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The Management of Diabetes Mellitus in General Practice
THE MANAGEMENT OF DIABETES MELlITUS IN GENERAL PRACTICE ELLIOTT
P.
M.D., Se.D., F.A.C.P.*
JOSLIN,
Two outstanding diabetic discoveries were made in 1943: first, the production of diabetes by the administration of alloxan and, second, the demonstration of a hitherto unsuspected incidence of diabetes in young men. In addition to these achievements, I also point out to my patients the growing importance of the complications of diabetes because of their increasing exposure to them due to the steadily lengthening diabetic life. No matter whether my patients are young or old, I like them to be au courant with investigations going on in connection with their disease which, after all, is largely up to them to manage and control. ALLOXAN AND HOPE FOR BETTER DAYS FOR DIABETICS
Alloxan is the ureide of oxalic acid and has the formula: H
'"
N-C=O
I I
I I
O=C
H
/
c=o
N-C=O
One might look upon uric acid as a three-story house with an "L." Tak~, away the "L" and alloxan remains: H
'"I
N---C=O
o=c I
/
H
I
H", C----N )c-o
11
N----C----N
H
/
Alloxan has been known for years and was recognized as a component of the body in 1862 by Liebig,l but no satisfactory test for it has been described and its unstable composition makes it elusive. It has been utilized as an oxidizing and reducing agent. From the George F. Baker Clinic, New England Deaconess Hospital. • Clinical Professor of Medicine Emeritus, Harvard Medical School; Medical Director, George F. Baker Clinic, New England Deaconess Hospital; Consulting Physician, Boston City Hospital. 1054
DIABETES MELLITUS IN GENERAL PRACTICE
1055
In 1937 Jacobs 2 found that following the injection of alloxan into an animal, hypoglycemia occurred, but it was reserved for Dunn, Sheehan and McLetchie3 in Glasgow in April, 1943, to note its selective action in causing the necrosis of the islands of Langerhans of the pancreas of a rabbit. Such animals died within 14 to 22 hours after the injection of 0.2 mg. of alloxan per kilogram of bodv weight. For a brief period the blood showed hyperglycemia, but this was soon followed by hypoglycemia and death. Cab ell Bailey and Orville Bailey,4 believing diabetes would be inevitable in such an animal if life could be prolonged, administered repeated injections of glucose to such rabbits and found that diabetes appeared in the next 24 hours. A summary of seventeen articles upon alloxan occurs in the New England Journal of Medicine for April, 19445 and another article reporting original work by Bniley, Bailey and Leech appeared in the same journal May 4, 1944. They observed that all alloxan diabetic rabbits developed cataracts within two months of the production of the diabetes. The significance of alloxan diabetes is far-reaching. It strikes nearer the core of the diabetic problem than anything hitherto reported. Here is a chemical which undoubtedly is to be 'found in the body, of which an excess can destroy the insulin-producing cells. What is its source? What influences its formation or destruction? What will neutralize its action? Does it first stimulate the island cells to secrete and thus exhaust them, or more likely is its power of producing necrosis exercised from the start? How can one recognize its presence? These are only a few of the questions which arise. Obviously alloxan presents opportunities for research in diabetes hitherto undreamed of and gives hope to patients and practitioners alike for further advances in the management of the disease. The production of diabetes in rabbits, rats and other animals in such a pure form is now so simple that studies of the disease and its complications are open to all who desire to make them. DIABETIC DIVIDENDS FROM SELECTIVE SERVICE
I. Disclosure of Unsuspected Incidence of Diabetes.-Blotner, Hyde and Kingsley6 have reported studies upon 45,650 selectees and volunteers among whom they found 208 cases of diabetes, 126 individuals with transient glycosuria and 33 individuals with what they term renal glycosuria. This is at least three to four times as high a diabetic incidence as was recognized in the National Health Survey study at ages under 25 and from four to five times at ages 25 to 45.- The National Health Survey figures were based on a house to house canvass-hearsay evidence-in contrast to those of Blotner, Hyde and Kingsley, which were based upon actual analyses of urine and blood. If such discrepancies exist in diabetic incidence at selectee ages, is • For a full discussion of these surprising and almost startling results, see an exhaustive editorial in the Journal of the American Medical Association. 7
1056
ELLlOIT P. JOSLlN
there any reason to doubt appreciable differences at other ages of life and "that current estimates of the amount of diabetes in the population are falsely optimistic"? The significance of these data in the general management of the disease is many fold. First of all, it will make our people far more diabetic-conscious and far more eager to come to the doctor to learn if they have the disease. Already they have become alert to the influence of heredity. Once their disease is diagnosed, they desire prompt treatment and this affords the physician a chance to treat a case with recent onset, and such patients offer far better prognoses. 2. Patients with an Original Diagnosis of Diabetes Eventually Accepted into Armed Forces.-During this year's follow-up of our 1626 childhood diabetics known to be alive at sor.: time during 1942 or 1943, it was found that 7 were in the armed forces. As the sex of diabetics differs little in this age group, it follows that nearly 1 per cent of our boys were not considered or recognized to have diabetes when they became men and were examined for t:he Army. What is the explanation? Salient facts are recorded in Table 1. A study of the protocols of the cases cited in Table 1 shows that the ages of the boys when the original diagnosis of diabetes was made varied between 6 and 14 years, and the interval between diagnosis and their induction into the Army, although not known exactly, was probably between 11 and 5 years. Heredity was known in three of the seven cases. Weights or heights were not extraordinary, although one boy weighed 192 pounds dressed, and his height with shoes was 5 feet, 8% inches. The first case, 10464, I will throw out at once, because although the patient showed 0.9 and 1.1 per cent glycosuria, and blood sugars of 210 and 200 mg. with venous blood, I find by my records he had f~runculosis. That is a warning against making a diagnosis in the presence of an infection of any character until it has been verified by subsequent tests when the infection has disappeared. It is true that all of these patients were recognized at the time to be rather borderline diabetics, because in no instance did a patient receive insulin save temporarily, and the carbohydrate in the diet of no patient was lowered below 200 gm. save in case of the 6-year-old child, and even his diet was gradually raised within 2 years to practicallyeverything. For the sake of argument, it is assumed that none of these patients has diabetes now, but of course that cannot be verified. All of the cases showed glycosuria and in three of them it reached between 1.1 and 2.2 per cent, but glycosuria alone, even of considerable proportions, does not justify a diagnosis of diabetes. All of the fasting blood sugars were normal, but this is a common occurrence in frank diabetes in young people, particularly in the first months of their disease. On the other hand, in no instance did the
TABLE I.-SEVEN CASES ORIGINALLY DIAGNOSED DIABETICS EVENTUALLY ACCEPTED INTO ARMED FORCES
Age at Body Case Diag- Weight No. nosis (Lbs.)
Sugar Date
Time
Urine (Per Cent)
Blood (Mg.)
-----1----1----1-------------------10464
6
41 (D)
4/ 5/31
4/ 6/31 11975
8
70 (D)
6/28/33
1 hr. after lunch 8:30 P.M.
1 hr.
"
14
182 (N)
2/23/35
"
"" ""
~,
Fasting
'""
i,
Fasting
! hr. after 100 gm. glucose "
2 hrs."
""
""
tr. tr.
o o
o o
o
d
! hr. after 100 gm. glucose 1 hr. " ".c .,
1 hr.
12/29/36
d"
"
Fasting
2 hrs."
2/ 8/36
""
! hr. after 50 gm. glucose 1 hr. " 2 hrs. ,.
13219
1.1
! hr. after 42 gm. sucrose 2 hrs. "
11/29/34
0.9
"
"
Fasting ! hr. after 100 gm. glucose 1 hr. " et" " 2 hrs." "" "
210 200
250 160 ?C.B. 140 100 170 150 120
o
100 160 150 130
o
110 200 150 130
o
100 170 liO 130
0.2 0.3 1. 2 0.2 1. 9 o7 0.2 0.8 0.8
V.B.
C.B.
V.B.
V.B.
V.B.
- - - - ----1----1------·_------- - - ----13386
9
50 (DJ
1/28/35
1/31/35
Fasting ! hr. after 50 gm. glucose " 1 hr. " " " 2 hrs." " " "
13
86 (DJ
1/30/35
o
o o
Fasting
90 200 140 100
0.1
80 180 210
! hr. after 50 gm. glucose
0 0 0
90 120 210
Fasting
o o
80 210 220 100
! hr. after glucose 1 hr."
13387
o
0.2
"
Fasting
C.R.
C.B.
C.B. hr. after 2nd 50 gm. glucose -----1----1--·--·- - - - - - - - - - - - - - 1 - - - - - - - 14673 13 94 (DJ 6/29/36 Fasting o 80 ! hr. after 100 gm. glucose o 180 V.B. 2.2 130 1 hr. " "" " 2 hr. " H" " 0.3 130 ---- - - - 1 - - - - 1 - - - - 1 - - - - - - - - - - - - - - - - - - - ' 13 16042 79 (N) 10/ 7/37 Fasting 80 V.B. ! hr. after 70 gm. glucose o 190 C.B. 1 hr. " " " (( o 180 2 hrs." "Co " o 140 ~
12/30/37
! hr. after 100 gm. glucose 1 hr. " 2 hrs."
"" ""
(C
••
0.2 0.6
D, dressed; N, naked; tr., trace; V.B., venous blood; C.B., capillary blood. 1057
V.B.
1058
ELLIOTT P. JOSLIN
blood sugar return to or below the normal value at the end of two hours. Therefore, according to this criterion diabetes was correctly diagnosed, but we have not been accustomed to consider such a procedure as a trustworthy diagnostic method. Capillary blood sugar determinations were certainly employed in two and p9ssibly three cases. In one of them, Case 11975, in which the patient was a child of 8 years, 42 gm. of sucrose was given and thereupon the value reached 250 mg. Our rule is to consider the normal fasting value of capillary blood to be the same as venous blood, but the upper normal diagnostic value with capillary blood in a sugar tolerance test to be under 200 mg. This case, therefore, was diagnosed diabetes. However, we had our doubts because of a second test, this time with 50 gm. of glucose, in which the capillary blood failed to rise above 170 mg. and therefore did not reach a diabetic level. On the other hand, with Case 16042 the tests were carried out with both capillary and venous blood, and with 70 gm. of glucose with capillary blood the diagnosis failed to show diabetes, but with 100 gm. of glucose with venous blood, the blood sugar rose to 220 mg. All in all, therefore, the fact that 7 patients originally diagnosed diabetics but possibly wrongly so diagnosed, were admitted into the Army, shows the necessity of caution, especially if any doubt exists, in designating an individual a diabetic when the fasting blood sugar is normal, even if the 2-hour blood sugar test shows no return to the original fasting value or the intervening tests rise with capillary blood to 200 or even above 200 mg., or with venous blood to 180 or as much as 220 mg. Moreover, no diagnosis of diabetes should be made if an infection is present unless the glycosuria and blood sugar values are outstanding at the time or tests are repeated when the individual is free from infection. As a matter of fact, invariably it has been our rule for some years to record the temperatures at the beginning and end of the test. Nevertheless, in 99 per cent of our cases, so far as we are aware, the original diagnosis has proved correct, and this is reassuring. 3. Diabetes Diagnosed Early Responds Well to Treatment.-Years ago I was able to show that the individual supposedly well but found to be diabetic by an examination for insurance outlived his neighbor whose diabetic symptoms forced him to consult his physician. Recently a group of Army cases has been referred to me for treatment, in which the presence of diabetes was learned because of Selective Service examinations. Improvement in these cases has been rapid despite .apparent severity. The diabetes in the patient I now present to you, Case 24001, 29 years of age in December, 1943, did show symptoms for a very few weeks before it was discovered and so it is not absolutely typical of the diabetes recognized by insurance or Selective Service. The case serves my purpose, however, in that the patient shows a rapid im-
1059
DIABETES MELLITUS IN GENERAL PRACTICE
provement, although at his first visit on December 28, 1943, the glyand the blood sugar 333 mg. cosuria was 8 per cent, diacetic acid No hospital bed being available, he was treated through the office and kept on with his work. His course is shown in Table 2. Diet.-Simplification of diet is necessary today for doctors and patients. I am accustomed to follow this plan. By prescribing four portions of 5 and 10 per cent carbohydrate vegetables daily, one can assume with considerable probability of accuracy that the carbohydrate content of the same will be 20 gm. To this can be added 10 gm. of carbohydrate which is represented by a half-pint mixture of equal parts of milk and cream. A bowl (large portion) of cooked oatmeal contains another 20 gm. of carbohydyrate, making a total for the vegetables, milk and cream mixture and oatmeal of 50 gm. A second
++
TABI,E 2.-0FFICE MANAGEMENT OF DIABETES OF RECENT ONSET
Sugar Date
Dec. 28, 1943 29 30 31 Jan. 3, 1944 17 21 28 Feb. 9 Apr. 10
Urine (Per Cent)
Blood (Mg.)
8.0 8.4 2.9
333*
.
"
0 0 0 0 0 0
Diet (C.)
... .
200
74 76 71 152 89 110 62
"
....
"
" " "
.,
"
Weight Dressed (Lbs.) 166
...
165 165 169 167 169 166 165
Insulin
8+@ 12 +@ 12 + 24. 1?+(f4l 8 + @) 4+@ @ @ @
* All of the blood sugars were taken in the late forenoon, except those of January 21 and February 9, which were taken after lunch. 50 gm. will be represented by three medium-sized oranges, thus raising the total carbohydrate to approximately 100 gm. To this can be prescribed bread, estimating that one slice, approximately an ounce (30 gm.), contains not far from 15 to 18 gm. of carbohydrate. This man was given six slices or a total of 100 gm. (90-108) which, added to his previous allowance, made the final carbohydrate in the neighborhood of 200 gm. With most patients the bread at the beginning is liIl}ited to three slices a day, making the total carbohydrate 150 gm. Subsequently, the diet can be altered with substitutions for fruit, cereal and bread. If glycosuria is avoided, it is easy to add weight by increasing the percentage of cream, or to reduce weight by its omission. The patient was told to take meat, fish, eggs, cheese and butter in moderate quantity, with the hope that the protein would be not far from 100 gm. and the fat 100 gm.
1060
ELLIOTT P. JOSLIN
It is surprising how many patients do so well on this schedule that their hospital reservation for three weeks later is cancelled. I still think the hospital-educated diabetic is overwhelmingly safer than the office-treated case, but with no beds available one is forced to treat his patients in an ambulatory fashion, although even then I try to get them to attend at least some of the hospital classes. lnsulin.- This patient received at the office 8 units of crystalline insulin and 12 of protamine zinc insulin, and the following morning 12 units of crystalline and 24 units of protamine zinc insulin. This was continued for five days, when a glycosuria and a blood sugar of 76 mg. led to a revision of the order to 8 units of crystalline and 18 of protamine zinc insulin, which were continued for 2 weeks when again the crystalline was lowered to 4 units and the protamine zinc to 16 units. I always like to give insulin in multiples of 4, because it is so much more easily registered on the syringes we prefer our patients to use, namely, a I-cc. syringe divided into tenths. Still later, crystalline insulin was omitted and protamine zinc insulin reduced to 12 units. For stilI milder cases in older patients, 8 units of protamine zinc insulin may be prescribed at the first visit and subsequently raised or lowered, remembering that with diet alone glycosuria will fall and with insulin will decrease still more rapidly. Furthermore, one must bear in mind that the full effect of the protamine zinc insulin will not be manifested until the third day. In general, one attempts to control the diabetes with diet and protamine zinc insulin and only adds crystalline insulin when the protamine zinc insulin has risen to 20, 24 or 28 units, above which one hesitates to go for fear of an insulin reaction during the night. However, many patients learn to control their diabetes with even larger quantities of protamine zinc insulin alone and no universal rule can be made. It is our practice to inject the crystalline and protamine zinc insulin separately. In certain clinics the two are mixed in the same syringe, but our experience, particularly with children, has prejudiced us against such a procedure. In diabetes one is dealing with many variables-exercise, diet and insulin-and if one introduces still another variable factor by mixing the two insulins, in our hands the results have not been favorable. For the same reason we hesitate to adopt other insulins which in themselves would be infinitely better than no insulin, because we do not wish to expose our patients to reactions at unaccustomed hours of the day. In general, with Hamlet, we prefer to "bear those ills we have than fly to others that we know not of." With patients taking protamine zinc insulin alone, if the urine voided on rising, or a specimen voided half an hour later to guard against the presence of sugar which may have accumulated in the bladder overnight, is not sugar-free, we are accustomed to add 4 units of protamine zinc insulin until the urine voided on rising is sugar-free
DIABETES MELLlTUS IN GENERAL PRACTICE
1061
or until about 20 to 28 units are injected. If then it appears that glycosuria is present fasting or even after meals, crystalline insulin is added in 4-unit doses and usually eventually will reach one-third to one-half that of the protamine zinc insulin. CAUSES OF DEATH DURING 1942 AND 1943 AMONG DIABETICS WITH ONSET OF THE DISEASE IN CHILDHOOD
Diabetic children live and some of them live a long while, so long in fact and so comfortably that often the tendency is to pursue with them a laissez faire policy as regards control of the disease. Subsequent to the first observation of a lO-year-old diabetic child in our group, the Metropolitan Life Insurance Company calculated its life expectancy, regardless of the duration of diabetes, and found it to be 40 years. But diabetic children do not all live those 40 years and, therefore, the causes of death of 23 during 1942 and 1943 among our 1626 diabetics with the onset of their disease in childhood deserve notice. At present 45 of the 1626 are untraced and there may be a death among this number. The reported causes of death are shown in Table TABLE 3.-TWENTY-THREE DEATHS IN 1942 AND 1943 AMONG 1626 DIABETICS WITH ONSET IN CHILDHOOD
Infections: Staphylococcus aureus. . . . . . . . . . .. Cavernous sinus thrombosis. . Pneumonia. .... Meningitis. . . . . . . . . Whooping cough. . . . . . . . . . . . . . . ..
1 1 1 1 1
Bums.............. Coronary thrombosis. . Diabetes. . . . . . Appendicitis. . . Coma............... Nephritis ..........................
1 2 5 2 4 4
3. The average duration of the diabetes was 10.7 years and average age of the patients at death was 20.2 years. I. An Infection Neglected.-I will not discuss here deaths from infections, one each with Staphylococcus aureus infection, cavernous sinus thrombosis, whooping cough, meningitis and pneumonia, but instead wish to show you Case 16593, a longshoreman, who is leaving the hospital today, because he illustrates the harmfulness of a laissez faire policy in dealing with infections, even though mild at the outset. This man, who developed diabetes in July, 1937, at the age of 37 years, consulted me the following year with a 5.1 per cent glycosuria and a blood sugar of 290 mg., and was discharged with a normal blood sugar and a diet of carbohydrate 160, protein 90 and fat 125 gm. and 8 units of protamine zinc insulin. He was not seen again until a few weeks ago when he entered the hospital with a tender right flank and abdomen. There was a previous history of a succession of boils and a carbuncle dating back 6 months. Investigation soon revealed symptoms and signs pointing to a paranephric abscess which was drained. After some weeks the patient again returned with discomfort below the right shoulder joint, comparatively little pain and only slightly elevated temperature, hoth characteristic features of diabetes with infection, and the localized collection of pus would have been easy to overlook had not our surgical friends, Dr.
1062
ELLIOIT P. JOSLlN
L. S. McKittrick and Dr. Francis D. Moore, disclosed it with a hypodermic needle. Fortunately it had not reached the shoulder joint and with wide opening of the area the condition rapidly healed. The patient leaves today sugar-free and in good condition.
Whether recurrence of such infections can be prevented with a small daily dose of sulfadiazine, as has seemed to be the case in certain other cases, time alone can tell. At any rate, this man and all of us who watched him know that infections in diabetes must not be tolerated. The deaths from coronary thrombosis and the five in which the diagnosis was simply designated "Diabetes" on the death certificate, as well as the one from burns, I will pass by. But I wish to say a word about appendicitis in diabetes and also about diabetic coma, reserving to the last the most depressing of all complications in diabetes, illustrated by the four deaths from chronic nephritis, because it is so often associated with blindness. 2. Appendicitis.-The premonitory symptoms of diabetic coma frequently simulate those of appendicitis and the leukocytosis common to each state further complicates the picture. Usually with the surgeon's aid a correct diagnosis can be made within a very few hours, but if there is reasonable doubt, an operation is indicated even if there is coexistent slight acidosis. The reactions with protamine zinc insulin sometimes also are confusing. For these reasons the prophylactic removal of an appendix must also be considered and within the last 12 months this has been carried out in the case of two of our patients. This was done for family reasons and because of remoteness from medical care. The two deaths from appendicitis cited in the table occurred in patients living at a distance. 3. Diabetic Coma.-Coma is a complication of diabetes which is seldom justifiable. The one case recently in which allowance could be made for its occurrence was in a young man who had done well for years but developed an acute infection while living alone, went into coma in his boarding house overnight and, although unconscious, fortunately was found, brought to the hospital and recovered. His case was one of 122 cases of diabetic coma which have been treated on our service at the New England Deaconess Hospital since August, 1940. Two deaths occurred in this group. In one fatal case the patient lived 67'2 hours, acidosis was overcome, but she succumbed to multiple abscesses in the sinuses accompanied by osteomyelitis. The other patient, 71 years of age, died 17'2 hours after admission with evidence at autopsy of two recent occlusions of her coronary arteries. All of these cases have been treated with insulin; dehydration was overcome with salt solution, almost invariably the stomach was emptied by lavage to prevent acute dilatation, and the best available nursing care was provided. The patients have not received alkalies or glucose; in fact, whenever we hear of a death from diabetic coma we now look to see if glucose or alkali was administered.
DIABETES MELLITUS IN GENERAL PRACTICE
1063
In one of our most recent cases, I confess, the patient did show hypoglycemia following the first day of coma. The onset of this patient's diabetes was at 10 years of age in November, 1941. She recovered from coma under our care in November, 1943, and again entered the hospital in coma April 7, 1944, with blood sugar of 600 mg., carhon dioxide 10 volumes per cent, and with a history of nausea, vomiting, drowsiness and Kussmaul respiration. She received 450 units of crystalline insulin between 9:00 A.M. and 3:00 P.M, and the next morning seemed so well and so comfortable that she was given a soft diet of carbohydrate ISO, protein 60 and fat 60 gm. but along with it, most unfortunately and unadvisedly, was allowed to take her usual morning dosage of 24 units of crystalline and 48 units of protamine zinc insulin. \\'hen I chanced to see her at 10:30 A.M., she responded with difficulty, and 400 cc. of 10 per cent intravenous glucose and 2000 cc. of 5 per cent glucose had to be administered before she was comfortable by 3: 30 in the afternoon. Improvement was rapid. She left the hospital on April 12, taking her diet of carbohydrate 180, protein 90 and fat 90 gm., and 22 units of crystalline insulin plus 42 of protamine zinc insulin, having excreted 15 gm. of sugar in the urine during the preceding 24 hours.
Of course the hypoglycemia in this case was totally avoidable and inexcusable because (1) the blood sugar was 99 mg. at 5:00 P. M. the preceding afternoon, (2) it is well known that large doses even of a quick-acting insulin exert a prolonged action, (3) the fasting blood sugar of the child, unfortunately unreported, was 48 mg. when the child was given her usual dosage of 24 crystalline plus 48 units protamine zinc insulin. I mention this case, first, because I like to record errors under conditions where such should not exist (just as it always does me good personally to give a patient three dollars when I miss a vein) since this helps to prevent others, but also because it indicates how easily with prompt treatment occurrences of this type if recognized can be relieved. "Ve believe in treating diabetic coma with insulin, because patients who have sufficient insulin do not develop it. We treat a deficiency of blood sugar, resulting from an excess of insulin, with glucose, because glucose neutralizes insulin. We never neutralize our insulin with glucose before we give it to a diabetic coma patient, because a diabetic coma patient needs insulin. 4. Chronic Nephritis.-Four deaths from nephritis in 1942-1943 occurred among our 1626 diabetics with onset in childhood, another patient died in February, 1944, and now I present to you four living patients coming to us in the last two weeks with the same corn plicatio!,. All are blind or likely to become so in the near future. I do not wish to discuss at this time the special type of nephritis, preferring only to call to your attention the threatening magnitude of this complication occurring in young diabetics who, with hardly an exception, have disregarded diet and calories and lived by the grace of insulin. So far as possible, I have used their own words or those of their relatives in proving the lack of diabetic control.
1064
ELLIOTI P. ]OSLIN
CASE 2726.-This boy, who developed diabetes in July, 1921, at the age of 13 years, consulted me first in 1922 and was not again seen until 1937. His diabetes was seldom controlled and he is reported to have had repeated attacks of diabetic coma and insulin reactions at his home. All his teeth were removed in 1931 and in 1937 evidences of nephritis appeared. In 1937 he wrote, "for several years past I have followed no set diet." In 1939 the urine contained 300 mg. of albumin with occasional granular casts, but the blood pressure did not rise to 160 until TABLE 4.-FOUR DEATHS FROM NEPHRITIS DURING 1942-1943 AMONG 1626 DIABETICS WITH ONSET IN CHILDHOOD Case No.
Sex
Age at Onset
5000 5431 9111 12588
F M F M
11.3 5.3 13.7 4.7
Date of Onset Dec., Dec., Feb., Jan.,
1925 1921 1930 1926
Date of Death
Duration
June, 1942 Nov., 1943 Jan., 1943 June, 1943
16.5 21.9 12.9 17.4
-
1938. The following year the albumin was 200 mg., and in 1941 the arteriosclerosis showed in the pelvic vessels by x-ray. In 1942 the albumin was 600 mg. and many coarse and fine granular casts were present. The nonprotein nitrogen was 43 mg. The right eye showed waxy exudate and punctate hemorrhages, the left was seen with difficulty. At the present time here in the hospital the albumin is 500 mg., many granular casts are in evidence, and the nonprotein nitrogen is 48 mg. Vision is lost in the left eye and hemorrhages are present in the right eye, through which occasionally he can read print.
CASE 4746.-This boy developed diabetes suddenly at 12 years of age in 1925. This was quite well controlled. In 1931 examination of the eyes by Dr. J. Herbert Waite showed them to be normal, and in 1932 there was no sclerosis of the anterior tibial arteries by x-ray. He had local abscesses in 1931 and 1932, and a perirectal abscess in 1935. In 1936, kidneys and blood pressure were still normal. Control of the diabetes was then somewhat, but by no means completely, relaxed. In 1941 old hemorrhages were found in each retina and in 1943 vitreous hemorrhages and retinitis proliferans developed. His blood pressure was 190/106, albumin 780 mg., and casts were present. In May, 1943, the right eye was enucleated on account of acute hemorrhagic glaucoma and in March, 1944, glaucoma was present in the left eye, the blood pressure was 200/100 and albumin 920 mg. As you see him today, his blood pressure is 240/126. The present pain in the eye, accompanied by nausea and vomiting, makes parenteral feeding obligatory. CASE 7730.-This boy developed diabetes at the age of 13.3 years in 1927 and was nearly in coma. He was seen at the office many tiines between 1930 and 1944, during which period at the office or at the hospital the urine was sugar-free on but two days. In 1931 I received the following note from his mother, "-can't keep him on his diet and he is dreadfully underweight, wants to sleep all the time and cranky. I am almost crazy trying to do for him." In 1937, in reply to a questionnaire, he wrote, "I am not on any diet." He had had an appendectomy in 1935. In January, 1944, the patient returned with severe headaches and dyspnea, showing 0.3 per cent sugar and albumin varying between 700 and 75 mg., hyaline, fine granular casts, and a nonprotein nitrogen of 63 mg. He was under observa-
DIABETES MELLITUS IN GENERAL PRACTICE
1065
tion off and on in January, February and March, 1944, and was here last on April 27 with marked edema which had not responded satisfactorily to previous rest in bed, digitalis, acacia and potassium nitrate. On that day the urine showed 0.6 per cent sugar, albumin 300 mg. and hyaline casts, the blood sugar was 196 mg., nonprotein nitrogen 61 mg. and total protein 4.1 per cent, and the blood pressure was 140/90. At that visit he stated, "I have never kept my diet for seventeen years and now I am sticking to it and it does not do any good." The following night his heart became still more incompetent and he was readmitted to a hospital in extremis. The eyes showed a few small, deep hemorrhages. CASE 24405.- This girl developed diabetes at the age of 6 years in 1925 and came to the office on April 21, 1944, with the statement from her physician that "while she was without question the most neglectful and uncooperative patient, she thrived. She never had less than 4 plus urines, but was able to live a very busy life as a secretary, never developed acidosis, kept her weight up to normal, and about a year ago gave no x-ray evidence of peripheral arteriosclerosis. Approximately six months ago she developed an abscess in her jaw from an infected tooth and this was followed by a severe nephritis. She had 4 plus albumin in the urine, many granular casts, a blood nonprotein nitrogen of 63 mg., a blood pressure of 200/140, and extensive hemorrhages in the retina with edema in the optic nerve. When first seen here, the urine contained 0.9 per cent sugar, 100 mg. of albumin and compound granular casts, the blood sugar was 315 mg., nonprotein nitrogen 84 mg. and hemoglobin 65 per cent., and the red blood count was 3,190,000. Her vision was reduced almost to complete blindness, the heart was enlarged, and moderate hydrothorax was present.
If these four cases of nephritis in young diabetics do not stimulate you and me to renewed effort to control the disease in season and out of season, I do not know what can. It is trite to tell our patients they can fool the doctor, but they cannot fool the disease, and recently I have quoted the following words of William James: "We are spinning our own fates, good or evil, and never to be undone. Every smallest stroke of virtue or of vice leaves its never so little scar. The drunken Rip Van Winkle, in Jefferson's play, excuses himself for every fresh dereliction by saying, 'I won't count this time!' Well! he may not count it, and a kind Heaven may not count it; but it is being counted none the less. Down among his nerve cells and fibres the molecules are counting it, registering and storing it up to be used against him when the next temptation comes. Nothing we ever do is, in strict scientific literalness, wiped out."8 ' In my experience, nephritis is rare in diabetics who diligently try to control their disease with diet and insulin, but even so I hardly dare show these pathetic patients to my other diabetics. I still believe and hark back to the words of Naunyn, that master of diabetes, when he wrote, "I hold it for a pessimistic restriction of the task resting upon the doctor in the treatment of diabetes if it shall be said 'The essential task of a doctor is and remains to preserve the patient a long time in a bearable' condition of life.' According to my view the treatment has a broader, more definite purpose, namely this, to strengthen (to better) the disturbed function or at least halt its further deterioration (the progressive development of the disease). "9
1066
ELLIOTT P. JOSLIN BIBLIOGRAPHY
1. Liebig, J. v.: Liebig's Ann., 121:80, 1862. 2. Jacobs, H. R.: Hypoglycemic Action of Alloxan. Proc. Soc. Exper. BioI. & Med., 37:407-409, 1937. 3. Dunn, J. S., Shcehan, H. L. and McLetchie, N. G. B.: Necrosis of Islets of Langcrhans Produced Experimentally. Lancet, 1:484-487, 1943. 4. Bailey, C. C. and Bailey, O. T.: Production of Diabetes Mellitus in Rabbits with Alloxan, J.A.M.A., 122:1165, 1943. 5. Joslin, E. P., Medical Progress: Diabetes Mellitus. New England J. Med.,
230:425-431, 1944.
6. Blotner, H., Hyde, R. W. and Kingsley, L. V.: Studies in Diabetes Mellitus and Transient Glycosuria in Selectees and Volunteers. New England J. Med., 229:885-892, 1943. 7. Editorial: The Incidence of Diabetes in Selectees. J.A.M.A., 124:1062, 1944. 8. Aldrich, Elizabeth P.: As William James Said: A Treasury of His Work. New York, The Vanguard Press, 1942, pp. 63-64. 9. Naunyn, B.: Der Diabetes Melitus, 2nd Ed. Wien, Alfred HOlder, 1906, p. 391.
P.
M.D., Se.D., F.A.C.P.*
JOSLIN,
Two outstanding diabetic discoveries were made in 1943: first, the production of diabetes by the administration of alloxan and, second, the demonstration of a hitherto unsuspected incidence of diabetes in young men. In addition to these achievements, I also point out to my patients the growing importance of the complications of diabetes because of their increasing exposure to them due to the steadily lengthening diabetic life. No matter whether my patients are young or old, I like them to be au courant with investigations going on in connection with their disease which, after all, is largely up to them to manage and control. ALLOXAN AND HOPE FOR BETTER DAYS FOR DIABETICS
Alloxan is the ureide of oxalic acid and has the formula: H
'"
N-C=O
I I
I I
O=C
H
/
c=o
N-C=O
One might look upon uric acid as a three-story house with an "L." Tak~, away the "L" and alloxan remains: H
'"I
N---C=O
o=c I
/
H
I
H", C----N )c-o
11
N----C----N
H
/
Alloxan has been known for years and was recognized as a component of the body in 1862 by Liebig,l but no satisfactory test for it has been described and its unstable composition makes it elusive. It has been utilized as an oxidizing and reducing agent. From the George F. Baker Clinic, New England Deaconess Hospital. • Clinical Professor of Medicine Emeritus, Harvard Medical School; Medical Director, George F. Baker Clinic, New England Deaconess Hospital; Consulting Physician, Boston City Hospital. 1054
DIABETES MELLITUS IN GENERAL PRACTICE
1055
In 1937 Jacobs 2 found that following the injection of alloxan into an animal, hypoglycemia occurred, but it was reserved for Dunn, Sheehan and McLetchie3 in Glasgow in April, 1943, to note its selective action in causing the necrosis of the islands of Langerhans of the pancreas of a rabbit. Such animals died within 14 to 22 hours after the injection of 0.2 mg. of alloxan per kilogram of bodv weight. For a brief period the blood showed hyperglycemia, but this was soon followed by hypoglycemia and death. Cab ell Bailey and Orville Bailey,4 believing diabetes would be inevitable in such an animal if life could be prolonged, administered repeated injections of glucose to such rabbits and found that diabetes appeared in the next 24 hours. A summary of seventeen articles upon alloxan occurs in the New England Journal of Medicine for April, 19445 and another article reporting original work by Bniley, Bailey and Leech appeared in the same journal May 4, 1944. They observed that all alloxan diabetic rabbits developed cataracts within two months of the production of the diabetes. The significance of alloxan diabetes is far-reaching. It strikes nearer the core of the diabetic problem than anything hitherto reported. Here is a chemical which undoubtedly is to be 'found in the body, of which an excess can destroy the insulin-producing cells. What is its source? What influences its formation or destruction? What will neutralize its action? Does it first stimulate the island cells to secrete and thus exhaust them, or more likely is its power of producing necrosis exercised from the start? How can one recognize its presence? These are only a few of the questions which arise. Obviously alloxan presents opportunities for research in diabetes hitherto undreamed of and gives hope to patients and practitioners alike for further advances in the management of the disease. The production of diabetes in rabbits, rats and other animals in such a pure form is now so simple that studies of the disease and its complications are open to all who desire to make them. DIABETIC DIVIDENDS FROM SELECTIVE SERVICE
I. Disclosure of Unsuspected Incidence of Diabetes.-Blotner, Hyde and Kingsley6 have reported studies upon 45,650 selectees and volunteers among whom they found 208 cases of diabetes, 126 individuals with transient glycosuria and 33 individuals with what they term renal glycosuria. This is at least three to four times as high a diabetic incidence as was recognized in the National Health Survey study at ages under 25 and from four to five times at ages 25 to 45.- The National Health Survey figures were based on a house to house canvass-hearsay evidence-in contrast to those of Blotner, Hyde and Kingsley, which were based upon actual analyses of urine and blood. If such discrepancies exist in diabetic incidence at selectee ages, is • For a full discussion of these surprising and almost startling results, see an exhaustive editorial in the Journal of the American Medical Association. 7
1056
ELLlOIT P. JOSLlN
there any reason to doubt appreciable differences at other ages of life and "that current estimates of the amount of diabetes in the population are falsely optimistic"? The significance of these data in the general management of the disease is many fold. First of all, it will make our people far more diabetic-conscious and far more eager to come to the doctor to learn if they have the disease. Already they have become alert to the influence of heredity. Once their disease is diagnosed, they desire prompt treatment and this affords the physician a chance to treat a case with recent onset, and such patients offer far better prognoses. 2. Patients with an Original Diagnosis of Diabetes Eventually Accepted into Armed Forces.-During this year's follow-up of our 1626 childhood diabetics known to be alive at sor.: time during 1942 or 1943, it was found that 7 were in the armed forces. As the sex of diabetics differs little in this age group, it follows that nearly 1 per cent of our boys were not considered or recognized to have diabetes when they became men and were examined for t:he Army. What is the explanation? Salient facts are recorded in Table 1. A study of the protocols of the cases cited in Table 1 shows that the ages of the boys when the original diagnosis of diabetes was made varied between 6 and 14 years, and the interval between diagnosis and their induction into the Army, although not known exactly, was probably between 11 and 5 years. Heredity was known in three of the seven cases. Weights or heights were not extraordinary, although one boy weighed 192 pounds dressed, and his height with shoes was 5 feet, 8% inches. The first case, 10464, I will throw out at once, because although the patient showed 0.9 and 1.1 per cent glycosuria, and blood sugars of 210 and 200 mg. with venous blood, I find by my records he had f~runculosis. That is a warning against making a diagnosis in the presence of an infection of any character until it has been verified by subsequent tests when the infection has disappeared. It is true that all of these patients were recognized at the time to be rather borderline diabetics, because in no instance did a patient receive insulin save temporarily, and the carbohydrate in the diet of no patient was lowered below 200 gm. save in case of the 6-year-old child, and even his diet was gradually raised within 2 years to practicallyeverything. For the sake of argument, it is assumed that none of these patients has diabetes now, but of course that cannot be verified. All of the cases showed glycosuria and in three of them it reached between 1.1 and 2.2 per cent, but glycosuria alone, even of considerable proportions, does not justify a diagnosis of diabetes. All of the fasting blood sugars were normal, but this is a common occurrence in frank diabetes in young people, particularly in the first months of their disease. On the other hand, in no instance did the
TABLE I.-SEVEN CASES ORIGINALLY DIAGNOSED DIABETICS EVENTUALLY ACCEPTED INTO ARMED FORCES
Age at Body Case Diag- Weight No. nosis (Lbs.)
Sugar Date
Time
Urine (Per Cent)
Blood (Mg.)
-----1----1----1-------------------10464
6
41 (D)
4/ 5/31
4/ 6/31 11975
8
70 (D)
6/28/33
1 hr. after lunch 8:30 P.M.
1 hr.
"
14
182 (N)
2/23/35
"
"" ""
~,
Fasting
'""
i,
Fasting
! hr. after 100 gm. glucose "
2 hrs."
""
""
tr. tr.
o o
o o
o
d
! hr. after 100 gm. glucose 1 hr. " ".c .,
1 hr.
12/29/36
d"
"
Fasting
2 hrs."
2/ 8/36
""
! hr. after 50 gm. glucose 1 hr. " 2 hrs. ,.
13219
1.1
! hr. after 42 gm. sucrose 2 hrs. "
11/29/34
0.9
"
"
Fasting ! hr. after 100 gm. glucose 1 hr. " et" " 2 hrs." "" "
210 200
250 160 ?C.B. 140 100 170 150 120
o
100 160 150 130
o
110 200 150 130
o
100 170 liO 130
0.2 0.3 1. 2 0.2 1. 9 o7 0.2 0.8 0.8
V.B.
C.B.
V.B.
V.B.
V.B.
- - - - ----1----1------·_------- - - ----13386
9
50 (DJ
1/28/35
1/31/35
Fasting ! hr. after 50 gm. glucose " 1 hr. " " " 2 hrs." " " "
13
86 (DJ
1/30/35
o
o o
Fasting
90 200 140 100
0.1
80 180 210
! hr. after 50 gm. glucose
0 0 0
90 120 210
Fasting
o o
80 210 220 100
! hr. after glucose 1 hr."
13387
o
0.2
"
Fasting
C.R.
C.B.
C.B. hr. after 2nd 50 gm. glucose -----1----1--·--·- - - - - - - - - - - - - - 1 - - - - - - - 14673 13 94 (DJ 6/29/36 Fasting o 80 ! hr. after 100 gm. glucose o 180 V.B. 2.2 130 1 hr. " "" " 2 hr. " H" " 0.3 130 ---- - - - 1 - - - - 1 - - - - 1 - - - - - - - - - - - - - - - - - - - ' 13 16042 79 (N) 10/ 7/37 Fasting 80 V.B. ! hr. after 70 gm. glucose o 190 C.B. 1 hr. " " " (( o 180 2 hrs." "Co " o 140 ~
12/30/37
! hr. after 100 gm. glucose 1 hr. " 2 hrs."
"" ""
(C
••
0.2 0.6
D, dressed; N, naked; tr., trace; V.B., venous blood; C.B., capillary blood. 1057
V.B.
1058
ELLIOTT P. JOSLIN
blood sugar return to or below the normal value at the end of two hours. Therefore, according to this criterion diabetes was correctly diagnosed, but we have not been accustomed to consider such a procedure as a trustworthy diagnostic method. Capillary blood sugar determinations were certainly employed in two and p9ssibly three cases. In one of them, Case 11975, in which the patient was a child of 8 years, 42 gm. of sucrose was given and thereupon the value reached 250 mg. Our rule is to consider the normal fasting value of capillary blood to be the same as venous blood, but the upper normal diagnostic value with capillary blood in a sugar tolerance test to be under 200 mg. This case, therefore, was diagnosed diabetes. However, we had our doubts because of a second test, this time with 50 gm. of glucose, in which the capillary blood failed to rise above 170 mg. and therefore did not reach a diabetic level. On the other hand, with Case 16042 the tests were carried out with both capillary and venous blood, and with 70 gm. of glucose with capillary blood the diagnosis failed to show diabetes, but with 100 gm. of glucose with venous blood, the blood sugar rose to 220 mg. All in all, therefore, the fact that 7 patients originally diagnosed diabetics but possibly wrongly so diagnosed, were admitted into the Army, shows the necessity of caution, especially if any doubt exists, in designating an individual a diabetic when the fasting blood sugar is normal, even if the 2-hour blood sugar test shows no return to the original fasting value or the intervening tests rise with capillary blood to 200 or even above 200 mg., or with venous blood to 180 or as much as 220 mg. Moreover, no diagnosis of diabetes should be made if an infection is present unless the glycosuria and blood sugar values are outstanding at the time or tests are repeated when the individual is free from infection. As a matter of fact, invariably it has been our rule for some years to record the temperatures at the beginning and end of the test. Nevertheless, in 99 per cent of our cases, so far as we are aware, the original diagnosis has proved correct, and this is reassuring. 3. Diabetes Diagnosed Early Responds Well to Treatment.-Years ago I was able to show that the individual supposedly well but found to be diabetic by an examination for insurance outlived his neighbor whose diabetic symptoms forced him to consult his physician. Recently a group of Army cases has been referred to me for treatment, in which the presence of diabetes was learned because of Selective Service examinations. Improvement in these cases has been rapid despite .apparent severity. The diabetes in the patient I now present to you, Case 24001, 29 years of age in December, 1943, did show symptoms for a very few weeks before it was discovered and so it is not absolutely typical of the diabetes recognized by insurance or Selective Service. The case serves my purpose, however, in that the patient shows a rapid im-
1059
DIABETES MELLITUS IN GENERAL PRACTICE
provement, although at his first visit on December 28, 1943, the glyand the blood sugar 333 mg. cosuria was 8 per cent, diacetic acid No hospital bed being available, he was treated through the office and kept on with his work. His course is shown in Table 2. Diet.-Simplification of diet is necessary today for doctors and patients. I am accustomed to follow this plan. By prescribing four portions of 5 and 10 per cent carbohydrate vegetables daily, one can assume with considerable probability of accuracy that the carbohydrate content of the same will be 20 gm. To this can be added 10 gm. of carbohydrate which is represented by a half-pint mixture of equal parts of milk and cream. A bowl (large portion) of cooked oatmeal contains another 20 gm. of carbohydyrate, making a total for the vegetables, milk and cream mixture and oatmeal of 50 gm. A second
++
TABI,E 2.-0FFICE MANAGEMENT OF DIABETES OF RECENT ONSET
Sugar Date
Dec. 28, 1943 29 30 31 Jan. 3, 1944 17 21 28 Feb. 9 Apr. 10
Urine (Per Cent)
Blood (Mg.)
8.0 8.4 2.9
333*
.
"
0 0 0 0 0 0
Diet (C.)
... .
200
74 76 71 152 89 110 62
"
....
"
" " "
.,
"
Weight Dressed (Lbs.) 166
...
165 165 169 167 169 166 165
Insulin
8+@ 12 +@ 12 + 24. 1?+(f4l 8 + @) 4+@ @ @ @
* All of the blood sugars were taken in the late forenoon, except those of January 21 and February 9, which were taken after lunch. 50 gm. will be represented by three medium-sized oranges, thus raising the total carbohydrate to approximately 100 gm. To this can be prescribed bread, estimating that one slice, approximately an ounce (30 gm.), contains not far from 15 to 18 gm. of carbohydrate. This man was given six slices or a total of 100 gm. (90-108) which, added to his previous allowance, made the final carbohydrate in the neighborhood of 200 gm. With most patients the bread at the beginning is liIl}ited to three slices a day, making the total carbohydrate 150 gm. Subsequently, the diet can be altered with substitutions for fruit, cereal and bread. If glycosuria is avoided, it is easy to add weight by increasing the percentage of cream, or to reduce weight by its omission. The patient was told to take meat, fish, eggs, cheese and butter in moderate quantity, with the hope that the protein would be not far from 100 gm. and the fat 100 gm.
1060
ELLIOTT P. JOSLIN
It is surprising how many patients do so well on this schedule that their hospital reservation for three weeks later is cancelled. I still think the hospital-educated diabetic is overwhelmingly safer than the office-treated case, but with no beds available one is forced to treat his patients in an ambulatory fashion, although even then I try to get them to attend at least some of the hospital classes. lnsulin.- This patient received at the office 8 units of crystalline insulin and 12 of protamine zinc insulin, and the following morning 12 units of crystalline and 24 units of protamine zinc insulin. This was continued for five days, when a glycosuria and a blood sugar of 76 mg. led to a revision of the order to 8 units of crystalline and 18 of protamine zinc insulin, which were continued for 2 weeks when again the crystalline was lowered to 4 units and the protamine zinc to 16 units. I always like to give insulin in multiples of 4, because it is so much more easily registered on the syringes we prefer our patients to use, namely, a I-cc. syringe divided into tenths. Still later, crystalline insulin was omitted and protamine zinc insulin reduced to 12 units. For stilI milder cases in older patients, 8 units of protamine zinc insulin may be prescribed at the first visit and subsequently raised or lowered, remembering that with diet alone glycosuria will fall and with insulin will decrease still more rapidly. Furthermore, one must bear in mind that the full effect of the protamine zinc insulin will not be manifested until the third day. In general, one attempts to control the diabetes with diet and protamine zinc insulin and only adds crystalline insulin when the protamine zinc insulin has risen to 20, 24 or 28 units, above which one hesitates to go for fear of an insulin reaction during the night. However, many patients learn to control their diabetes with even larger quantities of protamine zinc insulin alone and no universal rule can be made. It is our practice to inject the crystalline and protamine zinc insulin separately. In certain clinics the two are mixed in the same syringe, but our experience, particularly with children, has prejudiced us against such a procedure. In diabetes one is dealing with many variables-exercise, diet and insulin-and if one introduces still another variable factor by mixing the two insulins, in our hands the results have not been favorable. For the same reason we hesitate to adopt other insulins which in themselves would be infinitely better than no insulin, because we do not wish to expose our patients to reactions at unaccustomed hours of the day. In general, with Hamlet, we prefer to "bear those ills we have than fly to others that we know not of." With patients taking protamine zinc insulin alone, if the urine voided on rising, or a specimen voided half an hour later to guard against the presence of sugar which may have accumulated in the bladder overnight, is not sugar-free, we are accustomed to add 4 units of protamine zinc insulin until the urine voided on rising is sugar-free
DIABETES MELLlTUS IN GENERAL PRACTICE
1061
or until about 20 to 28 units are injected. If then it appears that glycosuria is present fasting or even after meals, crystalline insulin is added in 4-unit doses and usually eventually will reach one-third to one-half that of the protamine zinc insulin. CAUSES OF DEATH DURING 1942 AND 1943 AMONG DIABETICS WITH ONSET OF THE DISEASE IN CHILDHOOD
Diabetic children live and some of them live a long while, so long in fact and so comfortably that often the tendency is to pursue with them a laissez faire policy as regards control of the disease. Subsequent to the first observation of a lO-year-old diabetic child in our group, the Metropolitan Life Insurance Company calculated its life expectancy, regardless of the duration of diabetes, and found it to be 40 years. But diabetic children do not all live those 40 years and, therefore, the causes of death of 23 during 1942 and 1943 among our 1626 diabetics with the onset of their disease in childhood deserve notice. At present 45 of the 1626 are untraced and there may be a death among this number. The reported causes of death are shown in Table TABLE 3.-TWENTY-THREE DEATHS IN 1942 AND 1943 AMONG 1626 DIABETICS WITH ONSET IN CHILDHOOD
Infections: Staphylococcus aureus. . . . . . . . . . .. Cavernous sinus thrombosis. . Pneumonia. .... Meningitis. . . . . . . . . Whooping cough. . . . . . . . . . . . . . . ..
1 1 1 1 1
Bums.............. Coronary thrombosis. . Diabetes. . . . . . Appendicitis. . . Coma............... Nephritis ..........................
1 2 5 2 4 4
3. The average duration of the diabetes was 10.7 years and average age of the patients at death was 20.2 years. I. An Infection Neglected.-I will not discuss here deaths from infections, one each with Staphylococcus aureus infection, cavernous sinus thrombosis, whooping cough, meningitis and pneumonia, but instead wish to show you Case 16593, a longshoreman, who is leaving the hospital today, because he illustrates the harmfulness of a laissez faire policy in dealing with infections, even though mild at the outset. This man, who developed diabetes in July, 1937, at the age of 37 years, consulted me the following year with a 5.1 per cent glycosuria and a blood sugar of 290 mg., and was discharged with a normal blood sugar and a diet of carbohydrate 160, protein 90 and fat 125 gm. and 8 units of protamine zinc insulin. He was not seen again until a few weeks ago when he entered the hospital with a tender right flank and abdomen. There was a previous history of a succession of boils and a carbuncle dating back 6 months. Investigation soon revealed symptoms and signs pointing to a paranephric abscess which was drained. After some weeks the patient again returned with discomfort below the right shoulder joint, comparatively little pain and only slightly elevated temperature, hoth characteristic features of diabetes with infection, and the localized collection of pus would have been easy to overlook had not our surgical friends, Dr.
1062
ELLIOIT P. JOSLlN
L. S. McKittrick and Dr. Francis D. Moore, disclosed it with a hypodermic needle. Fortunately it had not reached the shoulder joint and with wide opening of the area the condition rapidly healed. The patient leaves today sugar-free and in good condition.
Whether recurrence of such infections can be prevented with a small daily dose of sulfadiazine, as has seemed to be the case in certain other cases, time alone can tell. At any rate, this man and all of us who watched him know that infections in diabetes must not be tolerated. The deaths from coronary thrombosis and the five in which the diagnosis was simply designated "Diabetes" on the death certificate, as well as the one from burns, I will pass by. But I wish to say a word about appendicitis in diabetes and also about diabetic coma, reserving to the last the most depressing of all complications in diabetes, illustrated by the four deaths from chronic nephritis, because it is so often associated with blindness. 2. Appendicitis.-The premonitory symptoms of diabetic coma frequently simulate those of appendicitis and the leukocytosis common to each state further complicates the picture. Usually with the surgeon's aid a correct diagnosis can be made within a very few hours, but if there is reasonable doubt, an operation is indicated even if there is coexistent slight acidosis. The reactions with protamine zinc insulin sometimes also are confusing. For these reasons the prophylactic removal of an appendix must also be considered and within the last 12 months this has been carried out in the case of two of our patients. This was done for family reasons and because of remoteness from medical care. The two deaths from appendicitis cited in the table occurred in patients living at a distance. 3. Diabetic Coma.-Coma is a complication of diabetes which is seldom justifiable. The one case recently in which allowance could be made for its occurrence was in a young man who had done well for years but developed an acute infection while living alone, went into coma in his boarding house overnight and, although unconscious, fortunately was found, brought to the hospital and recovered. His case was one of 122 cases of diabetic coma which have been treated on our service at the New England Deaconess Hospital since August, 1940. Two deaths occurred in this group. In one fatal case the patient lived 67'2 hours, acidosis was overcome, but she succumbed to multiple abscesses in the sinuses accompanied by osteomyelitis. The other patient, 71 years of age, died 17'2 hours after admission with evidence at autopsy of two recent occlusions of her coronary arteries. All of these cases have been treated with insulin; dehydration was overcome with salt solution, almost invariably the stomach was emptied by lavage to prevent acute dilatation, and the best available nursing care was provided. The patients have not received alkalies or glucose; in fact, whenever we hear of a death from diabetic coma we now look to see if glucose or alkali was administered.
DIABETES MELLITUS IN GENERAL PRACTICE
1063
In one of our most recent cases, I confess, the patient did show hypoglycemia following the first day of coma. The onset of this patient's diabetes was at 10 years of age in November, 1941. She recovered from coma under our care in November, 1943, and again entered the hospital in coma April 7, 1944, with blood sugar of 600 mg., carhon dioxide 10 volumes per cent, and with a history of nausea, vomiting, drowsiness and Kussmaul respiration. She received 450 units of crystalline insulin between 9:00 A.M. and 3:00 P.M, and the next morning seemed so well and so comfortable that she was given a soft diet of carbohydrate ISO, protein 60 and fat 60 gm. but along with it, most unfortunately and unadvisedly, was allowed to take her usual morning dosage of 24 units of crystalline and 48 units of protamine zinc insulin. \\'hen I chanced to see her at 10:30 A.M., she responded with difficulty, and 400 cc. of 10 per cent intravenous glucose and 2000 cc. of 5 per cent glucose had to be administered before she was comfortable by 3: 30 in the afternoon. Improvement was rapid. She left the hospital on April 12, taking her diet of carbohydrate 180, protein 90 and fat 90 gm., and 22 units of crystalline insulin plus 42 of protamine zinc insulin, having excreted 15 gm. of sugar in the urine during the preceding 24 hours.
Of course the hypoglycemia in this case was totally avoidable and inexcusable because (1) the blood sugar was 99 mg. at 5:00 P. M. the preceding afternoon, (2) it is well known that large doses even of a quick-acting insulin exert a prolonged action, (3) the fasting blood sugar of the child, unfortunately unreported, was 48 mg. when the child was given her usual dosage of 24 crystalline plus 48 units protamine zinc insulin. I mention this case, first, because I like to record errors under conditions where such should not exist (just as it always does me good personally to give a patient three dollars when I miss a vein) since this helps to prevent others, but also because it indicates how easily with prompt treatment occurrences of this type if recognized can be relieved. "Ve believe in treating diabetic coma with insulin, because patients who have sufficient insulin do not develop it. We treat a deficiency of blood sugar, resulting from an excess of insulin, with glucose, because glucose neutralizes insulin. We never neutralize our insulin with glucose before we give it to a diabetic coma patient, because a diabetic coma patient needs insulin. 4. Chronic Nephritis.-Four deaths from nephritis in 1942-1943 occurred among our 1626 diabetics with onset in childhood, another patient died in February, 1944, and now I present to you four living patients coming to us in the last two weeks with the same corn plicatio!,. All are blind or likely to become so in the near future. I do not wish to discuss at this time the special type of nephritis, preferring only to call to your attention the threatening magnitude of this complication occurring in young diabetics who, with hardly an exception, have disregarded diet and calories and lived by the grace of insulin. So far as possible, I have used their own words or those of their relatives in proving the lack of diabetic control.
1064
ELLIOTI P. ]OSLIN
CASE 2726.-This boy, who developed diabetes in July, 1921, at the age of 13 years, consulted me first in 1922 and was not again seen until 1937. His diabetes was seldom controlled and he is reported to have had repeated attacks of diabetic coma and insulin reactions at his home. All his teeth were removed in 1931 and in 1937 evidences of nephritis appeared. In 1937 he wrote, "for several years past I have followed no set diet." In 1939 the urine contained 300 mg. of albumin with occasional granular casts, but the blood pressure did not rise to 160 until TABLE 4.-FOUR DEATHS FROM NEPHRITIS DURING 1942-1943 AMONG 1626 DIABETICS WITH ONSET IN CHILDHOOD Case No.
Sex
Age at Onset
5000 5431 9111 12588
F M F M
11.3 5.3 13.7 4.7
Date of Onset Dec., Dec., Feb., Jan.,
1925 1921 1930 1926
Date of Death
Duration
June, 1942 Nov., 1943 Jan., 1943 June, 1943
16.5 21.9 12.9 17.4
-
1938. The following year the albumin was 200 mg., and in 1941 the arteriosclerosis showed in the pelvic vessels by x-ray. In 1942 the albumin was 600 mg. and many coarse and fine granular casts were present. The nonprotein nitrogen was 43 mg. The right eye showed waxy exudate and punctate hemorrhages, the left was seen with difficulty. At the present time here in the hospital the albumin is 500 mg., many granular casts are in evidence, and the nonprotein nitrogen is 48 mg. Vision is lost in the left eye and hemorrhages are present in the right eye, through which occasionally he can read print.
CASE 4746.-This boy developed diabetes suddenly at 12 years of age in 1925. This was quite well controlled. In 1931 examination of the eyes by Dr. J. Herbert Waite showed them to be normal, and in 1932 there was no sclerosis of the anterior tibial arteries by x-ray. He had local abscesses in 1931 and 1932, and a perirectal abscess in 1935. In 1936, kidneys and blood pressure were still normal. Control of the diabetes was then somewhat, but by no means completely, relaxed. In 1941 old hemorrhages were found in each retina and in 1943 vitreous hemorrhages and retinitis proliferans developed. His blood pressure was 190/106, albumin 780 mg., and casts were present. In May, 1943, the right eye was enucleated on account of acute hemorrhagic glaucoma and in March, 1944, glaucoma was present in the left eye, the blood pressure was 200/100 and albumin 920 mg. As you see him today, his blood pressure is 240/126. The present pain in the eye, accompanied by nausea and vomiting, makes parenteral feeding obligatory. CASE 7730.-This boy developed diabetes at the age of 13.3 years in 1927 and was nearly in coma. He was seen at the office many tiines between 1930 and 1944, during which period at the office or at the hospital the urine was sugar-free on but two days. In 1931 I received the following note from his mother, "-can't keep him on his diet and he is dreadfully underweight, wants to sleep all the time and cranky. I am almost crazy trying to do for him." In 1937, in reply to a questionnaire, he wrote, "I am not on any diet." He had had an appendectomy in 1935. In January, 1944, the patient returned with severe headaches and dyspnea, showing 0.3 per cent sugar and albumin varying between 700 and 75 mg., hyaline, fine granular casts, and a nonprotein nitrogen of 63 mg. He was under observa-
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tion off and on in January, February and March, 1944, and was here last on April 27 with marked edema which had not responded satisfactorily to previous rest in bed, digitalis, acacia and potassium nitrate. On that day the urine showed 0.6 per cent sugar, albumin 300 mg. and hyaline casts, the blood sugar was 196 mg., nonprotein nitrogen 61 mg. and total protein 4.1 per cent, and the blood pressure was 140/90. At that visit he stated, "I have never kept my diet for seventeen years and now I am sticking to it and it does not do any good." The following night his heart became still more incompetent and he was readmitted to a hospital in extremis. The eyes showed a few small, deep hemorrhages. CASE 24405.- This girl developed diabetes at the age of 6 years in 1925 and came to the office on April 21, 1944, with the statement from her physician that "while she was without question the most neglectful and uncooperative patient, she thrived. She never had less than 4 plus urines, but was able to live a very busy life as a secretary, never developed acidosis, kept her weight up to normal, and about a year ago gave no x-ray evidence of peripheral arteriosclerosis. Approximately six months ago she developed an abscess in her jaw from an infected tooth and this was followed by a severe nephritis. She had 4 plus albumin in the urine, many granular casts, a blood nonprotein nitrogen of 63 mg., a blood pressure of 200/140, and extensive hemorrhages in the retina with edema in the optic nerve. When first seen here, the urine contained 0.9 per cent sugar, 100 mg. of albumin and compound granular casts, the blood sugar was 315 mg., nonprotein nitrogen 84 mg. and hemoglobin 65 per cent., and the red blood count was 3,190,000. Her vision was reduced almost to complete blindness, the heart was enlarged, and moderate hydrothorax was present.
If these four cases of nephritis in young diabetics do not stimulate you and me to renewed effort to control the disease in season and out of season, I do not know what can. It is trite to tell our patients they can fool the doctor, but they cannot fool the disease, and recently I have quoted the following words of William James: "We are spinning our own fates, good or evil, and never to be undone. Every smallest stroke of virtue or of vice leaves its never so little scar. The drunken Rip Van Winkle, in Jefferson's play, excuses himself for every fresh dereliction by saying, 'I won't count this time!' Well! he may not count it, and a kind Heaven may not count it; but it is being counted none the less. Down among his nerve cells and fibres the molecules are counting it, registering and storing it up to be used against him when the next temptation comes. Nothing we ever do is, in strict scientific literalness, wiped out."8 ' In my experience, nephritis is rare in diabetics who diligently try to control their disease with diet and insulin, but even so I hardly dare show these pathetic patients to my other diabetics. I still believe and hark back to the words of Naunyn, that master of diabetes, when he wrote, "I hold it for a pessimistic restriction of the task resting upon the doctor in the treatment of diabetes if it shall be said 'The essential task of a doctor is and remains to preserve the patient a long time in a bearable' condition of life.' According to my view the treatment has a broader, more definite purpose, namely this, to strengthen (to better) the disturbed function or at least halt its further deterioration (the progressive development of the disease). "9
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ELLIOTT P. JOSLIN BIBLIOGRAPHY
1. Liebig, J. v.: Liebig's Ann., 121:80, 1862. 2. Jacobs, H. R.: Hypoglycemic Action of Alloxan. Proc. Soc. Exper. BioI. & Med., 37:407-409, 1937. 3. Dunn, J. S., Shcehan, H. L. and McLetchie, N. G. B.: Necrosis of Islets of Langcrhans Produced Experimentally. Lancet, 1:484-487, 1943. 4. Bailey, C. C. and Bailey, O. T.: Production of Diabetes Mellitus in Rabbits with Alloxan, J.A.M.A., 122:1165, 1943. 5. Joslin, E. P., Medical Progress: Diabetes Mellitus. New England J. Med.,
230:425-431, 1944.
6. Blotner, H., Hyde, R. W. and Kingsley, L. V.: Studies in Diabetes Mellitus and Transient Glycosuria in Selectees and Volunteers. New England J. Med., 229:885-892, 1943. 7. Editorial: The Incidence of Diabetes in Selectees. J.A.M.A., 124:1062, 1944. 8. Aldrich, Elizabeth P.: As William James Said: A Treasury of His Work. New York, The Vanguard Press, 1942, pp. 63-64. 9. Naunyn, B.: Der Diabetes Melitus, 2nd Ed. Wien, Alfred HOlder, 1906, p. 391.