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THE INSULIN-GLUCOSE TOLERANCE TEST. A MODIFIED PROCEDURE FOR THE DETECTION OF HYPOGLYCEMIA UNRESPONSIVENESS IN PITUITARY AND ADRENAL INSUFFICIENCY Frank L. Engel, James L. Scott J Clin Invest. 1950;29(2):151-160. https://doi.org/10.1172/JCI102241. Research Article Find the latest version: https://jci.me/102241/pdf THE INSULIN-GLUCOSE TOLERANCE TEST. A MODIFIED PROCEDURE FOR THE DETECTION OF HYPOGLYCEMIA UNRESPONSIVENESS IN PITUITARY AND ADRENAL INSUFFICIENCY By FRANK L. ENGEL AND JAMES L. SCOTT (From the Department of Medicine, Duke University School of Medicine, Durham, North Carolina) (Received for publication July 5, 1949) In 1941, Fraser, Albright, and Smith (1), results in equivocal responses and the necessity described the application of three carbohydrate for repeating the test. Even in presumably nor- tolerance tests to the diagnosis of disturbances mal individuals the symptoms of hypoglycemia in the endocrine control of metabolism. These may sometimes be sufficiently distressing as to were the glucose tolerance test, the insulin tol- make it desirable to terminate the procedure by erance test, and the glucose-insulin tolerance giving glucose. test. When properly employed and interpreted, The purpose of this communication is to de- these tests are of considerable value. However, scribe a modification of the insulin tolerance test, in practice, the insulin tolerance test has of- the insulin-glucose tolerance test, which was de- ten proven disappointing in those situations signed to overcome some of the disadvantages of in which it should be most valuable, i.e., condi- the former test. It is based on the observation by tions characterized by hypoglycemia unresponsive- Somogyi (2) that in normal individuals the ad- ness. Characteristically in adrenal and pituitary ministration of glucose 30-60 minutes after insulin, insufficiency, and less so in hyperinsulinism, the i.e., during hypoglycemia, resulted in the devel- response to insulin is somewhat exaggerated and opment of greater hyperglycemia than the admin- the spontaneous rise in blood sugar after hypogly- istration of the same amount of glucose without cemia is much retarded. This is clear from the insulin. Thus, glucose magnified the normal data of Fraser et al., when the individual curves homeostatic response to hypoglycemia. This re- for patients with hypopituitarism and Addison's sponse is presumably mediated by the hormones disease are compared with the mean of the nor- of the anterior pituitary, adrenal medulla and mals, or conversely, when cases of myxedema or adrenal cortex. It was found in the present study anorexia nervosa are compared to the mean of that compared to normal individuals, patients with the panhypopituitary group. However, in prac- adrenal and pituitary insufficiency did not have tice, we have found considerable overlapping be- the capacity to raise their blood sugar levels rap- tween the curves from cases of panhypopituitarism idly from hypoglycemic levels when given glu- and Addison's disease and those from cases of cose. This made for a considerably greater sepa- myxedema and anorexia nervosa and with the ration between this group of patients and normals normals, which makes individual curves -difficult and other pathological conditions than is achieved to evaluate. While varying degrees of adrenal and by the insulin tolerance test, although it did not pituitary insufficiency may occur in myxedema and eliminate overlapping. Furthermore, and of very anorexia nervosa, it is doubtful whether all the ab- great importance, the administration of glucose normal insulin tolerance tests in these conditions shortly after insulin considerably decreased the have this origin. Furthermore, the intravenous dangers from prolonged hypoglycemia in patients injection of insulin into patients with panhypopi- with adrenal or pituitary insufficiency. Although tuitarism or Addison's disease is attended by a the test has its greatest value in the hypoglycemia very definite risk of severe or even fatal unresponsive group, it was applied to a variety of hypo- other for glycemia. For this reason, Fraser et al. recom- conditions comparative purpose. mended that one-half or one-third the usual dose METHODS of insulin be given to patients seriously suspected Normal medical students and hospitalized patients were of suffering from these conditions. Often this the subjects for these tests. All hospitalized patients were 151 152 FRANK L. ENGEL AND JAMES L. SCOTT on. the regular hospital diet for at least three days prior Panhypopituitorism to the test. This contains approximately 2,600 calories 210 (protein 100, fat 130, and carbohydrate 250). The nor- 200 mal medical students ate their regular diets which were 190 of variable composition. Although it is recognized that I80 rigid control of the diet is important in tests of this sort, 170 this precaution is so rarely followed faithfully in practice 160 that it was felt desirable to compare the results.under the 4 150 less favorable circumstances under which the tests are apt it 140 to be carried out. o 130 PROCEDURE 0o 120 The subject is fasted overnight. Venous blood is with- -J ItHo 4i 100- I.P* drawn in the morning and 0.1 unit of regular insulin per eon Normal Kg. body weight injected intravenously. In individuals 90- .p weighing 40 Kg. or less U40 insulin should be diluted I80 L, tenfold with saline in order to administer an accurate z 70 dose. At 30 minutes or when the first significant symp- 0v 60 w toms of hypoglycemia appear, depending on which is first, 0. S50l 0.8 gram of glucose per Kg. body weight is given by mouth. Additional blood samples are taken at 60, 90, 120, and 180 minutes from the initial sample. For com- parative purposes the blood sugar levels are recorded as per cent of the initial blood sugar, which is taken as 100 lol 3 60 9 1 5 180 30 60 90 120 150 180 per cent. MINUTES RESULTS FIG. 2. INSULIN-GLUCOSE TOLERANCE CURVES FROM Figure 1 records the mean curve (+ stand- THREE PATIENTS WITH PANHYPOPITUITARISM ard deviation) of the insulin-glucose tolerance test The shaded area in this and subsequent figures repre- sents twice the standard deviation of the mean normal in 30 subjects: 20 medical students and 10 hos- and should include the curves from 97 per cent of normal pitalized patients who were well nourished and had individuals. The probability of a curve falling outside no -evidence of organic disease. Although the med- this area being normal is very small. ical students were on variable diets there was no statistically significant difference in their response compared to the hospitalized controls. The two groups were therefore pooled for determination of Normal Controls (30) Mean ± S.D. the standard deviation of the mean. A character- istic biphasic pattern is apparent, with a prompt 180 T I170 rise of the blood sugar to a mean above the starting i 160 level 30 minutes and a peak 60 minutes after glu- I150 cose. In no single case was there a failure to ex- W, I 140- ceed the initial value at either 30 or 60 minutes af- 0 Uo 130 ter glucose. I120 ol0at 0.1 UNIT T Figure 2 records five curves after insulin and 110. INSULIN I T -i-i iI Per glucose, plotted as per cent of the, initial blood art Kg. _.V. 90. sugar, from three patients suffering from panhy- popituitarism. The diagnosis in each case was I.- 70 based on classical history, physical and laboratory z w 60- findings, including abnormally low urinary excre- <) 50- - tion of 17-ketosteroids and gonadotrophins. M. P. Er 40. 0.8 gin. GLUCOSE had a. craniopharyngioma and was slightly under- 30. Per K. p.o. nourished; R. L. had a chromophobe adenoma 20 30 60 90 120 150 180 which was removed surgically, and was moderately MINUTES obese; and L. T. was a classical example of post- FIG. 1. MEAN INSULIN-GLUCOsE TOLERANCE CUmRVE partum pituitary necrosis with pituitary cachexia. STANDAR DEIATION FOR 30 NORMAL INDIVIDUALS These five curves, as well as subsequent ones are INSULIN-GLUCOSE TOLERANCE TEST 153 plotted against a background of the mean normal either outside or just at the lower edge of the theo- curve surrounded by an area representing tuice retical normal range. Although the number of the standard deviation of the mean of the normal. cases is small they are consistent and, as will The probability of any curve falling outside the be noted below, were little changed by various shaded area being normal is small, since theoreti- types of therapy. cally the area should include over 97 per cent of Figure 3 shows a set of curves from eight pa- all normals, while half the area would include 67 tients with Addison's disease compared to the per cent of all normals. In actual fact no curve and mean normal with twice the standard deviation. only one single point of any of the 30 curves from The decreased or delayed response to glucose is normal subjects studied fell outside of the shaded again apparent as in the hypopituitary cases. All area, indicating that the limits of normal set by curves had one or more points outside of the this procedure are indeed liberal. This method of shaded area, particularly at 60 and 90 minutes, plotting, therefore, graphically illustrates the sig- leading to a flattened appearance to -the curve. In nificance of each curve compared to normal, and contrast to the normals where everyone exceeded gives a fairer indication of the validity of the test the initial value at either 30 or 60 minutes, or than is obtained by the usual custom of comparing both, none of the Addison's disease curves had them simply to the mean normal. Note that the reached this level at these times. One curve shapes of the curves from the hypopituitary pa- (marked with an asterisk) fell almost within the tients are very different from the normals.

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