CURRENT
PROBLEMS
IN DIABETES
By R. Klein, M.D., and Z. Laron, M.D.
Department of Pediatrics, University of Pittsburgh
4.8%
83.0%
5.9%
6.’2%
99.9%
6.6%
14.8%
5.9% 3.3%
83.0%
Camicer
Other causes
ADDRESS: (R.K.) Children’s hospital of Pittsburgh, Pittsburgh 1:3,Pennsylvania.
983
REVIEW
ARTICLE
T
lIE PREVENTION of the vascular diseaseaccompanying long-term diabetes
mel-titus is tile most important problem in
(ha-betes at the present time. The importance
of tiliS problem is dramatized by the
fol-lowing statistics from the Metropolitan Life
Insurance Company Policy Holder
Statis-tics amid those of the Joslin Clinic for 1954.1
Diabetic coma accounted for 4.8% of all deaths in diabetic patients among the Met-ropohitan Life Insurance Company policy holders and 0.7% amongst the deaths of
diabetics in the Joslin Clinic group. Eighty-three per cent of the deaths in diabetics in
the Metropolitan Life Insurance Company
groump were due to vascular changes. The
comparable figure for the Joslin Clinic
group is 72%. Table I shows the figures in
tabumban form. It has been shown that,
what-ever other factors there may be in the
cau-sation of the vascular components of dia-bctes, these degenerative manifestations do
increase with increasing length of survival
with diabetes meihitus. There seems to be general agreement on this fact. 2-7
There-‘FABLE I
(‘u1sFs (IF l)EuTmm AMONGST I)mABETmc l’TmENTs,
POLICY IIoLm)Ens OF’ LETm(oI’oLmTAN LmFE
INSIIIANCE COMPANY’ (1954)
1)iabetie (OmmlIl
Arteriosclerosis
Car(Iiac
Remial
Cerebral Gangremie
tJmmspecifie(l
fore, the increase in vascular mamiifcstatiomis associated with diabetes would be expected
in association with the decline of deaths from coma and the survival of diabetics for
an appreciable period of time.
The emotionalism aroimsed in the pro-ponents of the various regimens to prevent
vascular changes in diabetes mehhitus makes
it difficult to ascertain the facts about this problem but at the same time emphasizes
its importance.
An impartial review is needed of what is known about the etiology and prevention of these dread manifestations of diabetes melhitus. That is the main purpose of this article. To do this properly will require
consideration of many factors related to the disease. However, no discussion of the di-agnosis of diabetes non of the treatment of
actmte diabetic coma will be imndcrtaken, nor has there been any attempt on the part of the aumthons to completely review the literature on the general subject of diabetes melhitums.
Although vascular disease is the major problem of diabetes mellitums at all ages, it
is particimbanly important in juvenile diabetic
patients. White7 reported that 92% of 200 juvenile diabetic patients who survived 20
years of diabetes mellitus had vascular
dis-case: Others have reported similar fig-uncs.311 The incidence for 10 to 15 years duration is about 50%. Wagcnen2 reported
a rising incidence of vascumban complications
KLEIN CURRENT PROBLEMS IN DIABETES
Sixty-five per cemit of patiemits who had dia-betes from 11 to 15 years and 73% of all pa-tients who had the disease more than 20
years had retinopathy. Seventy-six per cent of patients under 30 years of age who had had diabetes for more than 10 years had
retinopathy, while amongst patients over 30
years of age who had diabetes for the same period of time only 64% had retinopathy. Others have not found any differences at-tnibutable to age at onset.3 Throughout this article, retinopathy as an example of vascu-han disease wihl be emphasized as there are more figures available for this. Larsson4 gives figures for other forms of vascular de-generation.
There are two schools of thought in re-gard to the prevention of late vascular
dis-ease in diabetes mehhitus. One group be-bieves that glycosunia and hyperglycemia are noxioums per se, and that these factors predispose to development of degenerative vascular disease. In addition, they are of the opinion that hyperglycemia exhausts the remaining islet tissue of the pancreas, and that episodes of acidosis and coma are precipitated by overeating of carbohy-drates. Therefore, they prescribe a fixed diet and attempt to produce an aglycosuric state. The other school maintains that hy-penglycemia with constant glycosunia (short of that leading to polyunia) is not harmful per se. Adherents to this philosophy main-tam that the incidence of degenerative dis-ease among patients managed by a liberal diet regimen has not been proved to be higher than among patients controlled by more rigid regimens.1#{176}
In actual practice the treatment of pa-tients has tended to become more and more similar no matter to which school the phy-sician owes allegiance. Lichtenstein4 tries to limit gbyeosuria to less than 40 gm/day, or approximately 10% of the intake of car-bohydrate, on a free diet and Tolstoihl limits it to that amount which will not pro-duce pobyuria. In addition, perhaps un-consciously, the practitioner has come to realize that there must be other factors, not understood, which are as important as
the ones discussed-because for a homig time there have been outstanding advocates of diametrically opposite philosophies as to
treatment of this disease. However, what-ever the practice may be, outside the van-ous centers upholding the two different schools of thought, it is important for us
to understand the basis of each philosophy so that we may compare them in a more on less pure state. This review will attempt to do this, but the reader is warned that the final solution for the problem will not be found in the next few pages. It should become increasingly evident that more knowledge of the actual pathogenesis of diabetes mebhitus, and of the vascular dis-ease associated with it, is urgently needed. It will also become apparent that the claims of both schools of management of diabetes are not supported by the necessary facts, which actually are not available.
One of the difficulties in assessing the effects of the various regimens of manage-ment is that adherents of each plan ap-proach the treatment of patients with a feeling that they have finally “received the
light”
and it would be inhumane of themto deny their special form of treatment to any patient. To our knowledge, there is no report in the literature of a group of patients, treated by the same individual or by the same clinic, of whom half were chosen by random selection to be treated by the aglycosunic regimen and the other half by the so-called free diet regimen.
Let us now consider the reports of the two schools. Jackson amongst pediatricians is the outstanding advocate of a rigid regi-men. He attempts to produce a state of aglycosunia and normal glycemia. Towards these ends, and to provide maximal control, he uses multiple doses of insulin and a weighed diet. In 1950 he reviewed 75 pa-tients from a group of 208 jtmvenibe diabetic patients who had the disease 10 years on more. The disease had begun in all 75
pa-tients below the age of 14% years; 46.6% had retinopathy, 14.6% had cataracts, 16% had
REVIEW ARTICLE
gave control ratings to ti me 1)cLtiemits
(iepemi(l-imlg on the amount of glycosunia lioted! under careful observation and depemiding on the
amount of elevation of the blood sugar. The incidence of retinopathy correlated with 1)0th duration of the disease amid! the over-all comitrol ratings that were assigned. Jackson was of the opinion, however, that the
cata-racts were rebated to the degree and number
of eniois of acidosis but not to the
dura-tion of the d!isease nor the control of the disease. He could miot relate the vascular disease to the age at the onset or the
seven-ity of the dlisease.
The Joslin groump has long been
consid-ened the oumtstanding practitioners of rigid
control of diabetes in the United States. Wilson, Root and Manble6 examined the
rc-suits fri 247 patients who had been followed l)y the Josbin group for 10 years on more.
They fotmnd that one-third of the total
nurn-her had neither retinal hemorrhages nor retinitis. They divided the patients into
de-gnees of comitrol by a system which
in-volved, in addition to the amount of
gly-cosumnia and iiypengiycemia, consideration of how soon after imiception of the disease
insulin was first administered and how as-sidimous the patients were in weighing of
the diet amid how frequently they came
back for follow-up, etc. Using these en-teria they elassffied only 7 patients as under
excellent control; 30 as under fairly good control; 51 as under fair control, and the
remaining 159 as poorly controlled. No
pa-tient with excellent or good control showed
advanced calcification of blood vessels or
retinitis even after periods of 20 on 30
years of diabetes. No case of ncphropathy occurred in patients under good on excellent
control evemi after 20 on 30 years. Others have reponted the same correlation be-tweemi degree of control of diabetes and the
incidence of vascular 12 In most of
these reports, both from the United States and from abroad, the severity of diabetes was estimated to be the same in the well-treated and the poorly-treated groups,
based on the fact that the insulin dosage was approximately the same in both groups.
Though this is not an absolute criterion, Lukenshi recently summarized some
exper-imental evidence to support the opinion that it is of clinical usefulness. In Spoont’s
series the patients with poor control re-quined double the average dosage of in-suhin used by patients with good control. He divided the patients as to control ac-cording to the amount of giycosunia. He then showed that nine of the poorly-con-tnohled patients when admitted to the
hos-pital were easily brought under what he
considered good control by use of a strict diet and insulin. While the methods used to divide the patients into well-controlled
and poorly controlled groups in these van-otis studies are arbitrary, enough different
methods were used to cancel out some of the possible biases.
On the other hand, TolstoP’ reported that of 28 patients who had diabetes oven 10 years, 13 had abbuminunia, 1 had
reti-nopathy and 1 had cataracts. Most of the
patients who had aibuminuria had minimal albuminuria. Of 20 patients reported by Tobstoi with diabetes of less than 10 years’ duration, only 3 had any complication. He also re-analyzed the figures of White7 and found that 45% of the patients reported as
having vascular disease had no
hypergly-cemia, and 40% who had hyperglycemia
were reported as having no complications.
He admitted the evidence from animal cx-peniments that hyperglycemia exhausted the islet tissue, but showed that patients studied did not have an increasing need for insulin in spite of persistent hyperglycemia. He found no interference with wound heal-ing and quoted the work of Minsky14 to
show that hyperglycemia does not favor ketoacidosis of coma.
Mention should be made of the report of Dolger3 who showed the incidence of
vascular degenerative disease is related to
the duration of diabetes and not to the method of treatment or degree of control
* Cliildremi.
of diabetes nieblitus. He found! no apparent
relation to the amount of insulin or the ability to control glycosunia, and no differ-ence between those maintained on a pre-scnibed diet (in an attempt to minimize
glycosunia and hyperglycemia) and those
on a so-called free diet (where no attempt was made to control glycosunia). He also reported that the duration of the disease
was correlated with vascular degeneration,
regardless of the age at onset of diabetes.
He found no relationship between choles-terol and vascular disease, and quoted the article of White7 which reported only 40%
of the patients with vascular disease among juvenile diabetics had a high concentration of cholesterol in the serum. In relation to this, Bock15 found typical retinopathy in
26.4% of Chinese diabetic patients after 7
years with the disease. None of these pa-tients had an elevation of cholesterol in the blood compared with the control series. Twenty-five pen cent of the patients had hypertension. It is apparent from other
work that cholesterol and lipids are not the primary factors in producing vascular
6971
Larsson’ analyzing the results from Liehtenstein’s clinic reported that 73% of the patients who had diabetes mellitus for
over 15 years had some degree of
neti-nopathy; only 39% had retinopathy beyond
the first stage, which corresponds to Wi!-son’s figure of 40% with advanced reti-nopathy. In the series reported by Jackson, 69% had retinopathy after more than 15
years of diabetes but the lesions were less advanced. In the series reported by Larsson
the imicidience of retinopathy uas 55i imi
those who had diabetes 10 to 15 years. Table II records the incidence of vascular disease in several series. Free diets were used in the patients reponted by Lansson and Doiger.
As nearly as can be ascertamed! froni these various reports, the incidence of de-generative vascular disease in patients
treated by the free diet regimen is not greaten than in those treated on a more re-stnicted regimen. It is apparent that hyper-glycemia and glycosunia pen sc are not the factors determining vascular disease. How-even, this does not negate the possibility that patients able to maintain a more nearly normal homeostasis on any regimen may have less vascular disease. The argument is resolved fairly simply if one admits that glycosunia is an index of poor control only when it persists in spite of attempts to pre-vent it. Amongst those who have tried! to
prevent glycoSunia, only Howlesi reported no correlation between the incidence of vascular disease and the degree of control. The answer is that we really do not know what constitutes good control. Using any of the known criteria, there have occurred in everyone’s experience a few well-con-trolled patients with severe vascular changes and a few poorly controlled pa-tients with minimal vascular change. Fun-thermore, as none of the physicians caring for the patients reported in these series tried to have one patient more poorly controlled than another, it is obviously possible that the so-called poorly controlled patients may
represent a group of diabetics with a
differ-TABLE II
INCIDENCE OF RETINOPATHY
Duration
Jacksonu* Wilson’ Dolger3* Howlestm Larssond* Sj)OOflt JI’/iile7* JI’(zgener2
>10 47% 64% 50% 6% 4% 64-76%
10-15 32% 55% 65%
1o-0 63% 44%
>15 69% 73%
ent sort of disease, a more severe form of diabetes or some complicating factor in the disease. Finally, as we shall see later, the
early signs of vascular disease may be
pres-ent before any signs of diabetes mellitus. Therefore, there are two possibilities: 1)
vascular concomitants may be due to some factor other than hypcrghycemia on
gbyco-suria, produced by inability to maintain homeostasis, or 2) some other factor which produces the vascular degenerative changes also causes diabetic patients to be less
easily well-controlled. As an example of
the first possibility, let us arbitrarily sup-pose that the amount of acidosis may be the factor which produces an increased incidence of vascimlan disease. If this were so, a group of patients could be kept free of acidosis as readily with hyper-giyeemia as without it, and certain patients in either group (i.e., with on without hyper-glycemia) would have an increased mci-dence of acidosis and therefore vascular disease. Certainly the patient who is more poorly controlled, according to whatever the proper criterion under any regimen, would tend to have more acidosis. To our knowledge this has not been carefully studied although Jackson correlated for-mation of cataracts to bouts of acidosis. The second possibility is discussed at more length in the following sections.
As it is impossible to determine from reports in the literature whether the treat-ment of one school is better than that of the other as regards the prevention of diabetic vascular disease, the problem may be attacked from a different viewpoint. Let us consider the etiology of diabetes mehhitus and the associated vascular disease, as well as possible factors other than
treat-ment, in the pathogenesis of the vascular
changes.
The development of diabetes depends
upon an inherited potentiality for, or
sus-ceptibility to the disease. The basic cvi-dence in favor of the inherited nature of diabetes according to Josbinbo is : 1) the ab-most simultaneous occurrence of diabetes in both members of pains of similar twins;
2) the greater incidence of diabetes in blood
relatives of diabetics than in those of the control population; 3) the demonstration of mendelian ratios of the recessive type found in a large series of cases selected at random; 4) the demonstration of expected cases in presumably latent cases; 5) the fact that the incidence of diabetics in the gene-ologies of patients with diabetes indicates it is a recessive trait.
In studies of four different series of families”’#{176} where neither parent was dia-betic the incidence of diabetes in sibs of the index case ranged from 3 to 8%. The incidence of diabetes in the sibs of the in-dcx case when one parent, either mother or father, was diabetic ranged from 9 to 15%. Thus it is apparent that diabetes is about twice as frequent among the sibs of diabetic patients who have a diabetic par-ent as among the sibs of diabetic patients who do not have a diabetic parent. White2’ reported that in families where both par-ents had diabetes, 32% of the children de-veboped diabetes as opposed to 9% where only one of the parents had diabetes. These figures are to be qualified to a certain cx-tent as they represent the experience in the Joshin Clinic at the time of writing whereas if all patients were followed to the time of death the incidence might be higher. Table III shows the incidence of diabetes amongst sibs of diabetic patients; there are no sex differences.
TABLE III
INCIDENCE OF DIABETES AMONGST Sums OF DIABETIC PATIENTS
(ArER STEINBERGR)
Author Harris’7 Thompson’9 Steinberg#{176} VonKries” White21
No. of famnilies 141 1631 1981 1305
-Neither parent (liabetic 3.5% 7 .7% 4.7% 3.
Oneparentdiabetic 11.7% 15.5%
Both parents (liahetic
* Imicludes all progeny of adult patients followed at Joslin Clinic.
has not been recognized. Steinberg there-fore concluded that 60 to 80% of those genetically liable to diabetes are not recog-nized by present methods of examintion. Many diabetic patients with a diabetic parent develop diabetes at an earlier age than did their parents. One-fourth of the siblings of a patient with diabetes would be genetically liable to diabetes if neither parent is diabetic. When one parent is dia-betic about half the sibs will be susceptible, and when both parents are diabetic 100%
will be genetically susceptible to diabetes. The factors that precipitate development of diabetes are not known. Joslin16 sug-gested three factors : 1) In childhood hy-perpituitarism caused diabetes. He based this on the finding that diabetics were taller when diabetes was first noted compared to the average of the population. However, most have not confirmed this finding. 2) In women at the menopause there is a higher incidence of development of diabetes, produced by an overexcretion of pituitary hormones. He infers this ex-cess excretion from the increased amount of pituitary gonadotropins in the blood. There is no definite evidence for this
theory. 3) Obesity; this is important in the development of diabetes in middle-aged adults who frequently can be relieved of the disease by reduction in weight but it is of little importance in the development of juvenile diabetes.
Certainly there is experimental evidence that pituitary hormones can produce
dia-11.4% 8.9% 9%
betes. Removal of the hypophysis has ameliorated diabetes, as shown by the ebas-sic experiments of Houssay and 2627 However, there is no evidence of any cmi-cally significant participation of the
pitui-tary in precipitating diabetes except as part of the general reaction to stress. Preg-nancy precipitated diabetes in 5% of the patients followed in the Joshmn Clinic and
also was shown to correlate with the
tempo-nary appearance of diabetes, followed by remission after delivery. Though infections exacerbate clinical diabetes, Marble28 does not believe that infections initiate or pre-cipitate the disease. The Joslin group foimnd only 10% of juvenile diabetics studied by them had a significant infection within the year prior to the onset of the disease. How-ever, others have found a higher incidence of infection shortly before, on simimbtaneous with the onset of diabetes. This, of course, raises the question of whether the infection merely brought the patient to a physician and the diabetes was then recognized. However, in children the period of well be-ing after the onset of the first symptoms of diabetes is relatively short so this qimestion does not entirely negate the results.
Determination of which of the genetically
989
cortisone. Only 3% of individuals without a
family history of diabetes responded in this fashion. The glucose tolerance curves of both groups were normal when the tests were done in the usual fashion. These
au-thors suggest that this may be a method of discovering future diabetic patients. At least these patients are more susceptible
to the diabetogenie effect of cortisone. The administration of adrenal corticoids to
normal individuals produces httle on tempo-nary intolerance to carbohydrate in contrast to more prolonged and greater effects ob-served in patients with diabetes. Another possible method of detection of a tendency to diabetes will be mentioned in the see-tion on sulfonylureas.
The genetic aspects of the disease are
very important for consideration of devel-opment of vascular degeneration as will be seen below.
Ditzcl3’ and others have correlated vas-cuban changes in the bulbar conjunctiva
with those in the retina of patients with diabetes. There is a higher incidence of
these changes in patients with diabetes
melbitus than in normals. He also studied
75 children born of normal mothers and 75 children born of diabetic mothers.32
Nineteen of the children of diabetic mothers
were born before, or coincident with the
recognition of the disease in the mother. These authors found that 77% of children born of diabetic mothers had changes in the conjunctival vessels of varying degrees. Seven of these children had frank diabetes, 13 had borderline glucose tolerance tests and 55 had normal glucose tolerance tests. Sixteen per cent of the normal children, of the same age as the children born of dia-betic mothers, had minor irregularities of the venules or a few of the capillaries had an angular course. The vascular changes in the children born of diabetic mothers eon-rebated with obesity and with the degree of true diabetes. The children of diabetic mothers were said to have been tall as well
as obese, to have had advanced bone age and dental development and high excretion of 17-ketostenoids in the urine; no figures
were given for the latter. This high mci-dence of vascular change before the onset of diabetes is very striking-all the more dramatic because, as discussed above, many of these children would not be expected to develop diabetes. These findings, though striking in their quantitative aspect, are not entirely unexpected qualitatively as
many patients are discovered to have
dia-betes by the ophthalmologist’s finding of the vascular changes. In addition Becker33 has seen diabetic retinopathy in patients even before they developed abnormal glu-cose tolerance responses. Patients with dia-bctes mehlitus have a predisposition to vascular disease even before the metabolic disorder is apparent. Why do some of them develop the changes before others and to greater degrees? This is merely a quanti-tative difference, because it is apparent that some degree of vascular change presents in
every diabetic if the duration of the dis-ease is long enough.
Dohan and Lukens34 have produced dia-betie retinopathy in a dog made diabetic for 5 years by the injection of pituitary extracts. Alboxan diabetes in rabbits does not lead to the appearance of diabetic
retinopathy. However, when Becker gave
adrenocorticotropin (ACTH) to alboxan dia-betic rabbits, diabetic retinopathy did de-velop. In addition, Rich et have pro-duced lesions like those found in
Wilson-Kimmelstiel syndrome in the kidneys of
rabbits by giving compound F on compound E. Diabetic retinopathy may appear during pregnancy and then disappear completely following 3 Furthermore,
exacer-bations of pre-existing diabetic retinopathy with pregnancy and amelioration after
of the Wilson-K.immelstiel syndrome were
24% greaten than those of a group of
dia-betics without this syndrome. Unfortunately the adrenal enlargement may be the re-sult, rather than the cause of the renal lesions in the Wilson-Kimmelstiel syn-drome. Sommens7 found a mucopolysac-ehanide similar to that found in the
kid-neys in the Wihson-Kimmelstiel syndrome
in the kidneys of cortisone-treated humans
without diabetes. The characteristic
mor-phoiogic changes in the kidneys in the Wilson-Kimmelstiel syndrome were not found in the cortisone-treated non-diabet-ics. Incidentally, the polysacchanides of serum are elevated in diabetics with vascu-lan degeneration and are normal in other diabeties38, 39
Amelioration, on at least arrest of the progressive worsening of diabetic reti-nopthy has been reported following ad-nenalectomy and following
hypophysect-omy.40’2 In addition Poubsen3 noted
re-eoveny from diabetic retinopathy following the onset of Simmonds’ disease. All these findings indicate some connection between adrenal cortical fumnetion and vascular changes in diabetes. However, ameliora-tion following adnenalectomy may merely mean that the adrenal hormone, necessary
only for its permissive action, has been lost.
The same can be said for hypophysectomy which obviously involves other factors as well.
To show that an excess of adrenal corti-coids produces the vascular concomitants of diabetes melhitus would require
demon-stration that adrenal cortical activity was greater in those patients in whom the more severe vascular changes were to develop in the future. There is no such evidence.
Is there evidence of hyperactive secretion of adrenal conticoids in any patients with diabetes melhitus before the development of vascular disease? Klein et have shown that adrenal corticoids in the serum increase dramatically in diabetic acidlosis. Previously, MacArthur et a!. had provided additional evidence of adrenal
hyperactiv-ity in diabetic acidosis and coma.45’7 More
recently Klein et al.48 have shown that
pa-tients with juvenile diabetes, presumably in good condition, had a higher concentra-tion of circulating free eorticoids in the serum than normal children the same age. The eoncentraion of circulating free conti-coids correlated with the degree of acido-sis as measured by depression of CO2 in the serum and by the amount of gbycosunia.#{176} The question still remains, which is cause and which is effect? In other words, did the stress resulting from lack of proper
eon-trol, leading to acidosis, cause overactivity of the adnenals on did hyperfunction of the adrenals make it more difficult to prevent acidosis? Do diabetic children have high concentrations of corticoids before they have diabetes melhitus on its vascular eon-comitants? For instance, do children born of diabetic mothers have a high concentra-tion of circulating free conticoids? There are three bits of evidence suggesting that there is hyperactivity of the adrenais in these children, although none of them is the proof needed. In Ditzcis’ study32 mentioned previously, it was reported that excretion of 17-ketosteroids was increased in the chil-dren he examined born of diabetic mothers. However, this correlated with changes in the vascular pattern of the conjunctiva so that these children already showed some of the vascular changes when increased adrenal function was noted. Furthermore no figures were given for the excretion of 17-ketostenoids.
450 carried oumt an interesting
study in newborn infants born of diabetic mothers. He found that the excretion of 17-ketostenoids and of conticoids was greater in children born of diabetic mothers than in children born of normal mothers. However,
it has been shown by Klein5l and by Migeon52 that the conticoids excreted by the normal child in the immediate neonatal period are the result of transference from
* Mortimer et al. found no differemice in urinary excretion of corticosteroids in patients with
dill-betes mellitus whether they had vascubar changes
REVIEW ARTICLE
time mother. IIoet53 has denionstrateci
corti-COldS imi time amimniotic fluid of a child of a
(hal)etic mmiother, whereas the amniotic fluid of children born of normal mothers
con-tains no free conticoids. These findings may
nienely indicate that the mothers with dia-1)etes have greater concentration of circu-lating corticoids than normal mothers, and
there is a greater transference, therefore, of
maternal conticoids to the amniotic fluid
and into the child. We know of no studies that record data on the circulating conti-coids in diabetic mothers. The findings in regard to 17-ketostenoids are different. Gardnen5 has shown that the fetal adrenal apparently produces androgen because the concentrations of 17-ketostenoids in the cord blood are greater than those in the ma-tennal blood at the time of delivery. There-fore, an increased excretion of 17-ketoster-oids may not be explained away with cer-tainty by postulating that the mother has a greaten concentration of 17-ketosteroids in the serum. However, this may represent a response to stress in utero, possibly such as stmggested by Berglund,55 i.e., the child born of a diabetic mother may come from a more stressful milieu than does the child bonn from the uterus of a normal mother.
Aker-r#{233}n5mentions a report by Hubtquist stating that stibhbonns of diabetic mothers have barge adrenahs. However, Warren and Lc-Compte37 found no abnormalities of the adnenals in such cases. Indeed, they showed
that the figures for adrenal weights of
normal newborns were inadequate, as 50%
of both the control babies and children of diabetic mothers had adnenabs that were overly large. We could not find in the hitera-tune any convincing report of adrenal hy-penpiasia in children bonn to diabetic mothers.
As the children in the series of Klein48
were free from obvious vascular degenera-tion, it follows that some children with diabetes have excessive concentration of
corticoids in the serum before they have
advanced vascular degeneration. Unfortun-ately, it is not known whether these are the children who will develop vascular
degen-eration sooner amid! iii a niore severe fashion.
The possibility that hyperactivity of time
1L(lnemmals is mmot secondary to varying
de-grees of disordered metabolism in dia-betes melhitus is even more speculative. It
would require some evidence that the chil-dren who are going to develop diabetes have hyperactivity of the adnenals in the months after birth when the possible ef-fects of maternal hormones are gone and when the children would have recovered from any stress which being born of a dia-betic mother might have pnodtmced. Then we could say that the hyperfunction of the adrenals was directly genetically deter-mined or was produced by the unknown metabolic defect that causes diabetes mel-bitus. Whether any hyperactivity of the adrenabs might be mediated through the
pituitary or not is not germane to the
dis-cussion.
Let us summarize the relation of adrenal cortical function to vascular changes in diabetes, as we understand it. Adrenal con-tical hormones can produce changes which mimic some, but not all of the changes as-sociated with vascular disease in diabetes, and these changes do not occur in dia-betics in the absence of adrenal corticoids. Hyperactivity of the adrenals exists before the development of major vascular changes. It is possible that it occurs before the ear-liest changes described by Ditzeh42 but this has not been proven. However, there is no evidence to show that hyperactivity of the adnenals is found in greaten degree or only in those diabetics who will develop vas-cular changes more rapidly and severely. While it is the authors’ opinion at the mo-ment that adrenal corticoids are involved in the production of the vascular con-comitants of diabetes, we know of no way of proving this at present. Even if hyper-activity of the adrenals was proved to con-relate with future vascular changes this could merely mean that both were caused by the same factor. In any event, even if excess corticoids mediate the vascular changes, we believe they are secondary
In connection with these endocrine fac-tons some consideration should be given to the problem of growth in diabetic children. Though most other writers disagree with the findings of White that diabetic chil-dren are taller than normal before the de-velopment of diabetes, all agree that a certain percentage of diabetic children are dwarfed. This was first described by Nob#{233}-count in 1919.58 Most of the children who
are dwarfed have hepatomegaby, in fact White59 found an incidence of 25% of hepa-tomegaly in all children she studied who had had diabetes 15 years or more. Engle-son6#{176}reported 40% of juvenile diabetics he studied had liver dysfunction. However, some of the patients so classified had only minimal changes by very sensitive tests. Mauriac6’ described the combination of dwarfing and hepatomegaly and this syn-drome beans his name. Little attention has been paid to it in the American literature though the problem exists. The patho-genesis is not entirely clean. Several have suggested the dwarfism is the result of hypopituitanism. White5 believed pituitary extracts were useful in accelerating growth. However, the extracts used apparently all had gonadotropic activity and the re-suits seem to have been the same as one would expect with testosterone. Further-more, White stated that since the use of long-acting insulin hepatomegaly and dwarfism were no longer problems. Dwarf-ism and hepatomegaly, already present, disappeared when long-acting insulin was administered. Lansson4 mentioned that dwarfing and hepatomegaly were no longer a problem after they provided a free diet regimen for the patients. With better con-trob, by any criteria, dwarfism and hepato-megaly are alleviated. However, if dwarf-ism is of long standing, final average height may be less than the average in the general population or amongst other dia-betics. One shouhd also remember that in-sulin itself has certain growth promoting
effects62 It seems most likely that the signs
of hypopituitarism in these diabetics, such as retarded sexual maturation, are similar
to those seen in other chnomiic d!isease, e.g., congenital heart disease, where retarded sexual maturation and dwarfing may occur. Frequently with improvement of the gen-era! health, following cardiac surgery or better treatment of the diabetes, these signs tend to disappear, the patient begins to excrete gonadotropin, begins pubesence and has a normal growth spurt.
We must understand the basic defect which leads to the disordered metabolism of diabetes mellitus before we can properly approach the problem of the vascular con-comitants. Minsky has held for years that many if not all cases of diabetes might be produced by excessive destruction of
in-suhin rather than deficient production; either would give the same clinical picture. At the moment it may not be too important to determine whether the classic theory, deficient production of insulin is correct.
It is important to investigate means of
affecting the rate of destruction of insulin.
A variety of compounds, notably agents
promoting plant growth and materials cx-tracted from liver tissue, have been found to be competitive inhibitors of insulinase. These agents produce an hypoglycemic re-sponse when administered by mouth to normal animals, but not in ahhoxan diabetic
animals.68
Franke and Fuchs, Achehis and
Hande-beck66 and Bertram Benfeld and Otto65 re-cently demonstrated that oral administra-tion of
1-butyl-3-p-amino-benzenesubfony-lurea eliminated the need for exogenous in-sulin in many adult patients with diabetes mellitus. Mirsky66 demonstrated that the
sulfonylureas (he found
dis-REVIEW ARTICLE
(‘lSC in those vith onset l)efOre the age of 30 years. When diabetes was demonstrable imi the first decade of life, the correlation of hypoglycemic response to sulfonylurea with duration of disease was twice as good as it was with age at onset. In the next decades the ratio was even greaten until the decades after 40 were reached, when the ratio decreased because the response was almost invariable. From those studies it becomes apparent that nearly all, if not all, patients with diabetes have insulin avail-able early in the disease. Mirsky68 has also obtained preliminary data which suggest
that diabetic patients have more insulinase
activity in the liven than do normals. If this should be confirmed it would seem likely that the disturbance of carbohydrate metab-obism in diabetes is generally the result of an excess of insulinase or a deficiency of insulimiase inhibitor. Secondarily, if this inference is true, the pancreas eventually becomes exhatmsted.
The great advantage of these agents and of the hoped-for competitive inhibitor of insulinase is not so much that they can be taken by mouth but that they permit en-dogenous insulin to act from minute to minute as the need arises. Thus they should
make for a mucil more nearly normal homeostasis.
In addition, the agents may enable pen-sons with incipient diabetes to be dis-covered before the disease is manifest. When Minsky67 gave subfonylurea to non-mal individuals there was an immediate sharp decrease in blood sugar. The con-centration of blood sugar was then main-tamed slightly above the minimum for several hours. The same substance when administered to responsive diabetic pa-tients failed to produce the immediate hy-poglycemie response btmt produced a slowly appearing hypoglycemia which reached the lowest point only after 5 hotmrs. Minsky in-terpreted this to mean that the initial ac-tion of sulfonylunea in the normal is to re-lease stoned insulin; the diabetic has none. Relatives of patients with diabetes mellitus might show this delayed hypoglycemic
re-SP0I15C to suifonylurca, amid! thus might be discovered before the disease became mani-fest.
What are the implications of these find-ings as regards the development of vas-cular concomitants of diabetes mellitus? If vascular changes are the result of in-ability of the organism to maintain normal homeostasis even with the help of exoge-nous insulin and special diet, then the vas-culan complications should be minimized. Obviously this presupposes the sulfony-luncas will prove to be nontoxic (all non-competitive inhibitors must be suspect be-cause of the lack of specificity) or that a specific competitive inhibitor will be de-veboped. However, success of such agents does not depend on whether the changes produced by lack of normal homeostasis
may be mediated through increased adrenal activity or some other factor.
If the degenerative vascular disease is produced by lack of insulinase inhibitor, supplying the inhibitor should prevent the vascular concomitants of the disease.
If the vascular changes are produced by some other genetic factor, associated with lack of insulinase inhibitor or causing
hy-penactivity of insulinase, there is no remedy
at the present time. However, in this era of rapid advance in our understanding of the disease, pessimism is not warranted. The sulfonylureas may prove to have 5cr-ious drawbacks (medical history is replete with disappointments following too hasty acceptance of new agents without stiff!-cient study), and a specific competitive
inhibitor may not be immediately
forth-coming, but there is reason for confidence that the vascular changes associated with diabetes mellitus will be eliminated in the future.
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