient in preventing this transient hyperglyc~emia than multiple doses of soluble insulin. In our cases, whenever possible, the blood-sugar was determined four times throughout the day as stated above, in order to reveal periods of hyperglycemia. Most observers are content with holding the fasting blood-sugar normal, but it not infrequently happens that, with a normal fasting blood-sugar, hyperglyc~emia may exist for several hours later in each day and the true state of affairs may not always be wholly revealed by multiple daily glycosuria tests. I f the daily duration of hyperglycemia i s considerable, the carbohydrate tolerance may continue slowly to decline with the passage of years; this may have some bearing on the fact, to be referred to later, that we obtained 82"8 per cent. of good results in Series I I of our cases, whereas there was only 48"5 per cent. of good results in Series I. A more reliable method of control can be obtained by the four spaced blood-sugar tests as ~bove described; they need not be done more frequently than about once a week or so during the first few weeks of treatment; they need only be repeated at infrequent intervals after the blood sugar levels, diet and insulin


dosage have been stabilized, and they cause little trouble to the patient even if a micro-method is not used.

Joslin lays stress on the fact that exercise reduces the need for protamine zinc insulin even more than for soluble insulin; owing to the slow action of the former, the diabetic who knows that he is going to take unusual physical exercise should either slightly reduce his dose of protamine zinc insulin before it, or preferably he should take an additional small carbohydrate meal before the exercise and possibly another during i t or after it, in order to avoid hypoglyc~emie reactions.

We have divided our patients into two series. The first series consists of patients whose soluble insulin requirements were fairly well known over a considerable period, in many of them for several years. The second series is composed of recent first admissions. Several of the patients of the first series were pressed to enter the hospital because, for a variety of reasons, the fasting blood-sugars were found to be too high at recent tests. None showed any serious degree of ketosis.

When a patient was being changed from a morning to a night dose of protamine zinc insulin, or vice versa, the dose was given in two equal parts morning and night for one day and the next day the whole dose was given at one injection at the time stated in Tables I and I I ; in these tables the day of the split dose is not counted.

Whenever possible, and in the great majority of eases, the patients dealt with in this study of protamine zinc insulin were kept as ambulant patients in hospital for the early weeks of treatment, and requested to return after discharge as often as practicable for blood tests; as many of them lived at considerable distances frequent visits after discharge were not always possible.

On the whole, the results are very satisfactory, and we believe that probably the majority of cases of diabetes of average severity can be efficiently treated with one dose of protamine zinc insulin per day, provided that the diet is properly adjusted. The usual daily dosage of protamine zinc insulin for the average type of diabetic case on our dietary system seems to be about 30-40 units in a single dose after stabilization; a smaller dose is sufficient in some cases, but it may be occasionally necessary to give as much as 60 or 80 units or even more in severe eases ; one patient requires 100 units per day. We have no experience in the use of protalnine zinc insulin in coma. For stabilized patients who are changing from soluble insulin to protamine zinc insulin the number of units required seems to be approximately the same per 24 hours for both types of insulin, but some patients can do with less of the new preparation.

Hypogtyc~m~c Reunions. Hypoglyesemie reactions (see Table III) are perhaps even

more liable to occur with protamine zine insulin as compared with soluble insulin, either because of overdose, too great reduction of carbohydrate or too active exercises; they were particularly frequent in five out of our seven failures,


and, indeed, in these five patients were largely responsible for the failure with the single dose method. I t appeared to us as if in these five failures the insulin was absorbed both irregularly and often too rapidly; it is significant that 32 hypoglycmmie reactions out of a total of 68 occurred amongst five failures (Cases 20, 24, 25 and 26 of Series I, and Case 12 of Series II). I t is of interest also that in Series I eleven patients had 53 reactions, whereas in Series I I six patients had 15 reactions. I t has been frequently pointed out by other writers that these reactions with protamine zinc insulin may come on at times insidiously, and with large doses may persist for a considerable time and, therefore, necessitate more than one dose of glucose or carbohydrate to abolish their symptoms; hence the advisability for caution in dosage, especially in the early stages of treatment.

On the other hand, we have been several time.s much surprised at the low level to which the blood-sugar may fall without any hypoglyc~emic symptoms whatsoever; for example, it was on several occasions found to be as low as from 30 to 44 mg. per 100 c.c. in Case 24 of Series I, from 25 to 47 rag. in Case 26 of Series I, and as low as 54 rag. in Case 28 of Series I without reactions. In several cases the blood-sugar level was found quite low without reactions at one time, and about the same level in the same case with reaction symptoms at another. From a considera- tion of these findings we have come to believe that the degree of hypoglyc~emia may not be the only factor operative in causing hypoglyc~emic symptoms, provided that the blood-sugar does not fall below a certain critical level in the individual, but that the rate of fall of the blood-sugar level may be also of significance in this connection; if the rate of fall is not rapid, and provided that the degree of hyp0glyc~emia is not too great and possibly that it does not last for too long a period, the organism can apparently adjust itself in such a way that hypoglyc~emic symptoms may not occur.

One drawback of the single dose method o~f treatment with protamine zinc insulin is that frequently the blood-sugar level falls lower than one cares to see, ,e.g., about 50 rags. or less per 100 c.c. at some part of the day, often without hypoglyceemic reactions; this is theoretically not ideal and may be difficult at times to avoid, even with readjustment of the dietary and of the time of insulin administration.

In view of the cerebral lesions (parenchymatous degeneration of the cerebral cortex, thalamus and corpus stricture; vacuolation, liquefaction and homogenisation of ganglion cells; shrinkage of cytoplasm and nuclei of the cells and diminution in the number of cortical neurons) recently reported 6, 7 in cases of hyperinsulinism ir~ man, and in rabbits which were treated with insulin as an imitation of the insulin therapy of schizophrenia, marked and repeated hypoglycmmic reactions would seem most undesirable. In those cases of diabetes where the single dose of protamine zinc insulin causes a considerable degree of daily hypoglyc~emia, even without hypoglyc~emic reactions, it would seem, therefore, i n the

TD-E TREAT~ENT OF DIABETES 301

present stage of knowledge of the subject, more prudent to give two separate and smaller daily doses of protamine zinc insulin and soluble insulin, or one dose of the mi~ed insulins, in order to avoid the production of any considerable degree of hypoglycemia lasting for any considerable time.

None of our patients in whom hypoglyc~emia occurred showed the slightest clinical indication of permanent cerebral degenerative changes. Yet an attitude of caution is advisable in relation to insulin hypoglycmmia occurring daily for a considerable period and due to insulin over-dosage, until more information on this subject has been accumulated and appraised; this is especially true as regards protamine zinc insulin with which sympmmless hypoglyc~emia can frequently occur when the dose is too large, or the carbohydrate ration of the diet too small or imperfectly subdivided.

The treatment of the hypoglyc~emie reaction consists in giving by mouth about 5 to 10 grams of glucose, honey, or if these am unobtainable, cane sugar, provided that the patient can swallow; mild reactions may be overcome by giving three or four ounces of orange juice; it might in some cases be well to follow up these remedies by giving two cream-crackers or a little bread, the carbohydrate of which is slowly absorbed, in order to combat the con- tinued action of protamine zinc insulin. I f the reaction is severe enough to cause unconsciousness, 5 to 10 grams of glucose may be necessary intravenously, but this has never been required in any of our cases. The prevention of hypoglyc~emic reactions is related to care Lu avoiding excessive insulin dosage, an adequate allowance of carbohydrate and its proper distribution, the avoiding of unusual and excessive exercise or taking extra carbohydrate before or during it, and avoiding undue delay or omission of meals.

Particulars relative to hypogiyc~emic reactions in our patients are given in Table I I I ; these reactions became much less frequent and more mild as we gained experience in the use of protamlne zinc insulin and the dietetic management of the patients receiving it. Several reactions were due to patients omitting or delaying a meal; two were due to unusual and excessive exercise; very few were ueen in the last twenty patients and none of these were severe.

F~a~lure witl~ the ~ S i n g ~ Dose, Method.

In Series I there were five failures (Cases 2, 20, 24, 25 and 26). Case 15 was an elderly obese diabetic (weight 204 tbs.) who was not reliable in diet; he was classed as a failure until he was with difficulty persuaded to take 100 units daily in one dose one hour before breakfast; the result then could be classed as moderately good; he never had a hypoglyc~emic reaction. In Cases 2, 20, 24, 25 and 26 there was no apparent dietetic reason for the failure as far as we could discover. In Cases 20, 24, 25 and 26 the frequent hypoglyc~emic reactions contributed largely to the failure and in these cases the action of any single dose of protamine zinc insulin seemed largely unpredictable if it exceeded 30 units, which in each case was too small~ for adequate control. In Cases 2~ 20, 2~ and 25


quite good results were finally obtained by one dose of protamine zinc insulin and one of soluble insulin per day. Case 26 had eventually to return to 30, 20 and 16 units of soluble insulin per day.

In Series I I there was one frank failure (Case 12): with him there was an excellent result in hospital, but after discharge there was imperfect dietetic co-operation and, as the patient had several hypoglyc~emic reactions at home, he was eventually put On two daily doses of soluble insulin.

Site of I~je~t~on. It is important that the injection site should be varied and that

the same site should not be used again for a couple of weeks. This point is illustrated by Case 19 of Series I : her blood-sugar failed to fall to anything near normal levels over some weeks of treatment in hospital, during which time there was used by mistake the same injection site in which there was induration and lipodystrophy; on the other hand, the result in this case was moderately good when, after that was discovered, other and various injection sites were used. There were no local reactions in any of the patients.

Results. Our results with the single dose of protamine zinc insulin in lhe

treatment of diabetes are shown in Table IV: 48"5 per cent. of good results in Series I, 82"8 per cent. of good results in Series II, giving 65"7 per cent. of good results for the two series combined. For the purposes of the present communication a result is con- sidered good when the four space4 blood-sugars are reasonably normal, slight degrees of hypoglyemmia in one test being disregarded, for the latter was usually easily rectified by manipulation o f size or time of dose and dietary readjustment; a moderate post- prandial rise of blood-sugar 2 hours after breakfast alone is also disregarded, provided that it does not exceed about 170 to 180 rag. per 100 c.e. from a normal fasting level and provided that the other tests show fairly normal values. For example, a result would be classed as good if the following figures were obtained : - -

Blood-uugar, mg. per 100 c.c.

Fasting . . . . . . . . . . . . . . . 80 to 120 Two hours after breakfast . . . . . . 130 to 180 1 p.m. (just before " mid-day " meal) 90 to 120 6 p.m. (before fourth meal) . . . . . . 90 to 115

Some may consider such criteria of a good result too rigid; probably many cases of diabetes treated with multiple doses of soluble insulin show hyperglycmmic peaks at certain periods during the day and yet do quite well for long periods; yet we feel that, in order to appraise the value of the single dose method of treatment with protamine zinc insulin, a " good " result should show practically normal values for at least three of the four blood-sugar tests, allowing a slight rise (maximum about 180) alone in the test done two hours after breakfast. Some, diabetic patients gradually

THE TREATM~ENT OF DLkBETES 303

develop an increased carbohydrate tolerance in the early months of treatment; because of this and the consequent liability to hypoglyc~mic reactions with protamine zinc insulin, it might be wise to be content with holding the blood-sugar tests slightly above the normal for the early months of treatment and until stabilization occurs in patients who cannot be seen at short intervals.

I t may be of significance that almost twice the number of good results was obtained in Series I I (which consisted of .recent admissions, and, therefore, probably cases of short duration) as compared with Series I. All the patients of Series I were under treatment for diabetes with soluble insulin for a considerable time previously, many of them for several years. The question, therefore, arises as to whether in the first series of patients periods of hyperglyc~emia, even if only for some hours each day over a considerable time, may not have rendered the diabetes less susceptible to the action of the single dally dose of protamine zinc insulin.

Taking the period of observation of each patient as from the time when protamine zinc insulin was first used until the last blood tests were done, and including the period during which the patient was living under home conditions, then the average period of observation per case in Series I was 117 days and in Series I I 82 days; the maximum period for any patient in the former series was 337 and in the latter series 271 days. No patient was followed up for lesa than 30 days.

The objection may be raised to our appraisal of the results that a small minority of the cases, including the more recent ones, were not observed after being put on protamine zinc insulin for more than four weeks and that this period of observation should be longer before conclusions should be drawn. As a reply to this criticism it may be said that there is good reason to believe that the ~results obtained on careful regulation of the diet, insulin dosage and generaI mode of life, under the controlled ~conditions of the hospital, should be at least as good under home conditions, provided that the patient is reasonably faithful to the instructions given on discharge in relation to diet, insulin dosage, exercise and general mode of life. As a matter of fact, the great majority of the patients were repeatedly tested during several months under home conditions and the results lead us to believe that our experience represents what might be expected on a large scale, bearing in mind that human nature is what it is.

Sixty-five out of the 70 patients spent some weeks, usually three to four but often longer, in hospital for the start of the treatment with protamine zinc insulin. The five who were started on this treatment as extern patients were former diabetics experienced in insulin treatment, and were apparently reliable with the exception of Case 15 of Series I. Perfect co-operation could not be obtained in Case 10 of Series I, for she was an imbecile, but during her stay in hospital a moderately good result was obtained. After discharge the patients were requested to return for the four blood-sugar tests about once every month if possible, and the majority were in this

304 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

way re-tested at intervals over several months; in some, lapses in diet did occur occasionally, but we believe that the major i ty were reasonably fa i thful to dietetic rules a f te r discharge. As judged in ~his manner over several months, the action of protamine zinc inw seems to be as un i fo rm as tha t of soluble insulin in patients whom i t suits and who a re reasonably careful. Examples of our results are ~ v e n in Tables i and I I ; considerations of space prohibit set- t ing for th the ful l results i n all the cases.

We believe tha t one may reasonably expect tha t the major i ty of diabet ic pat ients can to-day lead practically normal and useful lives o n a single, adequate, daily dose of protamine zinc insuIin, provided tha t they str ict ly adhere to dietetic rules as based on modern .concepts.

Conclusion.

Protamine zinc insulin in a single dai ly dose adequately controlled 48"5 per cent. of 35 cases of diabetes mellitus who were u n d e r t rea tment with soluble insulin for a considerable time previously, 82-8 per cent. of 35 cases recent ly admitted, and 65"7 per cent. of the 70 cases comprising both series.

In the minor i ty of cases, when a single daily dose of protamine zinc insulin is inadequate, more perfect results can probably be vbtained b y two dai ly doses, or by one dose of pro tamine ziDc insulin and an additional dose of soluble insulin given daily and separately at appropria te times, or by one daily dose of the mixed insulins. I t would appear tha t the single daily dose of protamine zinc insulin is likely t o be unsuitable for the control Of ve ry severe diabetes; i f adequa te in size i t will probably be successful in the major i ty of cases of diabetes of average intensity, par t icu la r ly if the diabetes has not existed for too long a period of t ime before t rea tment is begun, and provided tha t the t ime of administrat ion and the diet are proper ly adjusted. I n judging of final success, however, one must not forget the desira- b i l i ty of avoiding any considerable degree Of hypoglycemia, even i f the la t ter is not symptomologically manifested.

B~bliography.

1. Joslin, E. P. : Nelson's Loose-leaf Medicine (New York), 1936, Vol. III, p. 115 H.

2. Joslin, E. P. : Jo. Amer. Med. Assn., 1937, 109, 497. 3. Laurence, R. D., and Archer, N. : Brit . Med. Jo., 1937, i, 487. 4. Hinsworth, H. P. : Brit . Med. Jo., 1937, i, 541. 5. Richardson, R. : Am. Jo. Med. ~ei., 1937, 193, 606. 6. Weil, ,A., Siebert, E., and Heilbrunn, G.: Arch. Neurol. and

PsychiaL, 1938, 39, 467. 7. Malamud, N., and Grosh, L. C. : Arc:h. Int . Med., 1938, 61, 579.

NoTE.--Since this paper was written we have treated an additional nine patients with a single daily dose of protamine zinc insulin; our experience with these cases has been substantially the same as related above.

We desire to record our thanks to the Sisters, house-physicians and resident students for their willing co-operation, and to Dr. O'FarreU, Pathologist to the Hospital, in whose laboratory the biochemical tests -were done.

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The treatment of diabetes mellitus with a single daily dose of protamine zinc insulin