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The Treatment of Diabetes Mellitus
The Treatment of Diabetes Mellitus From the joslin Clinic, Boston, Massachusetts
PRI8CILLA WHITE, M.D., F.A.C.P.
objectives in the overall treatment of diabetes have been broadened by the newer concept of the progression of diabetes through four distinct stages: prediabetes, chemical diabetes, acute overt and chronic diabetes. The goals of management have become the prevention of the progression of prediabetes to the second stage, the reversal of chemical diabetes, the alteration of the course of acute diabetes, the prevention, postponement or correction of the characteristics of chronic diabetes.
THE
PREDIABETES
Although the management of overt diabetes is the common problem of the physician, the recognition of and plan for the prediabetic is his new responsibility. Prediabetes is defined here as the period from conception until the time when the glucose tolerance test becomes positive. Diagnosis FAMILY HIS'fOHY. The recognition of prediabetes may he made in part or suspected by the family history. The expcrience through the years has supported the thesis that the tendency to develop diabetcs is inherited 12 and that the transmission is through Mendelian recessivc genes. The positive identification of prediabetes is possible in three genetic groups: the offspring of two diabetics, both parents of a family of children all of whom have diabetes, and the identical twins of diabetics. The probability for the development of diabetes is great: 85 per cent if one parent has diabetes and on the opposite side of the family a grandparent and aunt or uncle have it; 60 per cent if one parent has diabetes and on the opposite side a grandparent or aunt or uncle. The probability drops to 40 per cent if a parent has diabetes and on the opposite side a first cousin, 22 per cent if one parent has diabetes, 14 per cent if a grandparent, 9 per cent a first cousin. 15 The family history reveals the susceptibility of the group rather than the susceptible individual.
1177
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PmSCILLA WHl'l'E
PAST HIS'l'OHY. Past histories yield significant data. The correlation between heavy birth weight and maternal diabetes is well known. The chances for the development of diabetes in the mother are 100 per cent when the infant's birth weight is 14 pounds, 90 per cent when it is 13 poundR. 9 It is less well known that heavy birth weight (greater than 8 pounds 4 ounces) may predict the onset of diabetes in the individual in adult life. The events in the past history of females have shown a highly positive correlation with maturity onset diabetes. Early menarche is the rule. IS Women who develop diabetes after age 18 have the earliest recorded menarche. Obstetrical accidents are common. These obstetrical abnormalities include the occurrence of toxemia, hydramnios, intrauterine or intrapartum deaths. The status of the infant and child may forewarn of maternal diabetes. In addition to the large size of the newborn infant, the presence of congenital anomalies of islet hyperplasia and hypertrophy and the continued accelerated rate of growth of the child are significant signs of maternal prediabetes. The past history of erythroblastosis,4 chronic cystic fibrosis1 4 of the pancreas and pancreatitis as well as of functional hypoglycemia& should not be ignored in respect to the posRible future development of diabetes. PHYSICAI~ EXAMINATION. Pertinent physical signs are obesity,9 total growth in advance of the chronological age lS and the occurrence of congenital anomalies. 17 VASCULAR LESIONS. Important vascular changes, functional responses and histological lesions have been found in genetic prediabetes. Oscillographic pulse tracings in genetic prediabetes tend to be comparable to those of overt diabetes. The second component of the normally dicrotic wave appears to be obliterated (26 per cent sensitivity). The microvascular changes characteristic of diabetes appear in prediabetes. Venular dilatation was found in the bulbar conjunctiva in 92 per cent. Percutaneous renal biopsy and cutaneous ear lobe biopsy have shown basement membrane changes in electron microscopic studies. CHEMICAL TESTS. Chemical tests appear to help identify the prediabetic state also. Of all possible tests, the random blood sugar is the simplest. Hypoglycemia is of significance. 3 The curves of simultaneous venous and capillary bloods obtained in the course of the standard glucose tolerance test are informative. The sum of the difference between capillary and venous blood at 30 and 60 minutes should be greater than the sum of the difference between capillary and venous blood at 60 and 90 minutes and the index should be greater than 1. 12 The reverse is true in diabetes and genetic prediabetics have shown the characteristic curve of diabetes with blood sugars at normal levels. The sensitivity is 41 per cent. 1 Of greatest significance because it may be related to obesity in maturity onset and overgrowth in juvenile onset diabetes is the increase in the insulin-like activity of the serum in the genetic prediabetic. 16
The Treatment of Diabetes lYIellitus
1179
Research Programs
Programs have been designed to impede the progress of prediabetes. The interval of time which has elapsed since their introduction has not been significant. Substances which protect islet tissue and favor hypertrophy and hyperplasia are being used; for example, sulfonylureas. The use of a schedule utilizing muscular exercise is favored. The value of muscular exercise is not limited to the rapid utilization of glucose but is believed to favor the production of an X factor which is insulin-like in its activity promoting the transport of glucose across the cell membrane. 6 A third part of the program limits the quantity and the concentration of carbohydrate in the diet. CHEMICAL DIABETES
Diagnosis
Chemical diabetes is defined as the stage of diabetes in which the level of the random blood sugar is normal. The clinical symptoms of diabetes are absent but the administration of glucose provokes a hyperglycemic response. No uniformity for diagnostic levels of glucose in chemical diabetes exists. The diagnostic level of glucose accepted by the Joslin Clinic is the rise to 150 mg. true glucose postprandially or fall of glucose to a level of 110 mg. or more in two hours for venous blood, rise to 180 mg. for capillary blood or fall to 100 mg. in three hours. Programs
The plans for long-range observation in respect to chemical diabetes are noteworthy. Conn and Fajans have recommended the use of sulfonylureas in chemical diabetes. Hoet S has advised insulin to tolerance in gestational chemical diabetes. In his patients, whose diets were fairly free and consisted of large quantities of potato, the dose required was 30 units of regular insulin twice daily. With controlled diets, Wilkerson 19 found 6 to 20 units of intermediate acting insulin adequate for control. The rate of progression of chemical diabetes is variable. It may be rapid or slow or it may be a stable state. In youth it is difficult to demonstrate and progression from the stage characterized by normal glucose tolerance to overt diabetes in young individuals may occur in a few months. OVERT DIABETES
Overt diabetes is characterized by the classical symptoms of polyuria, polyphagia, polydipsia and by the elevation of glucose in the random
1180
PRISCILLA VVHITE
sampling of blood. It exists in two forms, maturity and growth onset, which appear to be different degrees of the same disorder. In pathology, chemistry and in natural course, they show differences which are not only significant but which influence their respective therapies. MATURITY ONSET DIABETES CHARACTERISTICS. Total beta cell mass is reduced in maturity onset diabetes.ll The quantity of insulin which can be extracted from the pancreas (IEP) is 25 to 75 per cent of normal and insulin-like activity (ILA) is found in the serum in nearly normal quantities. In the natural course of typical maturity onset diabetes, the status is one of more or less stability. Neither remissions nor rapid progression are striking and common events. Dietary Treatment
CALOIUES. Dietary control of this type of diabeteH is not only possible but desirable. The caloric prescription is influeneed by the objeetives, which may be to maintain ideal weight for height and age, more often to promote reduction of weight, less often to achieve increase in weight. Using the measure of body weight in kilograms, the maintenance diet is 30 calories per kilogram of body weight, the reducing diet 20 calories per kilogram and the weight-increasing diet 40 calories per kilogram. PARTI'l'ION. In contrast to the caloric prescription which is not controversial, the partition of the diet into its components, carbohydrate, protein and fat, is controversial and influenced by several theories. The division of the normal diet is generally considered to be carbohydrate 50 per cent of the calories, protein 15 per cent and fat 35 per cent. All possible variations have been used in the prescription of the diabetic diet. The quantity of protein prescribed in the diet is usually the equivalent of the protein in the normal diet, 1 to 1.5 grams per kilogram of body weight. Positive nitrogen balance has been achieved with a fantastically low quantity of protein. High protein diets have been advocated when chemical control is difficult to achieve. Although wide fluctuations of blood sugars are avoided by maintaining carbohydrate below the nondiabetic (50 per cent) level, high carbohydrate diets have been prescribed in an effort to lower serum cholesterol. The quantity prescribed at the Joslin Clinic is some 40 per cent of the total calories and rarely exceeds 200 grams daily. The portion of the dietary calories given as fat has tended to increase recently so that 65 per cent of the fat calories may be given as polyunsaturated fatty acids. The division of the diet recommended by the Committee on Nutrition of the American Diabetes Association was carbohydrate 40 per cent, protein 15 to 20 per cent and fat 40 to 45 per cent.
The Treatrnent of Diabetes M ellitus
1181
It is obvious that the protein used should be of a high biological value, the fats adequate and of polyunsaturated variety, and the carbohydrate of low concentration with special consideration given to sugars not requiring insulin in the metabolism such as levulose, sorbital, etc. Thirty grams of sorbital may be added to the diabetic diet without producing hyperglycemia or glycosuria. Side effects, however, occur in the form of abdominal cramps and diarrhea. WEIGHED vs. ESTIMATED. The choice of the prescription of weighed or estimated diets or a combination depends upon two factors: the physician's concept of the seriousness of diabetes and the patient's natural compulsiveness. The combination of weighing and estimating is our own recommendation. CALCULATED VS. EXCHANGE. The use of calculated or exchange diets also depends upon the physician's attitude and the patient's aptitude. More patients have received and followed better diets since the introduction of the exchange system than ever before. It can be taught and understood readily. The more inquisitive patient is bothered by the inaccuracies of this system. FREE VS. DIABETIC OR NORMAL. The popularity of the free diet appears to be diminishing. Just as the psychiatrists set limits on behavior so, too, the students of diabetes are again setting limits upon the dietary prescription. Few physicians today advocate the free diet as defined as one without restrictions and one to be taken on demand. Standards for Control
The standards for the degree of control of diabetes are three: (1) physiological or ideal control; (2) chemical control and (3) clinical control. In the patient with ideal control, postprandial blood sugars are maintained at normal levels, the urine free from sugar and from ketone bodies and the level of blood lipids normal. Chemical control, considered good but not perfect, includes the normal levels of blood sugars before meals, the quantity of glucose excreted in 24 hours held ideally at 5 per cent and not exceeding 10 per cent of the carbohydrate intake, absence of ketonuria and normal levels for serum eholesterol. Clinical control sets no limits to the level of blood and urinary sugar, but insists upon freedom from symptoms, absence of ketonuria and normallipids. Clinical control has as its physiological basis the experimental evidence that the higher the level of blood sugar the higher the utilization of glucose. In clinical diabetes, however, the ensuing glycosuria is devastating. Clinical experience of the Joslin Clinic has shown the precipitation of retinopathy, nephropathy and neuropathy after bouts of poor chemical control and the reversibility of stages of these complications with the resumption of good chemical control.
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PRlSCILLA
W HI'l'l<~
Oral Substitutes for Insulin
When dietary treatment alolle fails in maturity onset diabetes, oral substitutes for insulin may be employed and, for the most part, either sulfonylureas or phenethylbiguanides may be used. The most probable explanation for the action of the sulfonylureas is the stimulation of the release of insulin and of the biguanides action through anaerobic glycolysis. The maximum dose of therapy recommended daily is 3 grams of Orinase, 500 mg. of Diabinese and 200 mg. of DBI. An Orinase screening test helps to sereen patients suitable for oral substitutes. Thus, if 3 grams of Orinase produce a 50 per cent fall of blood sugar in four hours, the patient is a suitable candidate for this therapy. The rules established originally to identify suitable patients continue to be helpful. These include an age at onset of diabetes of 40 or more years, an individual of stocky build and one whose requirements for insulin do not exceed 40 units. Secondary failures oecur in approximately 10 to 15 per cent of the eases. These probably represent the progression of diabetes in its natural course. Insulin Therapy
INSULINS. If the patient fails to maintain weight and strength with dietary management alone or with the addition of oral substitutes, insulin therapy is indicated. All insulins are good and none is perfect. It has been well established that exogenous insulin stimulates antibody production, that it may be antagonized, inhibited, destroyed, bound and always fails to respond to the demand of the body at the moment. Types. The choices for insulin therapy today ine1ude three elasses: short, quick; intermediate; and long, slowly acting. The short, quiekacting insulins are regular, semi-Iente and crystalline. The intermediateacting insulins are globin, lente and NPH; and the long, slowly-acting insulins are protamine zinc and ultra-Iente. Most students of diabetes choose among the intermediate group alone or in mixtures or in split-dose schedules. REGULATION OF PAT'l'ERNS OF TESTS. No matter which type of insulin is selected the maturity onset, nonketonic patient may be safely started with some 20 units and the insulin then regulated by tests. One of two techniques is usually employed; the first designated as "following the rainbow" and the other as "anticipating the poor tests." In the latter, which we practice, tests are made one day to plan the insulin program for the following day. These arc done most simply by using the pre-meal and retiring specimens-whenever possible, the second of two specimens. The second speeimen represents more nearly the level of the blood sugar or the metabolic state of the moment. Thus, if all the tests are poorpre-breakfast, pre-Iunch, pre-supper and bedtime-the total dose of
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1183
insulin is inadequate and the correction is attempted by an increase of some 4 units. This procedure is followed until some of the tests clear. When intermediate-acting insulins are used, a common response would be that the pre-Iunch test is difficult to clear but all other specimens are controlled easily. This indicates the need for quick-aeting insulin and the following day a mixture of rapidly-acting and intermediate-acting insulins is given before the breakfast meal. With severer degrees of diabetes, the glycosuria may be controlled during the day but nocturnal hyperglycemia develops. With maturity onset of diabetes the problem may be solved by a change from intermediate to long-acting insulin or the intermediate-acting insulin may be split and a dose of insulin given before breakfast and at bedtime. If two periods, pre-breakfast and bedtime, specimens are poor, then the timing of the insulin is changed to prebreakfast and pre-evening meal. It is usually unwise to alter both dietary and insulin prescriptions simultaneously. Certain escape periods, as after the evening meal, with intermediate-acting insulins, however, may be controlled by the subtraction of carbohydrate from the evening meal and the addition of carbohydrate at bedtime. With increasing duration of diabetes, more difficult problems in regulation arise (see Table 1). Thus, the patterns designated 8 and 9 Table 1.
Regulation of Quick- and Intermediate-Acting Insulins by Blood and Urine Tests URINE TESTS
-----~----
PATTERN
PreBreakfast
---~-----
PreLunch
Pre-
Supper
++++ ++++ 0 ++++
1
Bedtime
++++ ++++
0
0
++++
0 0
4
0
0
0
++++
5
0
0
2 3
0
++++ ++++
6
BSi
++++
0
BSN
0
0
7
BSi
++++
0
BSN
0
++++
8
BSi
0
-+-+++
0
0
9
BSi
+
0
0
0
BSi
REGULATION OF INSULIN
Increase total Add regular insulin Increase intermedia teacting Subtract carbo from supper, or give regular insulin before supper Increase pre-breakfast in termedia te Add intermediate at bedtime Pre-supper mixture regular and intermediate Increase or add bedtime intermediate Iteduce regular insulin; increase intermediate
1184
PRISCILLA WHITE
require a sophisticated approach. Pattern 8 is characterized by absence of glucose in the pre-breakfast specimen but the fasting blood sugar is elevated. This is commonly attributed to a high threshold but actually it represents a late rise of blood sugar, perhaps at 5:00 A.M. The urine was secreted earlier. A second specimen of urine obtained perhaps after breakfast and pre-Iunch is poor, and the correction is the addition of or increase in the bedtime dose. In Pattern 9 the slight elevation of blood sugar fasting and fall of blood sugar in the afternoon may be corrected by increasing intermediate and decreasing regular insulin before breakfast. With the patient requiring insulin, the division of the carbohydrate among the three major meals is important. A common popular division is one-fifth of the carbohydrate in the morning, two-fifths at noon and two-fifths at night. In addition, snacks are planned to match the peak action of the various types of insulin. Thus, the patient taking intermediate-acting insulin alone must be protected, particularly between two and four o'clock in the afternoon; the patient receiving regular insulin must be protected three hours after its administration; and the patient receiving the long-acting insulins must be protected, particularly during the night, by a bedtime snack. Management of Emergencies
Dietary and insulin rules must be changed to match emergency situations and altered states, examples of which would be the intercurrence of infections, the days of surgery and during the course of pregnancy. INFECTIONS. On a day of infection, for reasons which are not clear, the insulin requirement is increased; whether the insulin is actually inhibited, antagonized or altered is not known, so that a safe rule is the continuance of the basic dose of insulin and extra emergency, rapidlyacting insulin given at four-hour intervals (if the sugar is not controlled, at two-hour intervals). A simple dietary prescription is followed. Instead of the regular diet, liquids such as fruit juices, regular ginger ale and Coca-Cola, milk and eggnog may be employed. A good rule would be 8 ounces every two hours, eight feedings. When these simple rules arc forgotten by patients, keto-acidosis is common during epidemics of influenza, grippe, etc. SURGERY. On the day of operation the usual dose of insulin is frequently halved, one-half being given at the usual time and the second immediately following the surgical procedure, and the dietary needs of the day are given in the form of intravenous glucose. Every effort should be made to have the patient utilize a minimum of 100 grams of glucose. PREGNANCY. The demands of pregnancy, both for diet and insulin, are great indeed. In the first trimester, when pituitary inhibition occurs, the insulin requirement may fall dramatically, but in the second and
The Treatment of Diabetes M ellitus
1185
third trimesters the insulin need increases. The average for our own series of patients was an increase of 66 per cent. The requirement for carbohydrate and protein is relatively high, although the total calories should be controlled to prevent an excessive gain in weight. Our own program includes a diet of 200 grams of carbohydrate, 100 of protein, and fat to complete the caloric prescription of 30 calories per kilogram of initial weight, and this is maintained until almost the end of pregnancy when the fat prescription is increased slightly. Insulin is sometimes combined with oral substitute. The evidence of potentiation of the action of insulin by oral substitute is significant in relation to phenethylbiguanides but not conclusive in relation to sulfonylureas. One hundred and fifty to 200 mg. of phenethylbiguanide will replace approximately 50 per cent of the required insulin. This combination may be desirable when the patient has insulin reactions without warning. GROWTH
O~SE'I'
DIABETES
Acu'r.l<~ ONSET. In growth onset diabetes, dramatic chemical and structural changes occur in a relatively short period of time. At the diagnosis of growth onset diabetes, the insulin-like activity of the serum is greater than normal. By the fifth year of the duration of diabetes it has dropped to zero in the majority of cases. The quantity of insulin extracted from the pancreas, slightly subnormal at diagnosis, drops to zero to 10 per cent by the fifth year, and the hypertrophied islets characteristic of growth onset diabetes at diagnosis have disappeared by the fifth year, at which time the islets have become few and are atrophic. They show no granules indicating release of insulin. Remissions of growth onset diabetes are documented in one-third of the patients. They last on the average 1.'5 months, but intensification of diabetes in this age group follows growth, the development of puberty and infections, so that by the fifth year of the duration of diabetes 94 per cent have become totally diabetic.
The Management of Growth Onset Diabetes
The principles for the management of growth onset diabetes include insulin for the treatment of the diabetes itself and a dietary program to promote normal rates of growth and development. INSULIN THERAPY. The quantity of insulin to be prescribed for growth onset diabetes depends more upon the size and age of the individual than it does upon the degree of hyperglycemia and glycosuria. For the nonketotic child, a safe initial dose is U unit per pound of body weight, for the child with extreme hyperglycemia and acetonuria, Y2 unit per pound of body weight, and for the patient who has significant
1186
PRISCILLA
W HI'l'E
ketosis, 1 unit per pound of body weight. The rules for the regulation of insulin are the same as for the adult. When the totally diabetic state has been reached, the insulin requirement becomes Yz unit per pound of body weight, and to control the nocturnal hypcrglycemia the intermediate-acting insulin must be split. The choice of insulin for growth onset diabetes is of the intermediate-acting type. Because of the severity of the disease in childhood, when rapidly acting insulin is used it must be given four times in 24 hours and the last dose of insulin to achieve chemical control would be at two o'clock in the morning. The long, slowly-acting insulins appear ideal, but with them the tendency to produce severe nocturnal hypoglycemia is too great, and the best, the simplest, the most uncomplicated states are achieved by the use of intermediate-acting insulins in this age group. DIET. The dietary rules for the growth onset patients are as follows: A simple rule is to prescribe 1000 calories at age 1, add 100 calories per each year of age until the completion of growth. Girls complete their growth at age 13 and their maximum diet would be 2200 calories. Boys grow until the age of 20 and their maximum diet is some 3000 calories. Because obesity is one of the plaguing problems with the adolescent diabetic girl, the dietary prescription may require reduction to the level of the adult patient, 30 calories per kilogram of ideal body weight for hcight and age. Another rule is 100 calories per kilogram of body weight in infancy, dropping to 80 at age ,1'>, 60 at age 10, and 40 at age 15. Still another is based upon height, 35 ealories per inch, and another upon basal metabolism, based on surface area double the theoretieal basal metabolism. The division of the diet for this age group is 40 per cent of the calories as carbohydrate, 20 per cent as protein, and 40 per cent as fat. Although sulfonylureas and phenethylbiguanides eontrol growth onset diabetes during the remission phase, for psychological reasons sueh a program is not advocated. When insulin has been started, omitted, and then must be restarted, a difficult family situation is ereated. COMPLICATIONS OF ACUTE DIABE'l'ES Complications of acute overt diabetes include coma, infections, and severe hypoglycemia without warning. Infections in the population with diabetes respond to antibiotics and chemotherapy, just as they do in the general population. The type of infeetion sites are speeific in diabetes, namely, skin, urinary traet, bone and lung. Today the management of diabetic coma is so satisfactory that reeovery is guaranteed unless the patient has a lethal complication or enters the hospital moribund. It ineludes adequate doses of rapidly-acting insulin, fluid to correct dehydration, and electrolytes to repair their loss.
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1187
Attempts to Alter the Course of Diabetes
Attempts to precipitate and prolong remissions have been made. Brusch and Umber recommended almost simultaneously the use of overinsulinization at onset. White tried to duplicate the Houssay experiment, using thyroxin, cortisone, sulfonylureas and biguanide in the remission phase. Transplants of fetal pancreas and islet cell tumors have been given in overt and chronic stages of diabetes. No permanent effect upon the course of growth onset diabetes has been established by these methods. CHRONIC DIABETES
Chronic diabetes is defined here as that stage of diabetes in which vascular lesions are manifest clinically. Although neuropathies occur in any period they, too, tend to be more conspicuous in this later stage of diabetes. The vulnerability of the vascular system in the diabetic has already been emphasized by the demonstration of changes demonstrable by the electron microscope and the plasmograph, oscillograph, and the magnifying instruments used to examine the bulbar conjunctiva. These changes were d(~monstrable in the prediabetic state, at the time prior to the period when hyperglycemia could be provoked. The therapy of chronic diabetes is confined to the attempts to reverse or correct the vascular lesions. The sites of vascular damage in chronic diabetes are the vessels of the foot and leg in the aged, the coronary vessels in those who develop diabetes in middle life, the glomerulus and the retina in those who develop diabetes in youth. MANAGEMENT OF VASCULAH CHANGES OF THE EXTHEMITIES. Prevention of the foot lesions characteristic of chronic diabetes is sought by the establishment of open collateral circulation through general and specific exercise. Prevention of the lesions, too, is sought by prompt treatment of infections and the avoidance of injury. In our experience, vasodilators have not been fortuitous. Arterial reconstruction and conservative surgical procedures give these patients a better prognosis than they had formerly. HEAHT DISEASJ
1188
FRISCILLA
W Hl'rE
RETINOPA'l'HY. The correlation of control, that is, the effect of improved control of diabetes is best seen in the retinal lesions. In this discussion, retinopathy is divided into three classes, Grades I, Il and Ill. Grade I is characterized by micro-aneurysms, round hemorrhages, dilated veins; Grade Il by the presence of exudate and blotchy hem orrhages; and Grade III by preretinal hemorrhages, vitreous hemorrhages, scars and new blood vessel formation. A positive correlation between retinopathy and keto-acidosis is well established. Grades I and Il retinopathies are precipitated during periods of poor chemical control, and reversals are seen when good control of diabetes is resumed. Control, however, is not the only factor that influences the course of retinopathy. Lesions are precipitated with infections and reversals follow the elimination of the infection. The lesions may be precipitated in pregnancy and reversed with the termination of pregnancy. The characteristic lesions of Grade In retinopathy, the scars and new blood vessel formation do not appear to he reversed with good control. The most dramatic examples of reversal have occurred in the patients who have developed pituitary necrosis or those in whom the operation for stalk section has been done. 7
SUMMARY
Today the expectation of life of individuals with diabetes is greater than three-quarters of the normal. Control of diabetes has been facilitated with combinations of the insulins and oral substitutes. Prediabetes is recognized; chemical diabetes appears to be reversible in some instances; attempts have been made to alter the course of overt diabetes, and some of the lesions characteristic of chronic diabetes have been reversed in part or in whole. REFERENCES 1. Camerini, R.: Proc. 4th Congress International Diabetes Federation, 1961. 2. Camerini, R., Marble, A., Dhamdhere, M. R., Rees, S. B., Lawrence, D. G. and Freedlender, A.: Ibid. 3. Conn, J. W.: Diabetes 7: 347,1958. 4. Diamond, L.: Personal communication. 5. Fajans, S.: Proc. 4th Congress International Diabetes Federation, 1961, p. 167. 6. Fajans, S. and Conn, J. W.: Ibid. 7. Field, J., Hall, W. A., Contreras, J. S. and Sweet, W. H., New England J. Med. 14: 689, 1961. 8. Hoet, J. P. and Lukens, F. D. W.: Diabetes 3: 1, 1954. 9. Joslin, E. P., Root, H. F., White, P. and Marble, A.: Treatment of Diabetes Mellitus. 10th Ed. Philadelphia, Lea & Febiger, 1959. 10. Kinsell, L.: Am. J. Clin. Nutrition 3: 247, 1955. 11. LeCompte, P.: In Diabetes eR. H. Williams, Ed.). New York, Harper, Inc., 1959, p. 9. 12. Pincus, G. and White, P.: In Joslin, E. P., Root, H. F., White, P. and Marble, A.9
The Treatment of Diabetes M ellitus 13. 14. 15. 16. 17. 18. 19. 20.
1189
Post, R. and White, P.: Diabetes 7: 27,1958. Schwachman: Personal communication. Steinberg, A.: Eugenics Quart. 2: 26, 1955. Steinke, J., Camerini, R., Marble, A. and Renold, A.: Metabolism 10: 707,1961. Wagner, R., White, P. and Bogan, 1. K: Am. J. Dis. Child. 63: 667,1942. White, P.: Diabetes .9: 345, 1960. Wilkerson, H. L. C.: Am. J Public Health 49: 1032, 1959. Wrenshall, G.: In Diabetes (R. H. WilIiams, Ed.). New York, Harper, Inc., 1959, p. 436.
15 Joslin Road Boston 15, Massachusetts
PRI8CILLA WHITE, M.D., F.A.C.P.
objectives in the overall treatment of diabetes have been broadened by the newer concept of the progression of diabetes through four distinct stages: prediabetes, chemical diabetes, acute overt and chronic diabetes. The goals of management have become the prevention of the progression of prediabetes to the second stage, the reversal of chemical diabetes, the alteration of the course of acute diabetes, the prevention, postponement or correction of the characteristics of chronic diabetes.
THE
PREDIABETES
Although the management of overt diabetes is the common problem of the physician, the recognition of and plan for the prediabetic is his new responsibility. Prediabetes is defined here as the period from conception until the time when the glucose tolerance test becomes positive. Diagnosis FAMILY HIS'fOHY. The recognition of prediabetes may he made in part or suspected by the family history. The expcrience through the years has supported the thesis that the tendency to develop diabetcs is inherited 12 and that the transmission is through Mendelian recessivc genes. The positive identification of prediabetes is possible in three genetic groups: the offspring of two diabetics, both parents of a family of children all of whom have diabetes, and the identical twins of diabetics. The probability for the development of diabetes is great: 85 per cent if one parent has diabetes and on the opposite side of the family a grandparent and aunt or uncle have it; 60 per cent if one parent has diabetes and on the opposite side a grandparent or aunt or uncle. The probability drops to 40 per cent if a parent has diabetes and on the opposite side a first cousin, 22 per cent if one parent has diabetes, 14 per cent if a grandparent, 9 per cent a first cousin. 15 The family history reveals the susceptibility of the group rather than the susceptible individual.
1177
1178
PmSCILLA WHl'l'E
PAST HIS'l'OHY. Past histories yield significant data. The correlation between heavy birth weight and maternal diabetes is well known. The chances for the development of diabetes in the mother are 100 per cent when the infant's birth weight is 14 pounds, 90 per cent when it is 13 poundR. 9 It is less well known that heavy birth weight (greater than 8 pounds 4 ounces) may predict the onset of diabetes in the individual in adult life. The events in the past history of females have shown a highly positive correlation with maturity onset diabetes. Early menarche is the rule. IS Women who develop diabetes after age 18 have the earliest recorded menarche. Obstetrical accidents are common. These obstetrical abnormalities include the occurrence of toxemia, hydramnios, intrauterine or intrapartum deaths. The status of the infant and child may forewarn of maternal diabetes. In addition to the large size of the newborn infant, the presence of congenital anomalies of islet hyperplasia and hypertrophy and the continued accelerated rate of growth of the child are significant signs of maternal prediabetes. The past history of erythroblastosis,4 chronic cystic fibrosis1 4 of the pancreas and pancreatitis as well as of functional hypoglycemia& should not be ignored in respect to the posRible future development of diabetes. PHYSICAI~ EXAMINATION. Pertinent physical signs are obesity,9 total growth in advance of the chronological age lS and the occurrence of congenital anomalies. 17 VASCULAR LESIONS. Important vascular changes, functional responses and histological lesions have been found in genetic prediabetes. Oscillographic pulse tracings in genetic prediabetes tend to be comparable to those of overt diabetes. The second component of the normally dicrotic wave appears to be obliterated (26 per cent sensitivity). The microvascular changes characteristic of diabetes appear in prediabetes. Venular dilatation was found in the bulbar conjunctiva in 92 per cent. Percutaneous renal biopsy and cutaneous ear lobe biopsy have shown basement membrane changes in electron microscopic studies. CHEMICAL TESTS. Chemical tests appear to help identify the prediabetic state also. Of all possible tests, the random blood sugar is the simplest. Hypoglycemia is of significance. 3 The curves of simultaneous venous and capillary bloods obtained in the course of the standard glucose tolerance test are informative. The sum of the difference between capillary and venous blood at 30 and 60 minutes should be greater than the sum of the difference between capillary and venous blood at 60 and 90 minutes and the index should be greater than 1. 12 The reverse is true in diabetes and genetic prediabetics have shown the characteristic curve of diabetes with blood sugars at normal levels. The sensitivity is 41 per cent. 1 Of greatest significance because it may be related to obesity in maturity onset and overgrowth in juvenile onset diabetes is the increase in the insulin-like activity of the serum in the genetic prediabetic. 16
The Treatment of Diabetes lYIellitus
1179
Research Programs
Programs have been designed to impede the progress of prediabetes. The interval of time which has elapsed since their introduction has not been significant. Substances which protect islet tissue and favor hypertrophy and hyperplasia are being used; for example, sulfonylureas. The use of a schedule utilizing muscular exercise is favored. The value of muscular exercise is not limited to the rapid utilization of glucose but is believed to favor the production of an X factor which is insulin-like in its activity promoting the transport of glucose across the cell membrane. 6 A third part of the program limits the quantity and the concentration of carbohydrate in the diet. CHEMICAL DIABETES
Diagnosis
Chemical diabetes is defined as the stage of diabetes in which the level of the random blood sugar is normal. The clinical symptoms of diabetes are absent but the administration of glucose provokes a hyperglycemic response. No uniformity for diagnostic levels of glucose in chemical diabetes exists. The diagnostic level of glucose accepted by the Joslin Clinic is the rise to 150 mg. true glucose postprandially or fall of glucose to a level of 110 mg. or more in two hours for venous blood, rise to 180 mg. for capillary blood or fall to 100 mg. in three hours. Programs
The plans for long-range observation in respect to chemical diabetes are noteworthy. Conn and Fajans have recommended the use of sulfonylureas in chemical diabetes. Hoet S has advised insulin to tolerance in gestational chemical diabetes. In his patients, whose diets were fairly free and consisted of large quantities of potato, the dose required was 30 units of regular insulin twice daily. With controlled diets, Wilkerson 19 found 6 to 20 units of intermediate acting insulin adequate for control. The rate of progression of chemical diabetes is variable. It may be rapid or slow or it may be a stable state. In youth it is difficult to demonstrate and progression from the stage characterized by normal glucose tolerance to overt diabetes in young individuals may occur in a few months. OVERT DIABETES
Overt diabetes is characterized by the classical symptoms of polyuria, polyphagia, polydipsia and by the elevation of glucose in the random
1180
PRISCILLA VVHITE
sampling of blood. It exists in two forms, maturity and growth onset, which appear to be different degrees of the same disorder. In pathology, chemistry and in natural course, they show differences which are not only significant but which influence their respective therapies. MATURITY ONSET DIABETES CHARACTERISTICS. Total beta cell mass is reduced in maturity onset diabetes.ll The quantity of insulin which can be extracted from the pancreas (IEP) is 25 to 75 per cent of normal and insulin-like activity (ILA) is found in the serum in nearly normal quantities. In the natural course of typical maturity onset diabetes, the status is one of more or less stability. Neither remissions nor rapid progression are striking and common events. Dietary Treatment
CALOIUES. Dietary control of this type of diabeteH is not only possible but desirable. The caloric prescription is influeneed by the objeetives, which may be to maintain ideal weight for height and age, more often to promote reduction of weight, less often to achieve increase in weight. Using the measure of body weight in kilograms, the maintenance diet is 30 calories per kilogram of body weight, the reducing diet 20 calories per kilogram and the weight-increasing diet 40 calories per kilogram. PARTI'l'ION. In contrast to the caloric prescription which is not controversial, the partition of the diet into its components, carbohydrate, protein and fat, is controversial and influenced by several theories. The division of the normal diet is generally considered to be carbohydrate 50 per cent of the calories, protein 15 per cent and fat 35 per cent. All possible variations have been used in the prescription of the diabetic diet. The quantity of protein prescribed in the diet is usually the equivalent of the protein in the normal diet, 1 to 1.5 grams per kilogram of body weight. Positive nitrogen balance has been achieved with a fantastically low quantity of protein. High protein diets have been advocated when chemical control is difficult to achieve. Although wide fluctuations of blood sugars are avoided by maintaining carbohydrate below the nondiabetic (50 per cent) level, high carbohydrate diets have been prescribed in an effort to lower serum cholesterol. The quantity prescribed at the Joslin Clinic is some 40 per cent of the total calories and rarely exceeds 200 grams daily. The portion of the dietary calories given as fat has tended to increase recently so that 65 per cent of the fat calories may be given as polyunsaturated fatty acids. The division of the diet recommended by the Committee on Nutrition of the American Diabetes Association was carbohydrate 40 per cent, protein 15 to 20 per cent and fat 40 to 45 per cent.
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1181
It is obvious that the protein used should be of a high biological value, the fats adequate and of polyunsaturated variety, and the carbohydrate of low concentration with special consideration given to sugars not requiring insulin in the metabolism such as levulose, sorbital, etc. Thirty grams of sorbital may be added to the diabetic diet without producing hyperglycemia or glycosuria. Side effects, however, occur in the form of abdominal cramps and diarrhea. WEIGHED vs. ESTIMATED. The choice of the prescription of weighed or estimated diets or a combination depends upon two factors: the physician's concept of the seriousness of diabetes and the patient's natural compulsiveness. The combination of weighing and estimating is our own recommendation. CALCULATED VS. EXCHANGE. The use of calculated or exchange diets also depends upon the physician's attitude and the patient's aptitude. More patients have received and followed better diets since the introduction of the exchange system than ever before. It can be taught and understood readily. The more inquisitive patient is bothered by the inaccuracies of this system. FREE VS. DIABETIC OR NORMAL. The popularity of the free diet appears to be diminishing. Just as the psychiatrists set limits on behavior so, too, the students of diabetes are again setting limits upon the dietary prescription. Few physicians today advocate the free diet as defined as one without restrictions and one to be taken on demand. Standards for Control
The standards for the degree of control of diabetes are three: (1) physiological or ideal control; (2) chemical control and (3) clinical control. In the patient with ideal control, postprandial blood sugars are maintained at normal levels, the urine free from sugar and from ketone bodies and the level of blood lipids normal. Chemical control, considered good but not perfect, includes the normal levels of blood sugars before meals, the quantity of glucose excreted in 24 hours held ideally at 5 per cent and not exceeding 10 per cent of the carbohydrate intake, absence of ketonuria and normal levels for serum eholesterol. Clinical control sets no limits to the level of blood and urinary sugar, but insists upon freedom from symptoms, absence of ketonuria and normallipids. Clinical control has as its physiological basis the experimental evidence that the higher the level of blood sugar the higher the utilization of glucose. In clinical diabetes, however, the ensuing glycosuria is devastating. Clinical experience of the Joslin Clinic has shown the precipitation of retinopathy, nephropathy and neuropathy after bouts of poor chemical control and the reversibility of stages of these complications with the resumption of good chemical control.
1182
PRlSCILLA
W HI'l'l<~
Oral Substitutes for Insulin
When dietary treatment alolle fails in maturity onset diabetes, oral substitutes for insulin may be employed and, for the most part, either sulfonylureas or phenethylbiguanides may be used. The most probable explanation for the action of the sulfonylureas is the stimulation of the release of insulin and of the biguanides action through anaerobic glycolysis. The maximum dose of therapy recommended daily is 3 grams of Orinase, 500 mg. of Diabinese and 200 mg. of DBI. An Orinase screening test helps to sereen patients suitable for oral substitutes. Thus, if 3 grams of Orinase produce a 50 per cent fall of blood sugar in four hours, the patient is a suitable candidate for this therapy. The rules established originally to identify suitable patients continue to be helpful. These include an age at onset of diabetes of 40 or more years, an individual of stocky build and one whose requirements for insulin do not exceed 40 units. Secondary failures oecur in approximately 10 to 15 per cent of the eases. These probably represent the progression of diabetes in its natural course. Insulin Therapy
INSULINS. If the patient fails to maintain weight and strength with dietary management alone or with the addition of oral substitutes, insulin therapy is indicated. All insulins are good and none is perfect. It has been well established that exogenous insulin stimulates antibody production, that it may be antagonized, inhibited, destroyed, bound and always fails to respond to the demand of the body at the moment. Types. The choices for insulin therapy today ine1ude three elasses: short, quick; intermediate; and long, slowly acting. The short, quiekacting insulins are regular, semi-Iente and crystalline. The intermediateacting insulins are globin, lente and NPH; and the long, slowly-acting insulins are protamine zinc and ultra-Iente. Most students of diabetes choose among the intermediate group alone or in mixtures or in split-dose schedules. REGULATION OF PAT'l'ERNS OF TESTS. No matter which type of insulin is selected the maturity onset, nonketonic patient may be safely started with some 20 units and the insulin then regulated by tests. One of two techniques is usually employed; the first designated as "following the rainbow" and the other as "anticipating the poor tests." In the latter, which we practice, tests are made one day to plan the insulin program for the following day. These arc done most simply by using the pre-meal and retiring specimens-whenever possible, the second of two specimens. The second speeimen represents more nearly the level of the blood sugar or the metabolic state of the moment. Thus, if all the tests are poorpre-breakfast, pre-Iunch, pre-supper and bedtime-the total dose of
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1183
insulin is inadequate and the correction is attempted by an increase of some 4 units. This procedure is followed until some of the tests clear. When intermediate-acting insulins are used, a common response would be that the pre-Iunch test is difficult to clear but all other specimens are controlled easily. This indicates the need for quick-aeting insulin and the following day a mixture of rapidly-acting and intermediate-acting insulins is given before the breakfast meal. With severer degrees of diabetes, the glycosuria may be controlled during the day but nocturnal hyperglycemia develops. With maturity onset of diabetes the problem may be solved by a change from intermediate to long-acting insulin or the intermediate-acting insulin may be split and a dose of insulin given before breakfast and at bedtime. If two periods, pre-breakfast and bedtime, specimens are poor, then the timing of the insulin is changed to prebreakfast and pre-evening meal. It is usually unwise to alter both dietary and insulin prescriptions simultaneously. Certain escape periods, as after the evening meal, with intermediate-acting insulins, however, may be controlled by the subtraction of carbohydrate from the evening meal and the addition of carbohydrate at bedtime. With increasing duration of diabetes, more difficult problems in regulation arise (see Table 1). Thus, the patterns designated 8 and 9 Table 1.
Regulation of Quick- and Intermediate-Acting Insulins by Blood and Urine Tests URINE TESTS
-----~----
PATTERN
PreBreakfast
---~-----
PreLunch
Pre-
Supper
++++ ++++ 0 ++++
1
Bedtime
++++ ++++
0
0
++++
0 0
4
0
0
0
++++
5
0
0
2 3
0
++++ ++++
6
BSi
++++
0
BSN
0
0
7
BSi
++++
0
BSN
0
++++
8
BSi
0
-+-+++
0
0
9
BSi
+
0
0
0
BSi
REGULATION OF INSULIN
Increase total Add regular insulin Increase intermedia teacting Subtract carbo from supper, or give regular insulin before supper Increase pre-breakfast in termedia te Add intermediate at bedtime Pre-supper mixture regular and intermediate Increase or add bedtime intermediate Iteduce regular insulin; increase intermediate
1184
PRISCILLA WHITE
require a sophisticated approach. Pattern 8 is characterized by absence of glucose in the pre-breakfast specimen but the fasting blood sugar is elevated. This is commonly attributed to a high threshold but actually it represents a late rise of blood sugar, perhaps at 5:00 A.M. The urine was secreted earlier. A second specimen of urine obtained perhaps after breakfast and pre-Iunch is poor, and the correction is the addition of or increase in the bedtime dose. In Pattern 9 the slight elevation of blood sugar fasting and fall of blood sugar in the afternoon may be corrected by increasing intermediate and decreasing regular insulin before breakfast. With the patient requiring insulin, the division of the carbohydrate among the three major meals is important. A common popular division is one-fifth of the carbohydrate in the morning, two-fifths at noon and two-fifths at night. In addition, snacks are planned to match the peak action of the various types of insulin. Thus, the patient taking intermediate-acting insulin alone must be protected, particularly between two and four o'clock in the afternoon; the patient receiving regular insulin must be protected three hours after its administration; and the patient receiving the long-acting insulins must be protected, particularly during the night, by a bedtime snack. Management of Emergencies
Dietary and insulin rules must be changed to match emergency situations and altered states, examples of which would be the intercurrence of infections, the days of surgery and during the course of pregnancy. INFECTIONS. On a day of infection, for reasons which are not clear, the insulin requirement is increased; whether the insulin is actually inhibited, antagonized or altered is not known, so that a safe rule is the continuance of the basic dose of insulin and extra emergency, rapidlyacting insulin given at four-hour intervals (if the sugar is not controlled, at two-hour intervals). A simple dietary prescription is followed. Instead of the regular diet, liquids such as fruit juices, regular ginger ale and Coca-Cola, milk and eggnog may be employed. A good rule would be 8 ounces every two hours, eight feedings. When these simple rules arc forgotten by patients, keto-acidosis is common during epidemics of influenza, grippe, etc. SURGERY. On the day of operation the usual dose of insulin is frequently halved, one-half being given at the usual time and the second immediately following the surgical procedure, and the dietary needs of the day are given in the form of intravenous glucose. Every effort should be made to have the patient utilize a minimum of 100 grams of glucose. PREGNANCY. The demands of pregnancy, both for diet and insulin, are great indeed. In the first trimester, when pituitary inhibition occurs, the insulin requirement may fall dramatically, but in the second and
The Treatment of Diabetes M ellitus
1185
third trimesters the insulin need increases. The average for our own series of patients was an increase of 66 per cent. The requirement for carbohydrate and protein is relatively high, although the total calories should be controlled to prevent an excessive gain in weight. Our own program includes a diet of 200 grams of carbohydrate, 100 of protein, and fat to complete the caloric prescription of 30 calories per kilogram of initial weight, and this is maintained until almost the end of pregnancy when the fat prescription is increased slightly. Insulin is sometimes combined with oral substitute. The evidence of potentiation of the action of insulin by oral substitute is significant in relation to phenethylbiguanides but not conclusive in relation to sulfonylureas. One hundred and fifty to 200 mg. of phenethylbiguanide will replace approximately 50 per cent of the required insulin. This combination may be desirable when the patient has insulin reactions without warning. GROWTH
O~SE'I'
DIABETES
Acu'r.l<~ ONSET. In growth onset diabetes, dramatic chemical and structural changes occur in a relatively short period of time. At the diagnosis of growth onset diabetes, the insulin-like activity of the serum is greater than normal. By the fifth year of the duration of diabetes it has dropped to zero in the majority of cases. The quantity of insulin extracted from the pancreas, slightly subnormal at diagnosis, drops to zero to 10 per cent by the fifth year, and the hypertrophied islets characteristic of growth onset diabetes at diagnosis have disappeared by the fifth year, at which time the islets have become few and are atrophic. They show no granules indicating release of insulin. Remissions of growth onset diabetes are documented in one-third of the patients. They last on the average 1.'5 months, but intensification of diabetes in this age group follows growth, the development of puberty and infections, so that by the fifth year of the duration of diabetes 94 per cent have become totally diabetic.
The Management of Growth Onset Diabetes
The principles for the management of growth onset diabetes include insulin for the treatment of the diabetes itself and a dietary program to promote normal rates of growth and development. INSULIN THERAPY. The quantity of insulin to be prescribed for growth onset diabetes depends more upon the size and age of the individual than it does upon the degree of hyperglycemia and glycosuria. For the nonketotic child, a safe initial dose is U unit per pound of body weight, for the child with extreme hyperglycemia and acetonuria, Y2 unit per pound of body weight, and for the patient who has significant
1186
PRISCILLA
W HI'l'E
ketosis, 1 unit per pound of body weight. The rules for the regulation of insulin are the same as for the adult. When the totally diabetic state has been reached, the insulin requirement becomes Yz unit per pound of body weight, and to control the nocturnal hypcrglycemia the intermediate-acting insulin must be split. The choice of insulin for growth onset diabetes is of the intermediate-acting type. Because of the severity of the disease in childhood, when rapidly acting insulin is used it must be given four times in 24 hours and the last dose of insulin to achieve chemical control would be at two o'clock in the morning. The long, slowly-acting insulins appear ideal, but with them the tendency to produce severe nocturnal hypoglycemia is too great, and the best, the simplest, the most uncomplicated states are achieved by the use of intermediate-acting insulins in this age group. DIET. The dietary rules for the growth onset patients are as follows: A simple rule is to prescribe 1000 calories at age 1, add 100 calories per each year of age until the completion of growth. Girls complete their growth at age 13 and their maximum diet would be 2200 calories. Boys grow until the age of 20 and their maximum diet is some 3000 calories. Because obesity is one of the plaguing problems with the adolescent diabetic girl, the dietary prescription may require reduction to the level of the adult patient, 30 calories per kilogram of ideal body weight for hcight and age. Another rule is 100 calories per kilogram of body weight in infancy, dropping to 80 at age ,1'>, 60 at age 10, and 40 at age 15. Still another is based upon height, 35 ealories per inch, and another upon basal metabolism, based on surface area double the theoretieal basal metabolism. The division of the diet for this age group is 40 per cent of the calories as carbohydrate, 20 per cent as protein, and 40 per cent as fat. Although sulfonylureas and phenethylbiguanides eontrol growth onset diabetes during the remission phase, for psychological reasons sueh a program is not advocated. When insulin has been started, omitted, and then must be restarted, a difficult family situation is ereated. COMPLICATIONS OF ACUTE DIABE'l'ES Complications of acute overt diabetes include coma, infections, and severe hypoglycemia without warning. Infections in the population with diabetes respond to antibiotics and chemotherapy, just as they do in the general population. The type of infeetion sites are speeific in diabetes, namely, skin, urinary traet, bone and lung. Today the management of diabetic coma is so satisfactory that reeovery is guaranteed unless the patient has a lethal complication or enters the hospital moribund. It ineludes adequate doses of rapidly-acting insulin, fluid to correct dehydration, and electrolytes to repair their loss.
The Treatment of Diabetes M ellitus
1187
Attempts to Alter the Course of Diabetes
Attempts to precipitate and prolong remissions have been made. Brusch and Umber recommended almost simultaneously the use of overinsulinization at onset. White tried to duplicate the Houssay experiment, using thyroxin, cortisone, sulfonylureas and biguanide in the remission phase. Transplants of fetal pancreas and islet cell tumors have been given in overt and chronic stages of diabetes. No permanent effect upon the course of growth onset diabetes has been established by these methods. CHRONIC DIABETES
Chronic diabetes is defined here as that stage of diabetes in which vascular lesions are manifest clinically. Although neuropathies occur in any period they, too, tend to be more conspicuous in this later stage of diabetes. The vulnerability of the vascular system in the diabetic has already been emphasized by the demonstration of changes demonstrable by the electron microscope and the plasmograph, oscillograph, and the magnifying instruments used to examine the bulbar conjunctiva. These changes were d(~monstrable in the prediabetic state, at the time prior to the period when hyperglycemia could be provoked. The therapy of chronic diabetes is confined to the attempts to reverse or correct the vascular lesions. The sites of vascular damage in chronic diabetes are the vessels of the foot and leg in the aged, the coronary vessels in those who develop diabetes in middle life, the glomerulus and the retina in those who develop diabetes in youth. MANAGEMENT OF VASCULAH CHANGES OF THE EXTHEMITIES. Prevention of the foot lesions characteristic of chronic diabetes is sought by the establishment of open collateral circulation through general and specific exercise. Prevention of the lesions, too, is sought by prompt treatment of infections and the avoidance of injury. In our experience, vasodilators have not been fortuitous. Arterial reconstruction and conservative surgical procedures give these patients a better prognosis than they had formerly. HEAHT DISEASJ
1188
FRISCILLA
W Hl'rE
RETINOPA'l'HY. The correlation of control, that is, the effect of improved control of diabetes is best seen in the retinal lesions. In this discussion, retinopathy is divided into three classes, Grades I, Il and Ill. Grade I is characterized by micro-aneurysms, round hemorrhages, dilated veins; Grade Il by the presence of exudate and blotchy hem orrhages; and Grade III by preretinal hemorrhages, vitreous hemorrhages, scars and new blood vessel formation. A positive correlation between retinopathy and keto-acidosis is well established. Grades I and Il retinopathies are precipitated during periods of poor chemical control, and reversals are seen when good control of diabetes is resumed. Control, however, is not the only factor that influences the course of retinopathy. Lesions are precipitated with infections and reversals follow the elimination of the infection. The lesions may be precipitated in pregnancy and reversed with the termination of pregnancy. The characteristic lesions of Grade In retinopathy, the scars and new blood vessel formation do not appear to he reversed with good control. The most dramatic examples of reversal have occurred in the patients who have developed pituitary necrosis or those in whom the operation for stalk section has been done. 7
SUMMARY
Today the expectation of life of individuals with diabetes is greater than three-quarters of the normal. Control of diabetes has been facilitated with combinations of the insulins and oral substitutes. Prediabetes is recognized; chemical diabetes appears to be reversible in some instances; attempts have been made to alter the course of overt diabetes, and some of the lesions characteristic of chronic diabetes have been reversed in part or in whole. REFERENCES 1. Camerini, R.: Proc. 4th Congress International Diabetes Federation, 1961. 2. Camerini, R., Marble, A., Dhamdhere, M. R., Rees, S. B., Lawrence, D. G. and Freedlender, A.: Ibid. 3. Conn, J. W.: Diabetes 7: 347,1958. 4. Diamond, L.: Personal communication. 5. Fajans, S.: Proc. 4th Congress International Diabetes Federation, 1961, p. 167. 6. Fajans, S. and Conn, J. W.: Ibid. 7. Field, J., Hall, W. A., Contreras, J. S. and Sweet, W. H., New England J. Med. 14: 689, 1961. 8. Hoet, J. P. and Lukens, F. D. W.: Diabetes 3: 1, 1954. 9. Joslin, E. P., Root, H. F., White, P. and Marble, A.: Treatment of Diabetes Mellitus. 10th Ed. Philadelphia, Lea & Febiger, 1959. 10. Kinsell, L.: Am. J. Clin. Nutrition 3: 247, 1955. 11. LeCompte, P.: In Diabetes eR. H. Williams, Ed.). New York, Harper, Inc., 1959, p. 9. 12. Pincus, G. and White, P.: In Joslin, E. P., Root, H. F., White, P. and Marble, A.9
The Treatment of Diabetes M ellitus 13. 14. 15. 16. 17. 18. 19. 20.
1189
Post, R. and White, P.: Diabetes 7: 27,1958. Schwachman: Personal communication. Steinberg, A.: Eugenics Quart. 2: 26, 1955. Steinke, J., Camerini, R., Marble, A. and Renold, A.: Metabolism 10: 707,1961. Wagner, R., White, P. and Bogan, 1. K: Am. J. Dis. Child. 63: 667,1942. White, P.: Diabetes .9: 345, 1960. Wilkerson, H. L. C.: Am. J Public Health 49: 1032, 1959. Wrenshall, G.: In Diabetes (R. H. WilIiams, Ed.). New York, Harper, Inc., 1959, p. 436.
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