• No results found

INSULIN-PRODUCING CAPACITY OF THE PANCREAS OF CHILDREN WITH DIABETES MELLITUS

N/A
N/A
Protected

Academic year: 2020

Share "INSULIN-PRODUCING CAPACITY OF THE PANCREAS OF CHILDREN WITH DIABETES MELLITUS"

Copied!
10
0
0

Loading.... (view fulltext now)

Full text

(1)

CHILDREN

WITH

DIABETES

MELLITUS

By R. Klein, M.D., J. Marks, M.D., and I. A. Mirsky, M.D.

JJepartment.s’ of Pediatrics 011(1 Clinical Science, Unicer.s’ity of Pittsburgh Medical School

(Accepted March 14, 1958; submitted I)ecemher 11, 1957.) l)r. Kleimi was a Markle Scholar iiiMedicine.

ADDRESS: (R.K.) Pittsburgh 13,Penmisylvania.

289

PEDIATRICS, Aumgust 1958

T

HE RELATIVELY small amounts of exog-enous insulin required early in the

COUSC of diabetes melhitus in the child and the marked decrease in such requirements

which may follow the initial period of

treatment suggest that the pancreas is still

capable of producing insulin at the onset of

the clinical disorder. Subsequently,

how-ever, pancreatic exhaustion and irreversible

insulin insufficiency ensue. We have

at-tempted to define the length of the interval

between the onset of clinical signs of

dia-betes amid the exhaustion of islet tissue by

umtihizing hypoglycemic agents which are

in-suhin dependent. Tolbutamide and

indole-3-acetic acid are such agents since they

pro-duce hypoglycemic responses only in the

presence of active beta cells of the islets

of Langerhans.12 The responses of both

nor-mal and diabetic children to these agents

form the basis of this report.

PATIENT MATERIAL AND METHODS

The response of concentration of sugar iii

tue

blood to the oral administratiomi of 50 mg/ kg of l)ody weight of tolbumtamide amid 2.0 gmn/m2 of indole-3-acetic acid* was determined

in children with diabetes mehhitus of varying

dumration amid in children withoumt evidemice of

mnetal)olic disorder. Similar responses were also

observed after the ingestion of sodium

bicar-bonate i)y 16 children who had had diabetes

mehhitums for a period of from 0 to 48 months.

These last comistituted a diabetic comitrol group. The dial)etic childremi receiving tolbutamide

and indlole-:3-acetic acid! were divided into foumr groups according to duration of disease.

Thirty-mime children were stuidied in their

in-o \Ve are nldcl)ted to I)r, %V. R. Kirthey, Eli

Lihl amid Comiipamiv, for generous supplies of

indohe-:3-acetic acid.

itial hospitalization after the diagnosis of

dia-betes melhitus had been made (i.e., within 3

months). Thirty-three children who had had clinical diabetes mehhitus for 6 to 24 months

were also studied. Twenty-three children had had diabetes mehhitus for 24 to 48 months amid

25 children had had evident disease for 48

months or more.

The patients with diabetes were given onl’ crystalline insulin on the day before the test

was carried out. No insulin was given the

morning of the test amid none of the subjects was fed before or during the test. A sample

of blood was obtained before the administra-tion of either hypoglycemic agent or the inert

material by mouth and specimens of blood were obtained subsequently 3, 1, 2, 3, 4 and 5

hours thereafter. The concentration of sugar

iii the blood was measured by the method of Nelson and Somogyi.3 During the first half of the study the measurements were made iii

duplicate. Thereafter they were made on a

single sample. Approximately one-third of the

early tests were carried out with samples of venous blood. The latter two-thirds of the tests

were carried out with samples of capillary

blood. There was no discernible difference and these figures are grouped together. During the period of the test the children were allowed

imp on the ward to engage in quiet play.

At-temps to discourage vigorous activity were not always entirely’ successful.

RESULTS

To facilitate comparison between

chil-dren and between groups of children, the

concentration of sugar in the blood at each

designated interval after the ingestion of

the various compounds was expressed as

the percentage of the initial fasting

concen-tration of each subject. The over-all

de-crease in the concentration of sugar during

(2)

1-.

.,.

1-o, c

-i+i I ,‘ o, t_+I t+ --p -o t_+I +I -‘p x±I +l ,-o “p +I +l -‘p -H #{176}‘+I 0o -p -f1 +I 0 #{176}‘-H “4 + ‘H -P0 +1 I-+1 - +1 z I’ z I’, z z .‘-0 0 C z C I-z z z r1 -0

+1 I +1

H

. cJ 0 0 - +1 -. -- 0 0 . . 0c, I+I SI-H t_’p

-I-H II I+i -HI

.4-00 0,0

cc;.’; .e

-‘‘H +I X’H

0

-‘,

+I +I ‘H +I

0-p ‘p

+I +I +I -H

0 .‘ 0).’)

‘p0)

-H +I 0+I -H

-P0) 0)-p

-P 0)’

,..+, 2+i ...-H -H

0-p P’p 0)-p -x

x ‘p.’,

x,4 t-4 -t

“H -t- 00) 0) 0 0 cc 1 ©cc E -.0 0 ‘p 81-H 40) -H +‘H Mx +l +1 0)0) +I 2-H 0)0 0)’p ‘pee ‘p +I ,.“H O;)1 -H +l 0)0) 1-0) 4 1-0) ..-H 2+i -x 0) 1-0) 1-0) 2 2+i ‘p.’) 0)4 4l4 1-0) X -0) ‘p 0) 0) 1-0 cc; 0 0 - 0 0) S 8 ‘0 0 0 0.0. 0 8 0 0 0 ccc 0 S 2 9 .0 .000 E V occ 00 4’. 0 .2

01

:

-01

1

1

92

0

(3)

0 0

-J

z-M

0

-4.,

cc..,

LL

0-Z

Q.E

z

w

z

0

I,)

TIME (hi)

Ftc. I. The response of nomidiabetic and diabetic children to administration of tolbutamide

and indole-3-acetic acid. The diabetic group consisted of children whose metabolic

derangement was of hessthan 3 months duration. The reported mean concentrations of

sugar in the blood for the groups are calculated from the individual levels recorded as percentage of individumal pretest levels.

0

I 2

3

4 5

per cent decrease” as computed from the

five hourly samples. The mean change in

concentration ± the standard error of the

mean of each group of subjects is

summar-ized in Table I.

As with healthy adults,2 the

administra-tion of tolbutamide to nondiabetic children

resulted in a decrease in the concentration

of sugar in the blood to 56 ± 5.8% of the

initial concentration within 30 minutes. The

concentration of sugar increased slightly by

the second hour and then remained at an

hypoglycemic level for the next 3 hours.

The nondiabetic children given

indole-3-acetic acid, however, showed no

statisti-cally significant changes in concentration of

suigar in the blood (Fig. 1).

The 16 diabetic children given sodium

bicarbonate had a decrease in the

concen-tration of sugar in the blood to 88 ± 5.5%

of the initial level in

5 hours.

The

over-all

response of this group was a statistically insignificant decrease of 3.4 ± 3.0%.

The administration of either tolbutamide or indole-3-acetic acid to the children

whose metabolic derangement was discov-ered at or shortly before the time of

admis-sion resulted in a marked, statistically

signif-icant hypoglycemic response to

approxi-mately 70% of the initial concentration of

sugar

in

the

blood.

The

over-all

decrease

in the concentration of sugar computed from the five hourly samples was 20.8 ±

3.7% in the children given tolbutamide and 19.3 ± 3.9% in those given indole-3-acetic

acid; the difference in mean response

be-tween these groups and that given sodium

bicarbonate was highly significant (Fig. 1).

A similar statistically significant decrease in

(4)

10 Oao

-J

z

,(

(Drcc

V)

0

z

0

I-z

LU

L)

z

0 U

z

LU ‘I)

LU

U

LU

AGE AT ONSET (yr) DURATION OF DIABETES (yr)

tic, 2. Influmemiec of initial coneeimtratiomi of sugar in the 1)100(1, dosage of insulin, age at onset amid

dtmra-tiomi of tIm svmidrome on the response to administration of tolbutamide ( ) and indole-:3-acetic acid

(--- --) of children with diabetes nielhitus. The only significant correlation (P < .001) is that between theduration of the syndrome amid the hypoglycemic response.

observed in the children with diabetes

me!-hitus of 6 to 24 months rlumration who were

given indole-3-acetic acid. The

hypogly-cemic response to tolbutamide, however,

was not significantly different from that of the groimp given sodium bicarbonate.

Although there was a significant decrease

in the concentration of sugar in the blood

of some of the 48 children with diabetes of

more than 2 years duration, the over-all de-crease in this group was not significantly

different from that of the group treatedi

with sodlium bicarbonate.

One of the factors accounting for some of

the variations imi the responses appeared

to be associated! with the adequacy with

which the child’s mrmetabohic derangement

was regulated. Thus, a group of seven chil-dren who responded poorly when tested

early in the first hospitalization showed a

significantly greater hypoglycemic response

when retested 1 month later. At the latter

period insulin requirements were smaller

but at neither time were there evidences of ketosis or polyuria. Further, among those

with diabetes of 6 to 24 months duration were two children who had beemi admitted

to the hospital with acidlosis; they did not respondi with a decrease in concentration of

sugar in the blood when given tolbutamide

1 to 3 days after they were hospitalized!.

Three

days

later,

however,

these

two

chil-dren

were

given

indole-3-acetic

acid

amid! a

marked decrease in the concemitration of

sugar in the bloodi ensumed. Elimination of

these initial tests dumring the post-ketotic

phase results in a group response to tolbu-tamide which is significantly greater than

100 300 400 OC 0

Initial Concentration of Sugar

(mg/IOO ml)

30 40 60

(5)

20

10

0.

DURATION OF DIABETES (mo)

Fic. :3. Relation of duration of the diabetic syndrome and the hypoglycemic response to adniinistratiomi of tohhutam-nide or indole-3-acetic acid. The dotted line depicts the mean

percentage decrease in the concentration of sugar in the blood of a groump of diabetic

children dumring the 5-hour period after administration of sodiumm bicarbonate.

0-3 6-23 24-47 48 +

U-0

I-..--.

z

LU

UO ZO

O-z

LU

<w

r

that of the diabetic children who were

given only sodium bicarbonate.

Two individual children with very “mild”

diabetes melhitus of 1 year’s duration or less

and a few children with newly discovered!

diabetes demonstrated responses to

tolbu-tamide identical to the responses of normal

individuals.

Statistical evaluation of the influence of

the age at which the diagnosis of diabetes

was established, the dosage of insulin, the

initial concentration of sugar in the blood

and the duration of the diabetic state

on the hypoglycemic response to the two

agents revealed that the duration of the

metabolic disorder was the only variable

which correlated significantly with the

re-spomise (Fig. 2).

Since the hypoglycemic response of

dia-betic children was essentially the same to

tolbumtamide and indohe-3-acetic acid, the

data obtained with both agents were pooled for each group of patients (Fig. 3). Analysis

of these data revealed that the children

comprising the groups with diabetes of

less than 24 months duration responded

to one or the other agent with a greater

over-all decrease in the blood sugar than

did the patients given sodium bicarbonate

(P < 0.01). The groups of children with

dia-betes of 24 or more months duration,

how-ever, showed essentially the same response

to tolbutamide or indole-3-acetic acid as

did the control group to sodium

bicar-bonate.

The influence of the duration of the

d!ia-betic state on the response to either

tolbuta-mide or indohe-3-acetic acid was determined

also by permitting an interval of from 5 to

9 months to elapse between tests. Thus, nine

children who were tested with one of the

agents at the time of first hospitalization

were retested after an interval of 6 to 9

months and then for a third time 5 to 6

months later. The mean decrease in

(6)

\

\

40

U-0

I-..--Zc

LU

U ZO

“-I

Z2O

<(9

Qt/) U

10-0

- -

-0

%

#{149} k{

1\

/

-I’’

_____

#{149}

---F I

-S cc’ #{149}

o

l’ic. 4. Influence of duration of diabetic syndromiie on response to administration of

tolbuta-ilil(le OI’ in(hole-3-acetic acid. The first test was performed during the initial hospitalization. The second test was performed from 6 to 9 months later and the third test 5 or 6 months

after tIm second test. The shaded areas represent the mean ± the standard error of the mean percemitage decrease in concentration of sumgar in the blood.

First Second Third

Test Test Test

hours of the first test was 34.5 ± 4.1% and

21.5 ± 3.8% d!uring the second test. While

the groups as a whole showed a further

decrease in the hypoglycemic response

(17.0 ± 4.6%) when tested!approximately 6

months later, some individuals showed

an improved hypoglycemic response. It is

quite possible that the improved response is related to a temporary improvement in

the metabolic syndrome such as is known

to occur with the institution of insulin

therapy (Fig. 4).

DISCUSSION

Iii accord! with previous studies,2’ the

data reported herein reveal that children

with

diabetes

melhitus

can

respond

to

tol-butamide and indole-3-acetic acid with a decrease in the concentration of sugar in the blood. The degree of the hypoglycemic

response, however, is determined by the (luration of the metabolic derangement: the longer the duration, the less is the

hypo-glycemic response to a standar! (lose of

either agent. Since the hypoglycemic action of both tolbutamide and indole-3-acetic

acid is dependent upon the presence of

functional beta cells, it is evident that chil-dren with diabetes are capable of producing

insulin early in the course of the syndrome.

The progressive decrease in the

(7)

(lutration of the syndrome increases suggests

a )rogressive decrease in the capacity of the

I)amicreas to manumfacture insulin.

These conclusions are in accord with the

observations of Wrenshall and colleagues,5

that the quantity of extractable insulin in

the pancreas of patients who die with

dia-betes mellitus is inversely related to the

d!uration of the syndrome; the negative cor-relation is particularly high in those

pa-tients who developed diabetes before the age of 20 years. It is in such patients, i.e.,

those with the “growth-onset” type of

diabetes, that %Vrenshall

et

a!. found the lowest concentrations of extractable insulin.

It is quite

possible

that

prolonged

stimula-tion of the pancreas to meet the peripheral

requirements for insulin for growth and

other synthetic functions in the child

re-suIts in exhaustion and degeneration of the

islets, sumch as occurs in the partially

depan-creatized dog receiving a high caloric

in-take or in the normal dog after the

pro-longed administration of growth hormone.

Various considerations make it evident

that

the

development of the insulin insuffi-ciency responsible for the metabolic

de-rangement cannot be due only to a decrease

iii the rate of production of insulin by the

pancreas.1 In fact, children who die with d!iabetes relatively soon after the onset of

the syndrome may have more extractable insulin in the pancreas than the concentra-tion below which diabetes ensues in the.

experimental animal.5 Accordingly, the in-sulin insufficiency must be due, in part at

least, to the activity of some mechanism

which prevents the peripheral action of in-suilin and thereby increases the peripheral

requirements beyond the pancreatic

capa-city to produce insulin. In accord with this

is the fact that indole-3-acetic acid, an

insuihinase inhibitor, is effective as an

hy-poglvcemic agent (luring the early stages of

diabetes niellitus in children. This

com-Poulmi(I is miot adequate for long term thera-peumtic purposes.

One secondary point that became clear

in the course of the investigat:on should be

mentioned. Responsiveness to tolbutamide

cannot

be

employed

as a test

for

excluding

the diagnosis of present or future diabetes melhitus since children with clinically

evi-dent

and

laboratory

confirmable

diabetes

may respond to tolbutamide in an entirely normal fashion during the early phases of

the syndrome.

SUMMARY

Children

with

diabetes

melhitus

of

vary-ing

duration

were

given

tolbutamide

and

indole-3-acetic acid by mouth. The response

of the concentration of sugar in the blood!

to

these

insulin-dependent

hypoglycemic

agents was measured. It was demonstrated!

that

children

with

diabetes

of recent

origin

do

respond

to

these

agents.

Hence,

it is

postulated that the pancreas is capable of

secreting insulin early in the course of juvenile diabetes. This ability is gradually

and steadily lost so that children with dia-betes of over 2 years duration are almost uniformly unresponsive to these two

hy-poglycemic agents. The data suggest that after a variable period of clinically evident

diabetes melhitus, the pancreas of the childi

becomes exhausted and incapable of secret-ing insulin.

ACKNOWLEDGMENT

The

authors

gratefully

acknowledge

their

debt to Miss T. Slifkin, R.N., Miss L. Toiler, R.N. and Mrs. M. Dehoff, R.N. for help in carrying out the tests.

REFERENCES

1. Mirsky, I. A.: Insulinase, insulinase-inhibi-tors, and diabetes mellitus. Recent Prog.

Hormone

Res.,

13:429,

1957.

2. Mirsky, I. A., Diengott, D., and Dolger, H.: The relation of various variables to the hypoglycemic action of 1-butyl-3-p-tolyl-sulfonylurea in patients with diabetes mellitus. Metabolism, 5:875, 1956. 3. Somogyi, M.: Notes on sugar determination.

J.

Biol. Chem., 195:19, 1952.

4. Camerini-Davalos, R., Marble, A., White, P., Belmonte, M., and Sargeant, L.: Ef-fect of sulfonvlurea compounds in dia-betic children. New England

J.

Med.,

(8)

5. Wrenshahl, C. A., Bogoch, A., and Ritchie, R. C.: Extractable insulin of pancreas; correlation with pathological amid clini-cal fimid!ings in diabetic amid! miondiahetic

cases. I)iabetes, 1:87, 1952.

SUMMARIO IN INTERLINGUA

Le

Production

Dc

Insulina

In

Le

Pan-creas

De

Patientes

Pediatric

Con

Diabete

Mellite

Tolbutamido e acido indole-3-acetic esseva administrate per via oral a patientes pediatric

con diabete melhite de vane durationes. Esseva mesurate he responsa del sucro sanguinee a iste

agentes hypoglycemic que depende in br

ef-fectos del presentia de insuhina. Esseva

con-statate qume juveniles con diabete de origine

re-cente responde a illos. Isto permnitte he postulato ne he pancreas vs capace de secerner insuhina

(lumrante he I)rimne phases de diabete juvemiil.

Tamen, il se tracta de un capacitate que se perde gradual-e constantemente, de maniera que juveniles con diabete de un duration de plus que 2 annos manifesta quasi uniforme-mente nulle responsa al duo mentionate agentes hypoglycemic. Le datos pare indicar que post umi plus o minus extense periodo de chinica-mente evidente diabete mellite he pancreas del patiente pediatric es exhaumrite e deveni

inca-pace

a

secerner insuhina.

how MANY INJECTIONS OF POLIOMYELITIS VACCINE FOR EFFECTIVE AND DURABLE

IMMUNITY? J. E. Salk. (J.A.M.A., 167:1, May 3, 1958.)

The author presents evidence that antibody against poliomyelitis virus may be expected in the serum for a number of years after an effective course of immunization with poliomyelitis vaccine. The level of antibody induced after the booster dose is influenced by the amount of antigen which was administered in the primary

vaccina-tion as well as by the amount of antigen contained in the booster dose. The

per-sistence of antibody is influenced similarly. Thus the answer to the question posed by the tithe of the paper is in part dependent upon the potency of the vaccine used in the primary vaccination and in the booster dose. Apparently all lots of commercially-prepared vaccine have not been of optimal potency. After considering all the theoretic and practical aspects of the problem the author indicates that the answer to the ques-tion “Should a fourth dose be given?” is answered in part by the assertion that it will do no harm. Without a knowledge of the degree of protection afforded by the primary immunization and a subsequent dose, the physician will be inclined to give a fourth dose of pohiomyehitis vaccine as a booster to gain further assurance of protection. It is estimated that this will be of additional benefit to no more than 10% of those who

(9)

1958;22;289

Pediatrics

R. Klein, J. Marks and I. A. Mirsky

DIABETES MELLITUS

Services

Updated Information &

http://pediatrics.aappublications.org/content/22/2/289

including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or in its

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

(10)

1958;22;289

Pediatrics

R. Klein, J. Marks and I. A. Mirsky

DIABETES MELLITUS

INSULIN-PRODUCING CAPACITY OF THE PANCREAS OF CHILDREN WITH

http://pediatrics.aappublications.org/content/22/2/289

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

References

Related documents

Field experiments were conducted at Ebonyi State University Research Farm during 2009 and 2010 farming seasons to evaluate the effect of intercropping maize with

MULTIPLE GENETIC MECHANISMS IN VITAMIN D-RESISTANT RICKETS.. V ITAMIN D-resistant rickets of the “sim- pie” type is one of the

In summary, we have presented an infant with jaundice complicating plorie stenosis. The jaundice reflected a marked increase in indirect- reacting bilirubin in the serum. However,

19% serve a county. Fourteen per cent of the centers provide service for adjoining states in addition to the states in which they are located; usually these adjoining states have

Parents, hybrids, parents against hybrids, the ability to combine plants (GCA) and genotypes, which include the unique ability of hybrids, mean squares in the analysis of

The paper is discussed for various techniques for sensor localization and various interpolation methods for variety of prediction methods used by various applications

It was decided that with the presence of such significant red flag signs that she should undergo advanced imaging, in this case an MRI, that revealed an underlying malignancy, which