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Hyperinsulinism: The Use and Misuse of the Term
HYPERINSULINISM: THE USE AND MISUSE OF THE TERM MELVIN T. GORSUCH AND EDWARD H. RYNEARSON HYPERINSULINISM was first described by Seale Harris1 in 1924. Since then the literature has contained many references to this condition. We are attempting in this brief discussion, first, to define hyperinsulinism, and second, to distinguish this condition from the broad field of spontaneous hypoglycemia. The term "hyperinsulinism" should be restricted to the condition produced by an excessive amount of insulin. Induced hyperinsulinism needs no elaboration; it is the typical insulin reaction, familiar to all physicians interested in the treatment of diabetes. Spontaneous or true hyperinsulinism is a very rare syndrome. We feel that this term should be used only in those cases in which an adenoma or carcinoma originating in the cells of the islands of Langerhans is found at operation or at necropsy. In all other cases in which hypoglycemia is present, the condition should be diagnosed as "spontaneous hypoglycemia" rather than as "hyperinsulinism." Hypoglycemia may occur in association with certain deficiencies of the pituitary body, the thyroid gland or of the suprarenal glands, with destruction of the liver, and with functional or organic disturbances of the nervous system. A review of the medical literature discloses a large number of cases of nervous or functional hypoglycemia. Usually the patient is emotionally unstable, and one is impressed by the nervous anxiety and tension state depicted. In a significant number of cases, hyperirritability of the autonomic nervous system with features of vagus nerve predominance is suggested. We are unwilling to accept the suggestion that these are representative instances of an excessive production of endogenous insulin. Keating and Wilder2 have stated that in this group of cases there may be an abnormal depression of the concentration of blood sugar owing to stimulation of nerves of the liver, or, an exaggeration of ordinary physiologic fluctuations in the concentration of the blood sugar owing to tension or anxiety, or, that an abnormal· sensitivity of the individual to physiologic excursions of the concentration of blood sugar may be responsible. Although in a review of the literature we found such terms as "dysinsulinism," "chronic hypoglycemia," and "functional hyperinsulinism," we believe that the terms "hyperinsulinism" and "spontaneous hypoglycemia" are sufficiently descriptive. 985
986
MELVIN T. GORSUCH, EDWARD H. RYNEARSON
The accompanying tabulation shows the etiologic factors in eighty.five cases that were observed at the Clinic in a period of three years, that is from January 1, 1940 to December 31, 1942. In the twenty-one cases in which hyperinsulinism was due to administration of excessive ETIOLOGIC CLASSIFICATION OF EIGHTY-FIVE CASES OF HYPERINSULINISM AND SPONTANEOUS HYPOGL YCEMIA
Hyperinsulinism Cases Administration of excessive amounts of insulin .................... 21 Tumor of the islands of Langerhans............................... 10 Spontaneous hypoglycemia Nervous or functionaL ............................................ 41 Hepatic origin (not proved)....................... .............. 2 Simmonds' cachexia.... ........................................... 1 Addison's disease................ .................................. 1 Cerebral degeneration....................................... ...... 1 Pernicious anemia (exploratory operation disclosed no abnormality) .. 1 Indeterminate (exploratory operation disclosed no abnormality).. . .. 4 Indeterminate (no exploratory operation).......................... 3 Total ........................................................ 85
amounts of insulin, the patients were referred to the Clinic because the hyperinsulinism was a major problem in the control of diabetes. This group does not include any case in which the patient had an occasional reaction to insulin. The symptoms and diagnosis of hyperinsulinism that is due to the administration of excessive amounts of insulin are too well known to warrant further consideration. Tumors of the islands of Langerhans were found in ten cases. This is by far the most interesting group and is quite distinct from the fiftyfour cases in which the patients were suffering from spontaneous hypoglycemia. A few patients in the latter group were found to have hypoglycemia as part of, or in' association with, other diseases. In seven cases the cause of the hypoglycemia is listed as indeterminate. In forty-one cases, a diagnosis of nervous or functional hypoglycemia was made. As an illustration of the history and findings in the cases in which a tumor of the islands of Langerhans was found, the following case IS reported. CASE I.-A female secretary, aged thirty-two years, was admitted to St. Mary's Hospital on October 19, 1942. The patient had been in excellent health until two years prior to this admission, when she first had noted an increasing number of errors in her stenographic work. She had discovered that eating fequently reduced these errors and would relieve her other symptoms of impaired concentration, mental confusion and sensations of unreality. Three months after the onset of this illness she had her first episode of unconsciousness, While she had
HYPERINSULINISM
987
been Christmas shopping, she had noted weakness, dizziness and recurrent episodes of disorientation, followed by unconsciousness. She had remained comatose for six hours; recovery had been spontaneous. Because her family had been unable to awaken her in the morning two days later, the patient had been admitted to a hospital. She had remained comatose until 4 P.M. of the following day, at which time the intravenous administration of dextrose had produced immediate recovery. A diagnosis of hypoglycemia of indeterminate origin had been made. The value for the fasting blood sugar had been found to be 95 mg. per 100 cc. immediately before a glucose tolerance test had been performed. The values for the blood sugar had been found to be 195 mg., 333 mg., 174 mg. and 160 mg., respectively, one, two, three and four hours after the oral administration of 100 gm. of dextrose. During the next three months, the values for the blood sugar had ranged from 45 to 75 mg. per 100 cc. Various types of treatment had been tried, including a high fat diet, a high protein diet, a high carbohydrate diet, injections of solution of posterior pituitary and subcutaneous injections of 1 cc. of epinephrine in oil twice daily. In addition to her meals and intermediate feedings, the patient had drunk the juice of three dozen oranges at intervals during each twenty-four hours. On such a regimen she had gained 45 pounds (20.4 kg.) but she had continued to have the following symptoms: diplopia, paresthesias of the face and extremities, difficulty in awakening, extreme exhaustion in the early morning hours, and impaired concentration. When the patient admitted to St. Mary's Hospital, the results of physical examination were essentially negative, except for the presence of obesity. After the administration of a glass of orange juice at 5 A.M., a fasting test for hypoglycemia was begun. The values for the blood sugar at8 and 11 A.M., and at 1 P.M. were 54, 34, and 25 mg. per 100 cc. respectively. Mental confusion was noted at 11 A.M., and at 12:50 P.M., the patient was unresponsive. At 1 P.M. the patient was having severe generalized convulsions. Intravenous administration of 2.5 gm. of dextrose was followed by complete relief of the hypoglycemic symptoms. On October 27, 1942, an adenocarcinoma, grade 1, of the islands of Langerhans, which measured 1.5 by 1 by 1 cm., was removed. Convalescence was complicated by pulmonary congestion and the development of a pancreatic fistula. The patient was dismissed on the nineteenth day after operation. She has written letters stating that she has not experienced any recurrence of her hypoglycemic symptoms and is feeling entirely well.
was
There are several points in this history which are worthy of emphasis. The patient, who formerly had been very stable, became unstable. The patient's symptoms were present when feedings were delayed or when she exercised, as in shopping, and all of the symptoms were promptly relieved by the ingestion of food or by the administration of dextrose. Complete recovery followed the successful surgical removal of the insulin-producing tumor. In the following case, the symptoms were similar to those in Case I but operation did not disclose any abnormality. CASE II.-A white man, aged thirty-eight years, registered at the Clinic on May 5, 1942. For ten years he had experienced episodes of mild indigestion.
988
MELVIN T. GORSUCH, EDWARD H. RYNEARSON
Except for these attacks he had enjoyed good health until a year and a half before he came to the Clinic. He then had begun to have attacks characterized by weakness, giddiness, perspiration, blurred vision, and amnesia. On two occasions he had lost consciousness. Six months before he came to the Clinic, his wife had been unable to awaken him at 11 A.M., which was his usual time for arising while working on the night shift. His wife said that on this occasion he had been "groggy," pale, and only slightly responsive. There had been fixation of gaze and grunting respirations, and his body had been moist with perspiration. From this semistuporous state he had sunk into a deep slumber from which he could not be awakened until 4 P.M. After this attack he had had weekly attacks which had been less severe than the previous attack and had not been associated with loss of consciousness. During these episodes his wife had noted that the patient was confused, belligerent, and walked with a staggering gait. Talking in a loud voice and automatic behavior also had been observed. The majority of these episodes had occurred during the early morning hours if his breakfast had been delayed or omitted. He had been advised to eat more carbohydrate at the time of his regular meals, but had not partaken of any intermediate feedings. During one episode, dextrose was given intravenously to restore consciousness. The patient was transferred to St. Mary's Hospital for special metabolic studies. The value for the fasting blood sugar, which was determined just before an Exton-Rose glucose tolerance test was started, was 49 mg. per 100 cc. The glucose tolerance disclosed the following values for the blood sugar: 69 mg. per 100 cc. at the end of half an hour and 81 mg. per 100 cc. at the end of one hour. After the patient had fasted for twenty-four hours the value for the blood sugar was 45 mg. per 100 cc. and the usual symptoms of hypoglycemia were present. An exploratory operation was performed but careful inspection and palpation of the pancreas failed to reveal any abnormality. Microscopic examination of two small sections of the pancreas disclosed only normal pancreatic tissue. A dietary regimen, which included feedings between meals, was prescribed. The patient was permitted to return to his home but was requested to return to the Clinic in four months. When he returned to the Clinic, he stated that he had had no symptoms during this interval. When the patient returned to the Clinic, the value for the blood sugar was 88 mg. per 100 cc.
In Case n, the hypoglycemic symptoms were sufficiently severe to warrant surgical exploration. The fact that frequent feedings completely relieved the symptoms raises the question as to whether medical treatment could not have been prescribed without the operation. This would have been unwise since' all tumors of the island cells must be regarded as either malignant or "premalignant." There is, as yet, no method of determining the presence or absence of a tumor except by operation. In the following case of nervous or functional hypoglycemia, the h~story and findings are in marked contrast with those in the two preVIOUS cases.
HYPERINSULINISM
989
CASE III.-A housewife, aged sixty-one years, had had recurring attacks of impaired concentration, headache, dimness of vision, irritability, tremors of the hands, generalized weakness, and perspiration since childhood. These attacks usually had occurred at 10 A.M. and 3 P.M. No hypoglycemic symptoms had been experienced as a result of a night's fast. Food, and particularly coffee, had produced instantaneous relief from these symptoms. The patient always had been obese. One year before she came to the Clinic she had experienced hypoglycemic symptoms during the performance of a glucose tolerance test, and since then she had felt justified in eating with more abandon. Obesity was her chief concern. The general symptoms gave further evidence of instability of the autonomic nervous system. Food idiosyncrasies were prominent and the partaking of certain foods invariably had been accompanied by eczema and urticaria. She had had relatively infrequent and irregularly recurring attacks of diarrhea which had been associated with dull aching in the cecal and sigmoid regions of the abdomen. A feeling of abdominal tension and "bloating" after meals had been a constant symptom. She had been extremely sensitive to cold. Cardiac irregularity had been a subjective sensation; this disturbance had been relieved by food. An electrocardiogram revealed sinus bradycardia, a cardiac rate of 54, and occasional premature auricular contractions. Vagal release was effected by the administration of atropine. Immediately before the oral administration of 90 gm. of dextrose for an ordinary glucose tolerance test, the value for the fasting blood sugar was found to be 100 mg. per 100 cc. The glucose tolerance test revealed the following values for the blood sugar: 188 mg. per 100 cc. at the end of half an hour, 154 mg. per 100 cc. at the end of two hours, 170 mg. per 100 cc. at the end of two and a half hours, 93 mg. per 100 cc. at the end of three hours, 72 mg. per 100 cc. at the end of four hours and 89 mg. per 100 cc. at the end of six hours. At the end of four hours, the patient had mild hypoglycemic symptoms, including cold perspiration and slight mental confusion. A fasting test for hypoglycemia was continued for thirty-two hours. At the end of this period, the value for the blood sugar was 111 mg. per 100 cc. The patient did not have any symptoms of hypoglycemia during this period. The patient returned to the Clinic after an absence of five months. During this interval the patient had been eating six times a day and the diet had furnished a total of 1,100 calories daily. This dietetic regimen had afforded complete relief from hypoglycemic symptoms and had produced a noticeable reduction in weight.
The interesting points in this case are the number of associated functional symptoms, some of which had been present since childhood, the "indefinite" history as contrasted with the clear-cut history of true hyperinsulinism, the absence of severe hypoglycemia at any time, the Bormal concentration of blood sugar and absence of symptoms, after a prolonged fast. This' patient and the other forty patients who had nervous or functional hypoglycemia did not require an operation. Many of them were more in need of a frank discussion and discipline. Thirteen of the fortyone patients had an associated neurosis, anxiety ·state of hypochond~i-
990
MELVIN T. GORSUCH, EDWARD H. RYNEARSON
asis and three patients had an associated epilepsy. Very few of the patients in this entire group had stable personalities. Most of their symptoms were more related to the sympathetic nervous system than to the concentration of the blood sugar. In only twenty-four cases was mention made of the restorative effect of dextrose; in seventeen cases, improvement was inconstant and questionable; in six cases, relief was definite, and in one case, the dextrose had no effect. Twenty-nine patients had experienced no difficulty at night. None except those with epilepsy had had convulsive seizures. Probably the most important test in distinguishing severe hypoglycemia from the functional or nervous type is the prolonged fast. Very few patients with hyperinsulinism can fast very long, particularly if exercise is employed. Patients with severe hyperinsulinism cannot fast for longer than two or three hours. This test has proved of more value than has the glucose tolerance test. Very often, the sugar tolerance curve is typical of diabetes, rather than "flat," in cases of proved hyperinsulinism. Portis and ZitmanB found "flat" curves in neuropsychiatric cases. Finally, it should be stated that in these forty-one cases of functional or nervous hypoglycemia hyperinsulinism was diagnosed or suspected. This does not include the many strictly nervous patients who, as part of their nervousness, frequently ate food or candy or drank carbonated beverages. SUMMARY AND CONCLUSIONS
Hypoglycemia can be related to many functional or pathologic disturbances. The term "hyperinsulinism" should be used only in cases in which the symptoms are caused by an excessive amount of insulin, either exogenous or endogenous. The term "hyperinsulinism" should not be abused by applying it to hypoglycemia that may be due to any one of many causes. True hyperinsulinism resulting from a tumor of th,e islands of Langerhans is very rare; the spontaneous hypoglycemia of the nervous individual is much more common. REFERENCES
1. Harris, Seale:
Hyperinsulinism and Dysinsulinism. J.A.M.A., 83:729-733 (Sept. 6) 1924. 2. Keating, F. R. and Wilder, R. M.: Spontaneous Hypoglycemia: Report of Cases. South. Med. & Surg., 103:125-131 (Mar.) 1941. 3. Portis, S. A. and Zitman, I. H.: A Mechanism of Fatigue in Neuropsychiatric Patients; Preliminary Report. l.A.M.A., 121:569-573 (Feb. 20)1943.
986
MELVIN T. GORSUCH, EDWARD H. RYNEARSON
The accompanying tabulation shows the etiologic factors in eighty.five cases that were observed at the Clinic in a period of three years, that is from January 1, 1940 to December 31, 1942. In the twenty-one cases in which hyperinsulinism was due to administration of excessive ETIOLOGIC CLASSIFICATION OF EIGHTY-FIVE CASES OF HYPERINSULINISM AND SPONTANEOUS HYPOGL YCEMIA
Hyperinsulinism Cases Administration of excessive amounts of insulin .................... 21 Tumor of the islands of Langerhans............................... 10 Spontaneous hypoglycemia Nervous or functionaL ............................................ 41 Hepatic origin (not proved)....................... .............. 2 Simmonds' cachexia.... ........................................... 1 Addison's disease................ .................................. 1 Cerebral degeneration....................................... ...... 1 Pernicious anemia (exploratory operation disclosed no abnormality) .. 1 Indeterminate (exploratory operation disclosed no abnormality).. . .. 4 Indeterminate (no exploratory operation).......................... 3 Total ........................................................ 85
amounts of insulin, the patients were referred to the Clinic because the hyperinsulinism was a major problem in the control of diabetes. This group does not include any case in which the patient had an occasional reaction to insulin. The symptoms and diagnosis of hyperinsulinism that is due to the administration of excessive amounts of insulin are too well known to warrant further consideration. Tumors of the islands of Langerhans were found in ten cases. This is by far the most interesting group and is quite distinct from the fiftyfour cases in which the patients were suffering from spontaneous hypoglycemia. A few patients in the latter group were found to have hypoglycemia as part of, or in' association with, other diseases. In seven cases the cause of the hypoglycemia is listed as indeterminate. In forty-one cases, a diagnosis of nervous or functional hypoglycemia was made. As an illustration of the history and findings in the cases in which a tumor of the islands of Langerhans was found, the following case IS reported. CASE I.-A female secretary, aged thirty-two years, was admitted to St. Mary's Hospital on October 19, 1942. The patient had been in excellent health until two years prior to this admission, when she first had noted an increasing number of errors in her stenographic work. She had discovered that eating fequently reduced these errors and would relieve her other symptoms of impaired concentration, mental confusion and sensations of unreality. Three months after the onset of this illness she had her first episode of unconsciousness, While she had
HYPERINSULINISM
987
been Christmas shopping, she had noted weakness, dizziness and recurrent episodes of disorientation, followed by unconsciousness. She had remained comatose for six hours; recovery had been spontaneous. Because her family had been unable to awaken her in the morning two days later, the patient had been admitted to a hospital. She had remained comatose until 4 P.M. of the following day, at which time the intravenous administration of dextrose had produced immediate recovery. A diagnosis of hypoglycemia of indeterminate origin had been made. The value for the fasting blood sugar had been found to be 95 mg. per 100 cc. immediately before a glucose tolerance test had been performed. The values for the blood sugar had been found to be 195 mg., 333 mg., 174 mg. and 160 mg., respectively, one, two, three and four hours after the oral administration of 100 gm. of dextrose. During the next three months, the values for the blood sugar had ranged from 45 to 75 mg. per 100 cc. Various types of treatment had been tried, including a high fat diet, a high protein diet, a high carbohydrate diet, injections of solution of posterior pituitary and subcutaneous injections of 1 cc. of epinephrine in oil twice daily. In addition to her meals and intermediate feedings, the patient had drunk the juice of three dozen oranges at intervals during each twenty-four hours. On such a regimen she had gained 45 pounds (20.4 kg.) but she had continued to have the following symptoms: diplopia, paresthesias of the face and extremities, difficulty in awakening, extreme exhaustion in the early morning hours, and impaired concentration. When the patient admitted to St. Mary's Hospital, the results of physical examination were essentially negative, except for the presence of obesity. After the administration of a glass of orange juice at 5 A.M., a fasting test for hypoglycemia was begun. The values for the blood sugar at8 and 11 A.M., and at 1 P.M. were 54, 34, and 25 mg. per 100 cc. respectively. Mental confusion was noted at 11 A.M., and at 12:50 P.M., the patient was unresponsive. At 1 P.M. the patient was having severe generalized convulsions. Intravenous administration of 2.5 gm. of dextrose was followed by complete relief of the hypoglycemic symptoms. On October 27, 1942, an adenocarcinoma, grade 1, of the islands of Langerhans, which measured 1.5 by 1 by 1 cm., was removed. Convalescence was complicated by pulmonary congestion and the development of a pancreatic fistula. The patient was dismissed on the nineteenth day after operation. She has written letters stating that she has not experienced any recurrence of her hypoglycemic symptoms and is feeling entirely well.
was
There are several points in this history which are worthy of emphasis. The patient, who formerly had been very stable, became unstable. The patient's symptoms were present when feedings were delayed or when she exercised, as in shopping, and all of the symptoms were promptly relieved by the ingestion of food or by the administration of dextrose. Complete recovery followed the successful surgical removal of the insulin-producing tumor. In the following case, the symptoms were similar to those in Case I but operation did not disclose any abnormality. CASE II.-A white man, aged thirty-eight years, registered at the Clinic on May 5, 1942. For ten years he had experienced episodes of mild indigestion.
988
MELVIN T. GORSUCH, EDWARD H. RYNEARSON
Except for these attacks he had enjoyed good health until a year and a half before he came to the Clinic. He then had begun to have attacks characterized by weakness, giddiness, perspiration, blurred vision, and amnesia. On two occasions he had lost consciousness. Six months before he came to the Clinic, his wife had been unable to awaken him at 11 A.M., which was his usual time for arising while working on the night shift. His wife said that on this occasion he had been "groggy," pale, and only slightly responsive. There had been fixation of gaze and grunting respirations, and his body had been moist with perspiration. From this semistuporous state he had sunk into a deep slumber from which he could not be awakened until 4 P.M. After this attack he had had weekly attacks which had been less severe than the previous attack and had not been associated with loss of consciousness. During these episodes his wife had noted that the patient was confused, belligerent, and walked with a staggering gait. Talking in a loud voice and automatic behavior also had been observed. The majority of these episodes had occurred during the early morning hours if his breakfast had been delayed or omitted. He had been advised to eat more carbohydrate at the time of his regular meals, but had not partaken of any intermediate feedings. During one episode, dextrose was given intravenously to restore consciousness. The patient was transferred to St. Mary's Hospital for special metabolic studies. The value for the fasting blood sugar, which was determined just before an Exton-Rose glucose tolerance test was started, was 49 mg. per 100 cc. The glucose tolerance disclosed the following values for the blood sugar: 69 mg. per 100 cc. at the end of half an hour and 81 mg. per 100 cc. at the end of one hour. After the patient had fasted for twenty-four hours the value for the blood sugar was 45 mg. per 100 cc. and the usual symptoms of hypoglycemia were present. An exploratory operation was performed but careful inspection and palpation of the pancreas failed to reveal any abnormality. Microscopic examination of two small sections of the pancreas disclosed only normal pancreatic tissue. A dietary regimen, which included feedings between meals, was prescribed. The patient was permitted to return to his home but was requested to return to the Clinic in four months. When he returned to the Clinic, he stated that he had had no symptoms during this interval. When the patient returned to the Clinic, the value for the blood sugar was 88 mg. per 100 cc.
In Case n, the hypoglycemic symptoms were sufficiently severe to warrant surgical exploration. The fact that frequent feedings completely relieved the symptoms raises the question as to whether medical treatment could not have been prescribed without the operation. This would have been unwise since' all tumors of the island cells must be regarded as either malignant or "premalignant." There is, as yet, no method of determining the presence or absence of a tumor except by operation. In the following case of nervous or functional hypoglycemia, the h~story and findings are in marked contrast with those in the two preVIOUS cases.
HYPERINSULINISM
989
CASE III.-A housewife, aged sixty-one years, had had recurring attacks of impaired concentration, headache, dimness of vision, irritability, tremors of the hands, generalized weakness, and perspiration since childhood. These attacks usually had occurred at 10 A.M. and 3 P.M. No hypoglycemic symptoms had been experienced as a result of a night's fast. Food, and particularly coffee, had produced instantaneous relief from these symptoms. The patient always had been obese. One year before she came to the Clinic she had experienced hypoglycemic symptoms during the performance of a glucose tolerance test, and since then she had felt justified in eating with more abandon. Obesity was her chief concern. The general symptoms gave further evidence of instability of the autonomic nervous system. Food idiosyncrasies were prominent and the partaking of certain foods invariably had been accompanied by eczema and urticaria. She had had relatively infrequent and irregularly recurring attacks of diarrhea which had been associated with dull aching in the cecal and sigmoid regions of the abdomen. A feeling of abdominal tension and "bloating" after meals had been a constant symptom. She had been extremely sensitive to cold. Cardiac irregularity had been a subjective sensation; this disturbance had been relieved by food. An electrocardiogram revealed sinus bradycardia, a cardiac rate of 54, and occasional premature auricular contractions. Vagal release was effected by the administration of atropine. Immediately before the oral administration of 90 gm. of dextrose for an ordinary glucose tolerance test, the value for the fasting blood sugar was found to be 100 mg. per 100 cc. The glucose tolerance test revealed the following values for the blood sugar: 188 mg. per 100 cc. at the end of half an hour, 154 mg. per 100 cc. at the end of two hours, 170 mg. per 100 cc. at the end of two and a half hours, 93 mg. per 100 cc. at the end of three hours, 72 mg. per 100 cc. at the end of four hours and 89 mg. per 100 cc. at the end of six hours. At the end of four hours, the patient had mild hypoglycemic symptoms, including cold perspiration and slight mental confusion. A fasting test for hypoglycemia was continued for thirty-two hours. At the end of this period, the value for the blood sugar was 111 mg. per 100 cc. The patient did not have any symptoms of hypoglycemia during this period. The patient returned to the Clinic after an absence of five months. During this interval the patient had been eating six times a day and the diet had furnished a total of 1,100 calories daily. This dietetic regimen had afforded complete relief from hypoglycemic symptoms and had produced a noticeable reduction in weight.
The interesting points in this case are the number of associated functional symptoms, some of which had been present since childhood, the "indefinite" history as contrasted with the clear-cut history of true hyperinsulinism, the absence of severe hypoglycemia at any time, the Bormal concentration of blood sugar and absence of symptoms, after a prolonged fast. This' patient and the other forty patients who had nervous or functional hypoglycemia did not require an operation. Many of them were more in need of a frank discussion and discipline. Thirteen of the fortyone patients had an associated neurosis, anxiety ·state of hypochond~i-
990
MELVIN T. GORSUCH, EDWARD H. RYNEARSON
asis and three patients had an associated epilepsy. Very few of the patients in this entire group had stable personalities. Most of their symptoms were more related to the sympathetic nervous system than to the concentration of the blood sugar. In only twenty-four cases was mention made of the restorative effect of dextrose; in seventeen cases, improvement was inconstant and questionable; in six cases, relief was definite, and in one case, the dextrose had no effect. Twenty-nine patients had experienced no difficulty at night. None except those with epilepsy had had convulsive seizures. Probably the most important test in distinguishing severe hypoglycemia from the functional or nervous type is the prolonged fast. Very few patients with hyperinsulinism can fast very long, particularly if exercise is employed. Patients with severe hyperinsulinism cannot fast for longer than two or three hours. This test has proved of more value than has the glucose tolerance test. Very often, the sugar tolerance curve is typical of diabetes, rather than "flat," in cases of proved hyperinsulinism. Portis and ZitmanB found "flat" curves in neuropsychiatric cases. Finally, it should be stated that in these forty-one cases of functional or nervous hypoglycemia hyperinsulinism was diagnosed or suspected. This does not include the many strictly nervous patients who, as part of their nervousness, frequently ate food or candy or drank carbonated beverages. SUMMARY AND CONCLUSIONS
Hypoglycemia can be related to many functional or pathologic disturbances. The term "hyperinsulinism" should be used only in cases in which the symptoms are caused by an excessive amount of insulin, either exogenous or endogenous. The term "hyperinsulinism" should not be abused by applying it to hypoglycemia that may be due to any one of many causes. True hyperinsulinism resulting from a tumor of th,e islands of Langerhans is very rare; the spontaneous hypoglycemia of the nervous individual is much more common. REFERENCES
1. Harris, Seale:
Hyperinsulinism and Dysinsulinism. J.A.M.A., 83:729-733 (Sept. 6) 1924. 2. Keating, F. R. and Wilder, R. M.: Spontaneous Hypoglycemia: Report of Cases. South. Med. & Surg., 103:125-131 (Mar.) 1941. 3. Portis, S. A. and Zitman, I. H.: A Mechanism of Fatigue in Neuropsychiatric Patients; Preliminary Report. l.A.M.A., 121:569-573 (Feb. 20)1943.