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Prediabetes
Prediabetes HENRY L. WILDBERGER, M.D. Assistant Professor of Medicine, Northwestern University M edical School; Staff, Chicago Wesley Memorial Hospital
HENRY T. RICKE1'TS, M.D. Professor of Medicine, University of Chicago School of Medicine; Staff, University of Chicago Hospitals and Clinics
CONCEPT AND DEFINITION
IT IS self-evident that a person who is presently diabetic must have been at one time prediabetic. But to begin at the other end of the time scale and identify the individual who is presently prediabetic is quite another matter. Such attempts require not only that we define prediabetes, but also that we discover how it can be recognized. It has been suggested that the term prediabetes is almost synonymous with the possession of genetic predisposition. In this view, the condition begins at birth, or even with conception. There are, however, varying degrees of predisposition. If, as is generally accepted, the tendency to diabetes is inherited as a Mendelian recessive gene, the child of two heterozygous parents mayor may not become diabetic, while the child of two parents who have the disease (homozygous), or the identical twin of a diabetic individual, will be expected to be maximally prediabetic and to manifest diabetes if he lives long enough. When he does so will depend upon food habits, endocrine function and doubtless other factors not yet known which facilitate the expression of the genetically determined defect. If the prediabetic state begins with conception, when does it end? At the latest, of course, with the onset of frank, symptomatic diabetes. But not before? What shall we say of the person who has nothing to show for his family history but an abnormal blood sugar curve after a glucose tolerance test (Gl'T)? If the curve were sufficiently abnormal,* most lie A normal glucose tolerance curve does not exceed the following blood sugar values as determined in venous blood by the Somogyi-Nelson method: Fasting, 90; 1 hour, 150; 2 hours, 90; 3 hours, 90 mg./lOO m!' An unequivocally diabetic curve is defined, for purposes of this discussion, a,s exceeding three or more of the following values: Fasting, 110; 1 hour, 170; 2 hours, 120; 3 hours, 110 mg./I00 m!' These criteria differ slightly, but probably not importantly, from those of Fajans and Conn. 7
61
62
lIENH,Y
L.
WILDBERGER, HENRY
T.
RICKErrrrS
would agree that he should be labeled diabetic, and the state of prediabetes should be deemed to have terminated at that point. But what if his curve deviated only slightly fron1 normal? lIe could hardly be called diabetic. Perhaps "latent" diabetes would be the proper term for this condition if other causes of impaired tolerance could be eliluinated, and the state of prediabetes could be said to have been replace~ ,by a condition representing a more overt but still not fully developed form of disturbance. rro retreat still farther frOlll the stage of outspoken diabetes, what if the standard GTT in the predisposed individual gives normal results but the cortisone glucose tolerance test (CGTT), described below, does not? IIere we are on even less certain ground. Although Conn5 found that diabetes eventually developed in 25 per cent of subjects with a family history of diabetes who yielded such results when thus doubly tested, as opposed to 3 per cent of subjects without diabetic relatives, experience with the CGI-'T has been too short to permit the conclusion that it is an accurate predictor of the disease. To date, it is not a test for anything, as its designers are the first to point out. It is not a test for a genetic defect, or even for prediabetes. It is a test of something-of the .ability to dispose of a glucose load under a specific stress. When it gives abnormal results in the person ,vith a diabetic inheritance, it suggests merely that he is more likely to become diabetic than most people,. but with a probability still far'from 100 per cent. It is implied by the foregoing, and it is probably true, that diabetes is a continuum, progressing, often imperceptibly, through stages of increasing apparency over a period of years. With boundary lines so hazy, it may be useful to be arbitrary. I~et us say that prediabetes ends when the standard GT1-' yields results intermediate between' the normal and the unequivocally diabetic, and let us call this latent diabetes. Let us not, in the present state of our knowledge, call anyone an out-and-out prediabetic with the implication that diabetes is inevitable. Let us, rather, say that prediabetes may exist in a person with the specific inherited tendency who exhibits any clinical or biochemical defect, short of the stage of latent diabetes, that is generally recognized to be associated either currently or later with deficient insulin activity. This concept of prediabetes is less restrictive than that of Conn and Fajans,6 who believe that, by the time any evidence of deficient insulin activity is demonstrable, diabetes itself 'is already present. It all depends upon what one means by diabetes. RECOGNITION
Despite the limitations of the cortisone glucose tolerance test (CGTT), it is the only test with much experience behind it that may provide b~ochemical evidence of insufficient insulin activity before the standard
Prediabetes
63
GTT does so. The test is performed as follows: 7 Subjects weighing less than 160 pounds are given 50 mg. of cortisone acetate orally eight and one-half hours and again two hours before a standard GT1' is performed. Subjects weighing 160 pounds or more receive 62.5 mg. For three days before the test the subject consumes daily a diet adequate for maintenance and containing 300 gm. of carbohydrate. A standard oral glucose tolerance test is then performed, using 1.75 gm. of glucose per kilogram of ideal body weight. Venous blood is drawn before administration of glucose and every half hour for three hours thereafter and analyzed for glucose by the Somogyi-Nelson method. The interpretation of the standard glucose tolerance test is given in the authors' own words: " ... we regard the combination of a one-hour value of 160 mg. per 100 cc. or above plus a two-hour value of 120 mg. or above as diagnostic of the existence of the diabetic state. A diagnosis of probable diabetes was made when the one-hour value exceeded 160 mg. and the two-hour value fell between 110 and 120 lUg. In order to eliminate a false diagnosis of diabetes on the occasional curve which drops abruptly at 1.5 hrs. and rebounds above 120 mg. by two hours, we have added a third criterion, namely, that the level at 1.5 hrs. be 140 mg. per 100 cc. or above to be diagnostic."
In the interpretation of the combined (cortisone glucose tolerance) test, a two-hour blood sugar level of 140 mg. or above represents a positive response, while lower values are considered negative. It is our opinion that a person who has a diabetic family background and who responds positively to the double test should be suspected of being in a prediabetic state although the label "prediabetic" should not be pinned on him. The intravenous tolbutamide test, modified by pretreatment with steroids, has been used by Barros Barreto and Recant 3 in normal human subjects with and without a family history of diabetes. Of eight ,vho had a "diabetic" blood sugar curve, six gave a positive family history. Apparently, however, many of those \vith diabetic relatives responded normally. Follow-up of subjects with a "diabetic" type of response was "too short to be conclusive." Conn and Fajans 6 found this procedure less sensitive than the glucose tolerance test. It is probable that other, more sensitive methods for the early detection or even the predietion of insufficient insulin activity will be developed in the future. Apparently paradoxically, excessive levels of insulin-like activity in blood have been found in the nondiabetic children of pairs of diabetie parents. 15 The fact that these offspring were not hypoglycemic is surprising. It may have several explanations. Among them is the possibility that much of the circulating insulin is present in an inactive, or bound, form as shown by Antoniades2 to be the case in patients with maturity onset diabetes. Thus, ttinsulindeficiency" might still be said to exist if this term is taken to mean subnormal amounts of the biologically active
64
HENRY
L.
WILDBERGER, HENRY
T.
RICKETTS
hormone. It is nevertheless true that some genetically predisposed individuals, reported in other studies,14 do experience hypoglycemia either spontaneously or in response to the ingestion of glucose, and of these, a significant number have become diabetic. It must be assumed that, at the time when low blood sugar levels are found, large amounts of "free" or active insulin are present. In this class of patients, then, the simple clinical observation of hypoglycemia, in contrast to the elaborate determination of blood insulin levels, can be utilized by any physician as a warning that he may be dealing with potential diabetes. There are other clinical conditions, having to do mainly with pregnancy, that often precede the onset of diabetes by months or years. In such cases, however, information is usually lacking which would allow one to assert with confidence that these conditions existed in the prediabetic state, using that term in its strict sense as defined earlier. Certainly they cannot be regarded as reliable predictors of the disease. Excessive fetal and newborn mortality prior to the development of maternal diabetes has been well documented. According to Jackson,ll a 15 to 20 per cent perinatal loss up to 20 years before the onset of clinical diabetes climbs to a 30 to 50 per cent loss in the two to five years preceding recognition of the disorder. These statistics, however, are more discouraging than those of most observers. Maternal prediabetes* may account for a significant number of severe congenital anomalies. 1o The fetus may provide other evidence of parental prediabetes in terms of excessive birth weight. 9 The mothers of 17 per cent of infants weighing over 10 pounds at birth will eventually become diabetic. The predictive value of excessive birth weight increases with increasing size until 60 per cent of the mothers of 13 pound infants will acquire diabetes. 13 Jackson ll reported that 31 per cent of babies of prediabetic mothers and 10.7 per cent of offspring of prediabetic fathers weighed over 10 pounds at birth, while only 3.7 per cent of infants of normal parents were that heavy. Luteinized cysts have been found in ovaries of infants born of diabetic! and of prediabetic mothers. ll An increase in size of the islets of Langerhans in the stillborn fetus has been associated with maternal diabetes, potential or actual. 16 Islet tissue has been estimated to constitute 7 per cent of the pancreas in the fetus of a prediabetic mother but only 1.3 per cent in the fetus of a normal mother. In addition, the proportion and granularity of beta cells have been reported to be increased in the former. ll Very recently a group of possibly prediabetic individuals, so desig.. nated because of genetic background, was subjected to a battery of tests. 4 The frequency of several selected abnormalities was indicated as III The term "prediabetes," although used loosely, is permissible here and in the immediately succeeding passages because we are dealing with women known to have acquired the disease long after the birth of the infants in question.
G5
Prediabetes
follows: increased conjunctival venular-arteriolar ratio in 92 per cent of subjects, two hour blood sugar above the fasting level in the oral glucose tolerance test in 69 per cent, three hour blood sugar value above the fasting level in 55 per cent, and arteriovenous blood sugar difference at 30 minutes greater than at 90 minutes in 41 per cent. The reliability of such findings as forerunners of diabetes can be determined only after prolonged follow-up. l"ests showing no abnormality in these subjects were velocity of nerve conduction, venular-arteriolar ratio in the retina, roentgenograms and electrocardiograms. TREATMENT
The clinical objective in the search for persons with possible prediabetes is to prevent or postpone the development of the full-blown disease or minimize its severity. The means of accomplishing this are few and not entirely effective, but such as they are, they should be utilized to the full. Obesity should be avoided at all costs. The diabetogenic effect of multiparity renders repeated pregnancies undesirable. Administration of adrenal steroids in the therapy of intercurrent illness should be undertaken with considerable caution. Tolbutamide has been shown to increase islet size in the partially depancreatized dog 18 and to improve glucose tolerance in early human diabetes. 8 Insulin therapy during pregnancy has reduced fetal mortality both in alloxanized rats17 and in prediabetic women/o but its effect in preventing diabetes in the latter, although under study, is not yet known. Similar measures, if not these, may be found to prevent diabetes in persons shown early to be susceptible. SUMMARY
Prediabetes is here defined as a condition existing in a genetically predisposed individual before even minor abnormalities in the standard glucose tolerance have developed. The appearance of such abnormalities marks the end of prediabetes and the beginning of latent diabetes. Prediabetes cannot be diagnosed with certainty by any means presentlyavailable. It can be suspected with a high degree of probability in persons who are relatives of diabetic patients and who show evidence, either spontaneously or on testing, of insulin deficiency short of that which results in the minor deviations in the standard glucose tolerance test that bespeak latent diabetes. In this connection, the cortisone glucose tolerance test, although not likely to prove infallible, is thus far the earliest and best biochemical indicator of potential diabetes. Prophylactic measures should be employed in persons in whom this diagnosis can be made.
Gf)
HENRY
1.1.
WILDBERGER, HENRY
T.
R,JCKETr:I'R
REFERENCES 1. Ahlvin, R. C. and Bauer. W. C.: Luteinized cysts in ovaries of infants born of diabetic mothers. J. Dis. Child. 93: 107, 1952. 2. Antoniades, H. N., Gundersen, K. and Pyle, H. M.: Studies on the state of insulin in blood: The role of glucose in the in vivo dissociation of insulin complexes. Endocrinology 69: 163-169 (July) 1961. 3. Burros Barreto, H. P. and Recant, L.: 1'olbutamide studies in prediabetes. Ann. New York Acad. Sc. 82: 560-569 (Sept.) 1959., 4. Camerini-Davalos, R. A., Rees, S. B., Caulfield, J., Steinke, J., Marble, A.: Development of methods for the detection of prediabetes. Program of the 22nd Annual Meeting of the American Diabetes Association, Chicago, June, 1962. 5. Conn, J. W.: 1'he prediabetic state in Inan. Diabetes 7: 347-357, 1958. 6. Conn, J. W. and Fajans, S. S.: The prediabetic state: A concept of dynamic resistance to a genetic diabetogenic influence. Am. J. l\ied. 31: 839 (Dec.) 1961. 7. Fajans, S. S. and Conn, J. W.: An approach to the prediction of diabetes mellitus by modification of the glucose tolerance test with cortisone, Diabetes 8: 296-304, 1954. 8. Fajans, S. S. and Conn, J. W.: Tolhutamide-induced improvement in carbohydrate tolerance of young people with mild diabetes mellitus. I)iabetes 9: 83-88 (March-April) 1960. 9. Fischer, A. E. and Moloshok, R. E.: Diabetic and prediabetic pregnancies with special reference to the newborn. J. Pediat. 57: 704-714 (Nov.) 1960. 10. Roet, J. J., Gommers, A. and Hoet, J. P.: Third Congress of International Diabetes Federation, Dusseldorf, July, 1958. 11. Jackson, W. P. D.: Present status of prediabetes. I)iabetes 9: 373-378 (Sept.Oct.) 1960. 12. Jackson, W. P. D.: Studies in prediabetes. Brit. M. J. 2: 690-696, 1952. 13. Kriss, J. P. and Futcher, P. H.: l'he relation between infant birth weight and subsequent development of maternal diabetes mellitus. J. Clin. Endocrino!. 8: 380-389, 1948. 14. Seltzer, H. S., Fajans, S. S. and Conn, J. W.: Spontaneous hypoglycemia as an early manifestation of diabetes mellitus. Diabetes 5: 437-442 (Nov.-Dec.) 1960. 15. Steinke, J., Camerini, R., Marble, A. and Renold, A. E.: Elevated levels of serum insulin-like activity (ILA) as measured with adipose tissue in early untreated diabetes and prediabetes. Metabolism 10: 707-711 (Sept.) 1961. 16. Van Beek, C.: Autopsy findings in stillbirths and neonatal death suggesting maternal diabetes. First Congress of International Diabetes Federation, Leyden, Holland, July 7, 1952. 17. Wells, L. J., Kim, J. N. and Lazarow, A.: Effects of insulin on the complication of diabetes and pregnancy in the rat. Diabetes 9: 490-493 (Nov.-Dec.) 1960. 18. Wildberger, H. L. and Ricketts, H. T.: Tolerance for glucose in the partially depancreatized dog during prolonged administration of tolbutamide. Diabetes 10: 211-217 (May-June) 1961. 251 East Chicago Avenue Chicago 11, Illinois (Dr. Wildberger)
HENRY T. RICKE1'TS, M.D. Professor of Medicine, University of Chicago School of Medicine; Staff, University of Chicago Hospitals and Clinics
CONCEPT AND DEFINITION
IT IS self-evident that a person who is presently diabetic must have been at one time prediabetic. But to begin at the other end of the time scale and identify the individual who is presently prediabetic is quite another matter. Such attempts require not only that we define prediabetes, but also that we discover how it can be recognized. It has been suggested that the term prediabetes is almost synonymous with the possession of genetic predisposition. In this view, the condition begins at birth, or even with conception. There are, however, varying degrees of predisposition. If, as is generally accepted, the tendency to diabetes is inherited as a Mendelian recessive gene, the child of two heterozygous parents mayor may not become diabetic, while the child of two parents who have the disease (homozygous), or the identical twin of a diabetic individual, will be expected to be maximally prediabetic and to manifest diabetes if he lives long enough. When he does so will depend upon food habits, endocrine function and doubtless other factors not yet known which facilitate the expression of the genetically determined defect. If the prediabetic state begins with conception, when does it end? At the latest, of course, with the onset of frank, symptomatic diabetes. But not before? What shall we say of the person who has nothing to show for his family history but an abnormal blood sugar curve after a glucose tolerance test (Gl'T)? If the curve were sufficiently abnormal,* most lie A normal glucose tolerance curve does not exceed the following blood sugar values as determined in venous blood by the Somogyi-Nelson method: Fasting, 90; 1 hour, 150; 2 hours, 90; 3 hours, 90 mg./lOO m!' An unequivocally diabetic curve is defined, for purposes of this discussion, a,s exceeding three or more of the following values: Fasting, 110; 1 hour, 170; 2 hours, 120; 3 hours, 110 mg./I00 m!' These criteria differ slightly, but probably not importantly, from those of Fajans and Conn. 7
61
62
lIENH,Y
L.
WILDBERGER, HENRY
T.
RICKErrrrS
would agree that he should be labeled diabetic, and the state of prediabetes should be deemed to have terminated at that point. But what if his curve deviated only slightly fron1 normal? lIe could hardly be called diabetic. Perhaps "latent" diabetes would be the proper term for this condition if other causes of impaired tolerance could be eliluinated, and the state of prediabetes could be said to have been replace~ ,by a condition representing a more overt but still not fully developed form of disturbance. rro retreat still farther frOlll the stage of outspoken diabetes, what if the standard GTT in the predisposed individual gives normal results but the cortisone glucose tolerance test (CGTT), described below, does not? IIere we are on even less certain ground. Although Conn5 found that diabetes eventually developed in 25 per cent of subjects with a family history of diabetes who yielded such results when thus doubly tested, as opposed to 3 per cent of subjects without diabetic relatives, experience with the CGI-'T has been too short to permit the conclusion that it is an accurate predictor of the disease. To date, it is not a test for anything, as its designers are the first to point out. It is not a test for a genetic defect, or even for prediabetes. It is a test of something-of the .ability to dispose of a glucose load under a specific stress. When it gives abnormal results in the person ,vith a diabetic inheritance, it suggests merely that he is more likely to become diabetic than most people,. but with a probability still far'from 100 per cent. It is implied by the foregoing, and it is probably true, that diabetes is a continuum, progressing, often imperceptibly, through stages of increasing apparency over a period of years. With boundary lines so hazy, it may be useful to be arbitrary. I~et us say that prediabetes ends when the standard GT1-' yields results intermediate between' the normal and the unequivocally diabetic, and let us call this latent diabetes. Let us not, in the present state of our knowledge, call anyone an out-and-out prediabetic with the implication that diabetes is inevitable. Let us, rather, say that prediabetes may exist in a person with the specific inherited tendency who exhibits any clinical or biochemical defect, short of the stage of latent diabetes, that is generally recognized to be associated either currently or later with deficient insulin activity. This concept of prediabetes is less restrictive than that of Conn and Fajans,6 who believe that, by the time any evidence of deficient insulin activity is demonstrable, diabetes itself 'is already present. It all depends upon what one means by diabetes. RECOGNITION
Despite the limitations of the cortisone glucose tolerance test (CGTT), it is the only test with much experience behind it that may provide b~ochemical evidence of insufficient insulin activity before the standard
Prediabetes
63
GTT does so. The test is performed as follows: 7 Subjects weighing less than 160 pounds are given 50 mg. of cortisone acetate orally eight and one-half hours and again two hours before a standard GT1' is performed. Subjects weighing 160 pounds or more receive 62.5 mg. For three days before the test the subject consumes daily a diet adequate for maintenance and containing 300 gm. of carbohydrate. A standard oral glucose tolerance test is then performed, using 1.75 gm. of glucose per kilogram of ideal body weight. Venous blood is drawn before administration of glucose and every half hour for three hours thereafter and analyzed for glucose by the Somogyi-Nelson method. The interpretation of the standard glucose tolerance test is given in the authors' own words: " ... we regard the combination of a one-hour value of 160 mg. per 100 cc. or above plus a two-hour value of 120 mg. or above as diagnostic of the existence of the diabetic state. A diagnosis of probable diabetes was made when the one-hour value exceeded 160 mg. and the two-hour value fell between 110 and 120 lUg. In order to eliminate a false diagnosis of diabetes on the occasional curve which drops abruptly at 1.5 hrs. and rebounds above 120 mg. by two hours, we have added a third criterion, namely, that the level at 1.5 hrs. be 140 mg. per 100 cc. or above to be diagnostic."
In the interpretation of the combined (cortisone glucose tolerance) test, a two-hour blood sugar level of 140 mg. or above represents a positive response, while lower values are considered negative. It is our opinion that a person who has a diabetic family background and who responds positively to the double test should be suspected of being in a prediabetic state although the label "prediabetic" should not be pinned on him. The intravenous tolbutamide test, modified by pretreatment with steroids, has been used by Barros Barreto and Recant 3 in normal human subjects with and without a family history of diabetes. Of eight ,vho had a "diabetic" blood sugar curve, six gave a positive family history. Apparently, however, many of those \vith diabetic relatives responded normally. Follow-up of subjects with a "diabetic" type of response was "too short to be conclusive." Conn and Fajans 6 found this procedure less sensitive than the glucose tolerance test. It is probable that other, more sensitive methods for the early detection or even the predietion of insufficient insulin activity will be developed in the future. Apparently paradoxically, excessive levels of insulin-like activity in blood have been found in the nondiabetic children of pairs of diabetie parents. 15 The fact that these offspring were not hypoglycemic is surprising. It may have several explanations. Among them is the possibility that much of the circulating insulin is present in an inactive, or bound, form as shown by Antoniades2 to be the case in patients with maturity onset diabetes. Thus, ttinsulindeficiency" might still be said to exist if this term is taken to mean subnormal amounts of the biologically active
64
HENRY
L.
WILDBERGER, HENRY
T.
RICKETTS
hormone. It is nevertheless true that some genetically predisposed individuals, reported in other studies,14 do experience hypoglycemia either spontaneously or in response to the ingestion of glucose, and of these, a significant number have become diabetic. It must be assumed that, at the time when low blood sugar levels are found, large amounts of "free" or active insulin are present. In this class of patients, then, the simple clinical observation of hypoglycemia, in contrast to the elaborate determination of blood insulin levels, can be utilized by any physician as a warning that he may be dealing with potential diabetes. There are other clinical conditions, having to do mainly with pregnancy, that often precede the onset of diabetes by months or years. In such cases, however, information is usually lacking which would allow one to assert with confidence that these conditions existed in the prediabetic state, using that term in its strict sense as defined earlier. Certainly they cannot be regarded as reliable predictors of the disease. Excessive fetal and newborn mortality prior to the development of maternal diabetes has been well documented. According to Jackson,ll a 15 to 20 per cent perinatal loss up to 20 years before the onset of clinical diabetes climbs to a 30 to 50 per cent loss in the two to five years preceding recognition of the disorder. These statistics, however, are more discouraging than those of most observers. Maternal prediabetes* may account for a significant number of severe congenital anomalies. 1o The fetus may provide other evidence of parental prediabetes in terms of excessive birth weight. 9 The mothers of 17 per cent of infants weighing over 10 pounds at birth will eventually become diabetic. The predictive value of excessive birth weight increases with increasing size until 60 per cent of the mothers of 13 pound infants will acquire diabetes. 13 Jackson ll reported that 31 per cent of babies of prediabetic mothers and 10.7 per cent of offspring of prediabetic fathers weighed over 10 pounds at birth, while only 3.7 per cent of infants of normal parents were that heavy. Luteinized cysts have been found in ovaries of infants born of diabetic! and of prediabetic mothers. ll An increase in size of the islets of Langerhans in the stillborn fetus has been associated with maternal diabetes, potential or actual. 16 Islet tissue has been estimated to constitute 7 per cent of the pancreas in the fetus of a prediabetic mother but only 1.3 per cent in the fetus of a normal mother. In addition, the proportion and granularity of beta cells have been reported to be increased in the former. ll Very recently a group of possibly prediabetic individuals, so desig.. nated because of genetic background, was subjected to a battery of tests. 4 The frequency of several selected abnormalities was indicated as III The term "prediabetes," although used loosely, is permissible here and in the immediately succeeding passages because we are dealing with women known to have acquired the disease long after the birth of the infants in question.
G5
Prediabetes
follows: increased conjunctival venular-arteriolar ratio in 92 per cent of subjects, two hour blood sugar above the fasting level in the oral glucose tolerance test in 69 per cent, three hour blood sugar value above the fasting level in 55 per cent, and arteriovenous blood sugar difference at 30 minutes greater than at 90 minutes in 41 per cent. The reliability of such findings as forerunners of diabetes can be determined only after prolonged follow-up. l"ests showing no abnormality in these subjects were velocity of nerve conduction, venular-arteriolar ratio in the retina, roentgenograms and electrocardiograms. TREATMENT
The clinical objective in the search for persons with possible prediabetes is to prevent or postpone the development of the full-blown disease or minimize its severity. The means of accomplishing this are few and not entirely effective, but such as they are, they should be utilized to the full. Obesity should be avoided at all costs. The diabetogenic effect of multiparity renders repeated pregnancies undesirable. Administration of adrenal steroids in the therapy of intercurrent illness should be undertaken with considerable caution. Tolbutamide has been shown to increase islet size in the partially depancreatized dog 18 and to improve glucose tolerance in early human diabetes. 8 Insulin therapy during pregnancy has reduced fetal mortality both in alloxanized rats17 and in prediabetic women/o but its effect in preventing diabetes in the latter, although under study, is not yet known. Similar measures, if not these, may be found to prevent diabetes in persons shown early to be susceptible. SUMMARY
Prediabetes is here defined as a condition existing in a genetically predisposed individual before even minor abnormalities in the standard glucose tolerance have developed. The appearance of such abnormalities marks the end of prediabetes and the beginning of latent diabetes. Prediabetes cannot be diagnosed with certainty by any means presentlyavailable. It can be suspected with a high degree of probability in persons who are relatives of diabetic patients and who show evidence, either spontaneously or on testing, of insulin deficiency short of that which results in the minor deviations in the standard glucose tolerance test that bespeak latent diabetes. In this connection, the cortisone glucose tolerance test, although not likely to prove infallible, is thus far the earliest and best biochemical indicator of potential diabetes. Prophylactic measures should be employed in persons in whom this diagnosis can be made.
Gf)
HENRY
1.1.
WILDBERGER, HENRY
T.
R,JCKETr:I'R
REFERENCES 1. Ahlvin, R. C. and Bauer. W. C.: Luteinized cysts in ovaries of infants born of diabetic mothers. J. Dis. Child. 93: 107, 1952. 2. Antoniades, H. N., Gundersen, K. and Pyle, H. M.: Studies on the state of insulin in blood: The role of glucose in the in vivo dissociation of insulin complexes. Endocrinology 69: 163-169 (July) 1961. 3. Burros Barreto, H. P. and Recant, L.: 1'olbutamide studies in prediabetes. Ann. New York Acad. Sc. 82: 560-569 (Sept.) 1959., 4. Camerini-Davalos, R. A., Rees, S. B., Caulfield, J., Steinke, J., Marble, A.: Development of methods for the detection of prediabetes. Program of the 22nd Annual Meeting of the American Diabetes Association, Chicago, June, 1962. 5. Conn, J. W.: 1'he prediabetic state in Inan. Diabetes 7: 347-357, 1958. 6. Conn, J. W. and Fajans, S. S.: The prediabetic state: A concept of dynamic resistance to a genetic diabetogenic influence. Am. J. l\ied. 31: 839 (Dec.) 1961. 7. Fajans, S. S. and Conn, J. W.: An approach to the prediction of diabetes mellitus by modification of the glucose tolerance test with cortisone, Diabetes 8: 296-304, 1954. 8. Fajans, S. S. and Conn, J. W.: Tolhutamide-induced improvement in carbohydrate tolerance of young people with mild diabetes mellitus. I)iabetes 9: 83-88 (March-April) 1960. 9. Fischer, A. E. and Moloshok, R. E.: Diabetic and prediabetic pregnancies with special reference to the newborn. J. Pediat. 57: 704-714 (Nov.) 1960. 10. Roet, J. J., Gommers, A. and Hoet, J. P.: Third Congress of International Diabetes Federation, Dusseldorf, July, 1958. 11. Jackson, W. P. D.: Present status of prediabetes. I)iabetes 9: 373-378 (Sept.Oct.) 1960. 12. Jackson, W. P. D.: Studies in prediabetes. Brit. M. J. 2: 690-696, 1952. 13. Kriss, J. P. and Futcher, P. H.: l'he relation between infant birth weight and subsequent development of maternal diabetes mellitus. J. Clin. Endocrino!. 8: 380-389, 1948. 14. Seltzer, H. S., Fajans, S. S. and Conn, J. W.: Spontaneous hypoglycemia as an early manifestation of diabetes mellitus. Diabetes 5: 437-442 (Nov.-Dec.) 1960. 15. Steinke, J., Camerini, R., Marble, A. and Renold, A. E.: Elevated levels of serum insulin-like activity (ILA) as measured with adipose tissue in early untreated diabetes and prediabetes. Metabolism 10: 707-711 (Sept.) 1961. 16. Van Beek, C.: Autopsy findings in stillbirths and neonatal death suggesting maternal diabetes. First Congress of International Diabetes Federation, Leyden, Holland, July 7, 1952. 17. Wells, L. J., Kim, J. N. and Lazarow, A.: Effects of insulin on the complication of diabetes and pregnancy in the rat. Diabetes 9: 490-493 (Nov.-Dec.) 1960. 18. Wildberger, H. L. and Ricketts, H. T.: Tolerance for glucose in the partially depancreatized dog during prolonged administration of tolbutamide. Diabetes 10: 211-217 (May-June) 1961. 251 East Chicago Avenue Chicago 11, Illinois (Dr. Wildberger)