Clinical experience with protamine and crystalline insulin in the treatment of diabetes mellitus in children

CLINICAL E X P E R I E N C E W I T I t PROTAMINE AND CRYSTALLINE ]NSULIN IN THE TREATMENT OF D I A B E T E S M E L L I T U S IN C H I L D R E N WALDO E. NF~SON, M.D., AND CLYDE DUMME~R, M.D.

CINCINNATI, OI~IO INCE the introduction of protamine insulin by tIagedorn, 1 there have been numerous reports concerning its clinical use which have substantiated the early claims that the action of~protamine insulin is less rapid but more prolonged than that of regular insulin, tIagedorn stated that protamine insulin, after injection, was active for from twelve to fourteen hours, or approximately twice as long as regular insulin. He advised the use of protamine insulin for the evening injection and regular insulin in the morning and, if necessary, at noon. By this method the fasting blood sugar in the morning was maintained within reasonable limits in contrast to the usual high blood sugar in diabetic children when regular insulin is given at the time of the evening m e a l From the work of Lawrence 2 it appears that there might be a relation between the size of the dose of protamine insulin and the length of its action; the larger the dose the more prolonged the effect. In fact, in one instance, Lawrence observed a prolongation of the action for fifty-five hours after the injection of 120 units of protamine insulin, when the patient was given a diet consisting of fat and protein. Wilder and his associates 3 kept a diabetic patient in a state of hypoglycemia from the ninth to the thirty-ninth hour after injection of protamine insulin. This patient received no food after injection until the thirty-ninth hour, when the hypoglycem!a was corrected. These authors made a distinct contribution when they showed that some diabetics may be kept in satisfactory glyeemie equilibrium by a single dose of protamine insulin given before breakfast. They did suggest, however, that in some instances a supplementary injection of regular insulin at the same time might be desirable. More recently in view of the work of Scott and Fisher, 4 zinc has been added to the protamine, producing a compound with an even more prolonged action. For a short period of time protamine calcium insulin was supplied for clinical trial. This product has been discontinued. Our experience has been successively with protamine insulin, protamine

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~'rom the Children's Hospital Research :Fo~ndatlon and the Department of Pediatrics, College of IVledicine, IJniversity of Cincinnati. A portion ~ the data was secured at the Camp for Diabetic Children, Glendale, Ohio. This camp was made possible in the summer of 1936 by a small group of Cincinnati citizens and was operated under the direction of the staff of the Children's Hospital. 446

NELSON

A N D DUN[NItS1%:

PROTAMINE

INSULIN

447

calcium insulin, and protamine zinc insulin. Protamine zinc insulin was employed in all of the children reported here. ~ An example of satisfactory results from a single injection of protamine insulin is shown in Chart 1. The marked difference between the effect upon the blood sugar of the following mo}'ning of equal doses of protamine insulin and of regular insulin given at supper time is shown in this chart as well as in most of the others. We have found that it is particularly advantageous when beginning the use of protamine insulin to administer the first dose in the evening and to continue thereafter with the regular morning injection. B y this method the blood sugar of the morning is usually within the normal range and the slowly acting protamine does not have to overcome the additional H.E.- l~a~- Hyrs.

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Chart 1.--Satisfactot'y results from one injection of protamine zinc insulin per day. Key to Charts: Graph: The figures indicate the hour at which blood samples were collected, light race numerals represent A.~. and dark face P.M. "R" signifies insulin shock; the numeral the hour of occurrence. Insulin: Plain numerals represent units of regular insulin; numerals enclosed in a circle, protamine insulin; and those in a square, crystalline insulin. Urine, qualitative ]~enediet tests: 0 ~ blue, + z green, + z greenish yellow to + + yellow, and + ~ orange through red. + In Charts I, 2, and 6, the urine was collected at 8:00 A.~I., 12 noon, 5:00 P.M. and 9:00 P.M., and in Charts 3, 4, 5, 7, 8, and 9 at 8:00 A.~., II:00 A.M., 4:00 P.M, and 8:00 P.~. All blood examinations were made on capillary blood.

burden of an existing hyperglycemia (for contrast see Chart 4). Our practice has been to establish reasonably satisfactory glycemic equilibrium w i t h regular insulin, then to administer the same number of units of protamine before the evening meal as had been given of regular insulin at this time. The following morning an injection of pro* T h e v a r i o u s p r o t a m i n e p r o d u c t s w e r e supplied t h r o u g h t h e c o u r t e s y of t h e Research Laboratories, Eli Lilly and Company, indianapolis, Indiana.

Lilly

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THE

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PEDIATRiC~

tamine insulin consisting of approximately the total daily requirements of regular insulin is given before breakfast according to the plan suggested by Wilder. Subsequent adjustments in dosage are made in accordance with the level of the blood sugar and the amount of urinary sugar. In general, we have not been able to maintain satisfactory glycemic balance by the administration of a single dose of protamine insulin in the morning. If an amount is given which is sufficient to lower adequately the level of the blood sugar after the noon and evening meals, the patient is quite likely to have a hypoglycemic shock during the night or early morning hours. On the other hand, if the amount of protamine is adjusted so that the blood sugar level of the following 500

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morning is within the normal range, the blood sugar levels during the day of administration are likely to be high. An example of such difficulties is illustrated in Chart 2. In these instances, although the blood sugar was mostly below 100 rag. per cent in the morning following injection of protamine, the Mood sugars at noon and at 5:00 P.~. were high and these children had large quantities of sugar in the urine. Of fourteen children who are now receiving protamine zinc insulin and of approximately as many more who were on this or other protamine compounds during a seven-week camp period, only one is being maintained satisfactorily on a single daily injection of protamine without regular insulin. With one exception, however, all are receiving their entire insulin dosage at the time of the morning injection, the protamine being supplemented with a small amount of regular insulin in order to secure an adequate effect upon the noon and late

NELSON

AND DUMMEtr

PROTAMINE

449

INSULIN

a f t e r n o o n blood sugar. E v e n o n this regime, it m a y be impossible to p r e v e n t the p o s t p r a n d i a l rise of the blood s u g a r a f t e r the evening I~.V/. - Y e r n ~ l e

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meal. This is illustrated in Charts 3 and 4. I n f a c t the blood s u g a r curve shown in C h a r t 4 is p r a c t i c a l l y a m i r r o r image of the blood s u g a r curves usually resulting f r o m the a d m i n i s t r a t i o n of r e g u l a r insulin in

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two or three daily doses in t h a t the 8:00 P.M. blood sugar is high in contrast to t h a t at 8:00 A.~. This rise at 8:00 P.m is f r e q u e n t l y of such short d u r a t i o n t h a t only small amounts of s u g a r a p p e a r in the urine. This does not a p p e a r to be i m p o r t a n t enough to necessitate the a d m i n i s t r a t i o n of an additional dose of r e g u l a r insulin at 5:00 or 6:00 P.~. An a t t e m p t was made to determine w h e t h e r the a d m i n i s t r a t i o n of p r o t a m i n e insulin in single large doses at periods of the day other t h a n at b r e a k f a s t time would prove to be more efficacious. Several children were given t h e i r injections at 6:00 A.~., 4:00 A.~r., 2:00 A.H. and 10:00 P.M. C h a r t 5 illustrates the effect u p o n the blood s u g a r a f t e r injection o f , p r o t a m i n e at the first three of these hours in contrast with several d a y s w h e n the injection of p r o t a m i n e was given before breakf a s t and s u p p l e m e n t e d with r e g u l a r insulin. There were occasional d a y s w h e n the blood s u g a r was s a t i s f a c t o r y a f t e r injections at all of these periods. Usually, however, in addition to the inconvenience of injecting the insulin at such hours, there was an actual d i s a d v a n t a g e in r e g a r d to the blood s u g a r response. W e h a v e concluded t h a t with the possible exception of 6:00 A.~. no added a d v a n t a g e is gained by such t i m i n g of the injections and t h a t more s a t i s f a c t o r y equilibrium is secured b y a combination of p r o t a m i n e a n d r e g u l a r insulin (in s e p a r a t e injections) at b r e a k f a s t time. ]in a camp for diabetic children d u r i n g J u l y and August, 1936, we were able to secure somewhat more s a t i s f a c t o r y blood s u g a r curves on single doses of p r o t a m i n e insulin w i t h o u t additional r e g u l a r insulin t h a n we h a v e been able to m a i n t a i n in the hospital or at home d u r i n g the school months. I t would appear, therefore, t h a t the f a c t o r of a c t i v i t y m a y be i m p o r t a n t . I f the daily a c t i v i t y is of sufficient a m o u n t and p r o p e r l y regulated, it m a y be possible to reduce m a t e r i a l l y the a m o u n t of r e g u l a r insulin and possibly in some instances to eliminate it entirely. One child is being m a i n t a i n e d at the p r e s e n t time on a somewha* u n o r t h o d o x plan. He is receiving 40 units of p r o t a m i n e insulin and 15 units of r e g u l a r insulin in the m o r n i n g and the same dosage again in the evening. W i t h this regime he is in a m u c h b e t t e r state of stabilization t h a n we have been able to m a i n t a i n otherwise. This is simply evidence of the need of individualization in the t r e a t m e n t of diabetic children and an additional a r g u m e n t against too rigid establishment of rules. I t is g e n e r a l l y stated t h a t h y p o g l y c e m i e reactions are less f r e q u e n t and less severe when protamine insulin is employed as compared with the n u m b e r and severity of these when r e g u l a r insulin is employed. This a p p e a r s to be the ease p a r t i c u l a r l y a f t e r the child is p r o p e r l y regulated. Nevertheless, reactions do occur, and t h e y m a y be quite severe. Insulin shocks f r o m p r o t a m i n e insulin are most likely to oeeur

N E L S O N A N D DU1K?CIEg:

451

PROTA1VIINE I N S U L I N

f r o m twelve to t w e n t y - f o u r hours a f t e r injection, so t h a t if the insulin is given at b r e a k f a s t time, the reaction m a y occur d u r i n g the night hours. In our experience t h e y have occurred most f r e q u e n t l y in the early m o r n i n g hours f r o m 4:00 A.M. to 8:00 A.M. While it m a y be a d v a n t a g e o u s to prescribe a small a m o u n t of :food at bedtime, our usual policy has been not to do this, but r a t h e r we h a v e a t t e m p t e d to determine the a m o u n t of p r o t a m i n e necessary to m a i n t a i n the blood s u g a r of the following m o r n i n g at a reasonable level, and, w h e n it is necessary to control the blood s u g a r at noon and at 4:00 e.~., to inject r e g u l a r insulin at the time of injection of protamine. The onset of h y p o g l y e e m i c reactions f r o m p r o t a m i n e insulin m a y be slower and more insidious t h a n a f t e r the injection of r e g u l a r insulin. I f these Die~-

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C h a r t 5 . - - C o m p a r i s o n of i n j e c t i o n s of p r o t a m i n e zinc i n s u l i n a t 6:00 A.•., a t 4:00 A.M. a n d a t 2:00 A.~. w i t h t h e c o m b i n e d u s e of p r o t a m i n e zinc i n s u l i n a n d r e g u l a r insulin a t b r e a k f a s t t i m e . N o t e h i g h blood s u g a r s a t 8:00 P.M.

mild s y m p t o m s are d i s r e g a r d e d , however, the child is liable to develop a v e r y severe shock. F u r t h e r m o r e , because of the longer continued effect of p r o t a m i n e insulin, several shocks m a y result f r o m a single injection (Chart 3). Thus, the child m a y have a second or even a third reaction a f t e r s a t i s f a c t o r y t r e a t m e n t of the initial shock. I t is import a n t to i n s t r u c t the child a n d his f a m i l y a b o u t these facts. A n o t h e r slowly acting insulin p r e p a r a t i o n , crystalline insulin, ~ has been i n t r o d u c e d recently. Several report@ concerning its clinical use have been published. I n general, it is stated t h a t this p r e p a r a t i o n has an effect upon the blood s u g a r which is less r a p i d and more p r o l o n g e d t h a n t h a t of r e g u l a r insulin but more r a p i d and less p r o l o n g e d t h a n * C r y s t a l l i n e i n s u l i n w a s Supplied t h r o u g h t h e c o u r t e s y of F r e d e r i c k C o m p a n y ; D e t r o i t , Mich.

Stearns

and

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TItE, J O U R N A L

OF P E D I A T R I C S

that of protamiue insulin. It is said that its effect upon tile blood sugar persists for from eight to f o u r t e e n hours. An a t t e m p t to use crystalline insulin in single large daily doses, as described for proD.b.-1"$ale-175zF~.-

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tamine insulin, was unsuccessful in controlling the blood sugar for a period of t w e n t y - f o u r hours. This is illustrated in Chart 6. A comparison of the effect of evening' injections of regular, crystalline, and

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454

T E E JOURI~AL OF PEDIATRICS

p r o t a m i n e insulin upon the fastil~g s u g a r of the following m o r n i n g is illustrated in Chart 7. There was no essential difference between the effect of r e g u l a r and crystalline insulin in c o n t r a s t to the good results obtained with protamine. A t t e m p t s were m a d e in several children who were receiving two or three daily injections of r e g u l a r insulin to control their blood s u g a r with two doses of crystalline insulin. An example of these results is shown in C h a r t 8. I t was possible to control the blood sugars at 4:00 P.lV~. and at times at 8:00 P.~. b y the m o r n i n g injection. H o w e v e r , we have been unable to control the blood s u g a r d u r i n g the night by injecting crystalline insulin either at 5:00 P.~. or 9:00 ~.~. P r a c t i c a l l y all a t t e m p t s to give a sufficient amount to lower s a t i s f a c t o r i l y the blood s u g a r of the following morning resulted in severe h y p o g l y c e m i c reactions which occurred at some time d u r i n g the n i g h t or e a r l y morning hours. A n o t h e r c o m p a r i s o n of results with regular, crystalline, and p r o t a m i n c insulin is d e m o n s t r a t e d in C h a r t 9, in which m u c h b e t t e r results were secured with morning injections of p r o t a m i n e and r e g u l a r insulin t h a n with two daily injections of r e g u l a r or crystalline insulin. We h a v e not used p r o t a m i n e or crystalline insulin in the t r e a t m e n t of diabetic coma and can see no reason f o r doing so. I f children who are receiving p r o t a m i n e insulin develop an infection severe enough to lower their tolerance for c a r b o h y d r a t e , our policy has been to continue the p r o t a m i n e at essentially the same dosage and to administer, temporarily, r e g u l a r insulin two or three times daily in amounts sufficient to control the glycosuria. SUMMARY

Our experience in the clinical use of p r o t a m i n e insulin has been distinctly satisfactory. The i n t r o d u c t i o n of p r o t a m i n e by H a g e d o r n is p r o b a b l y the most significant contribution in the t r e a t m e n t of diabetes mellitus since the discovery of insulin. More recently the p r o d u c t has been i m p r o v e d by the addition of zinc and b y the development of a c o m p o u n d which is stable for at least six months a f t e r mixing. This p e r m i t s the m a r k e t i n g of p r o t a m i n e zinc insulin in an a l r e a d y mixed state. The m e t h o d of a d m i n i s t r a t i o n b y a single daily dose, suggested b y W i l d e r and his associates, has aided m a t e r i a l l y in increasing the efficiency of the use of this product. I n our experience, however, it has been the exception r a t h e r t h a n the rule t h a t diabetic children can be m a i n t a i n e d in glycemic equilibrium w i t h o u t s u p p l e m e n t a r y r e g u l a r insulin a d m i n i s t e r e d at the same time as the injection of protamine. This is not a serious objection since the child continues to receive all of his insulin a~ one time, a l t h o u g h ]n two different sites instead of at three or f o u r times of the day. We feel t h a t there is an a d v a n t a g e in m a k i n g the initial injection of p r o t a m i n e in the evening, so t h a t the blood s u g a r of the following m o r n i n g is within the normal range.

NELSON AND DUMMER:

PROTAMINE INSULIN

455

We have not been able to determine that injection at other times of the day, with the possible exception of 6:00 A.~{., has a n y a d v a n t a g e over the a d m i n i s t r a t i o n j u s t p r e c e d i n g b r e a k f a s t time. There is still need for clinical investigation regarding' the time of a d m i n i s t r a t i o n and certainly a need f o r individualization in the t r e a t m e n t of each child. In our experience the clinical use of crystalline insulin does not have sufficient a d v a n t a g e over that of r e g u l a r insulin to w a r r a n t its general use at the p r e s e n t time, although it is w o r t h y of f u r t h e r clinical trial. REIFERE.NCE.S 1. }Iagedorn, H. C., Norman Jensen, B.~ Krarup, N. B., and Wodstrup, I.: J . A . M. A. 106: 177, 1936. 2. Lawrence, R. I)., and Archer, N.: Brit. M. jr. 1: 747, 1936. 3. Sprague, R. @., Blum, B. B., Osterberg, A., Kepler, E. J., and Wilder, R. IV[.: J. A. IV[. A. 1 0 6 : 1 7 0 1 (May 16), 1936. 4. Scott, D. A , and Fisher, A. 3&: J. Pharmaeoh & Exper. Therap. 55: 206, 1935. 5. Freund, Hugo A , and Adler, Sidney: J. A 3/I. A. 107: 573, 1936. Mains, M. Paul, and 3/[eMul!en, Clarence J. : J . A . 1VI.A . 107: 959, 1936. Altshuler, Samuel S., and Leiser, Rudolph: J . n . M . A . 107: 1626, 1936.