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Early insulin response to intravenous glucose in steroid-stress diabetes
Early Insulin Response to Intravenous Glucose in Steroid-Stress Diabetes By RALPH
W.
ALEXANDER, PETER H. FORSHAM AND GEROLD M. GRODSKY
Ten healthy people were found to have an abnormal response to corticosteroidglucose tolerance test during an industrial survey designed to detect subclinical diabetes and were compared to 10 normal controls selected from the same survey. Although insulin-to-glucose ratios, after intravenous injection of glucose, were similar in both groups, blood glucose values subsequent to the fasting level
were significantly higher in the stressdiabetic group, indicating a suboptimal insulin response. Such subjects appear to represent the earliest stage in progressive decompensation of glucose tolerance due to relative insulin insufficiency in the presence of a mild peripheral block to glucose utilization. (Metabolism 18: No. 3, March, 248-251, 1969)
D
IMINISHED INSULIN SECRETION in response to an intravenous glucose load is seen in juvenile1 and maturity-onset diabetes, with a fasting blood sugar greater than 150 mg./lOO ml.2 or a two-hour postprandial blood sugar greater than 300 mg./lOO ml.3 Attempts to identify an abnormal secretion of insulin, occurring before the stage of such frank diabetes, have yielded contradictory results. Nondiabetic persons with immediate diabetic relatives are reported to have a normal’ and greater5 or lesser” than normal insulin response to a glucose load. Part of this discrepancy at least may be explained by relating the insulin concentration to the blood glucose level.s The early insulin response after a glucose load would appear to be the most important phase in detecting beginning abnormalities.7 The present study shows that a group of persons identified as having steroid-stress diabetes had suboptimal early release of insulin after glucose injection, but that this abnormality was not as great as reported for prediabetics, such as people with a strong family history of diabetes. METHODS During a voluntary survey for diabetes in employees of a utility company, 10 persons were classified as having stress diabetes (subclinical) by means of a dexamethasone-glucose F~mn the Medical Department, Pacific Telephone Company, San Francisco, Cakf., and the Metabolic Resemch Unit aw! Departments of Medicine and Biochemistry, University of California Medical Center, San Francisco, Calif. Received for publication December 12, 1968. RALPH W. ALEXANDER, M.D.: Assistant Clinical Professor of Medicine, Department of Medicine, University of California Medical Center, San Francisco, Calif., and Medical Director, Pa&c Telephone Company, San Francisco, Calif. PETER H. FORSHAM, M.D.: Director, Metabolic Research Unit and General Professor of Medicine and Pediatks; Clinical Research Center, University of Californiu Medical Center, San Francisco, Calif. GEROLD M. GRODSKY,PH.D.: Professor of Biochemistry and Research Biochemist, Metabolic Research Unit and Department of Biochemistry, Uniuersity of California Medical Center, San Francisco, Calif. 248
EARLY
INSULIN
349
RESPONSE
240
,. __-~
~~~
FAST 3 5
l.-Blood
L
15
MINUTES
Fig.
-I
AFTER
glucose
L
30 1”
L
FAST
GLUCOSE
and insulin
response
after
..l
1_._.._.____
3
5
L
~~_ ___J
15
30
MINUTES
AFTER
I”
GLUCOSE
25 Gm.
of intravenous
glucose.
tolerance test described by Fajans tolerance test,s modified after the cortisone-glucose and Conn.9 This otherwise healthy group was composed of seven men and three women, 31 to 59 years of age, with an average age of 45. One had a history of diabetes in a parent and two others in distant relatives. Body weight was more than 10 per cent ideal in one subject. One of the women was on estrogens. Another group of ten persons with a normal dexamethasone-glucose tolerance test, taken from the same voluntary survey, was identically studied. This group was composed of eight men and two women, age 30 to 50, with an average age of 39 years. None had a diabetic history in the immediate family and four had distant relatives with diabetes mellitus. One was more than 10 per cent ideal weight, and one woman was on an ovulation suppressant. All subjects were told to eat six slices of bread daily with regular meals for three days preceding blood collection. After an overnight fast, a blood sample was drawn after which 25 Cm. of glucose in a 50 per cent solution was given intravenously for 2 minutes. Blood specimens were obtained from the opposite arm at 3, 5, and 30 minutes after completing the injection. Blood samples were analyzed for glucose by the Somogyi-Nelson technique for whole blood,10 and for insulin by the immunochemical assay of Crodsky and Forsham. RESULTS
Figure 1 shows the mean values t one standard error of the mean for the control and stress-diabetic groups. Fasting glucose levels are the same in both groups, and fasting insulin levels are slightly but significantly higher in the stress-diabetic group (Table 1). Both groups have a significant elevation ( < 0.05 per cent significance level) of glucose and insulin levels from baseline three minutes after glucose injection. Levels decrease slightly at 5 minutes and continue to drop, but do not reach fasting values at 30 minutes. Absolute values for glucose and insulin concentration rise to and are maintained at higher than control group levels in stress-diabetics. This difference is much more notable for glucose concentrations, where significance levels reach < 0.05 per cent at 5 and 30 minutes, than it is for insulin (Table 1). The difference between the two groups for the change from fasting values is only
250 Table l.--Significance
ALEXANDER,
FORSHAM
AND GRODSKY
Levels* of Differences Between Normals and Stress Diabetics for Insulin and Glucose Fasting
3 min. 5 min. per cent
30 min.
<5.0 N.S.f <5.0
<5.0 <0.5 N.S.
(10 <0.05 N.S.
<5.0 <0.05 N.S.
N.S. <0.5 N.S.
<5.0 <0.05 N.S.
N.S.
Absolute values I. Insulin (aU./ml. ) 2. Glucose (mg./lOO ml.) 3. Insulin-to-glucose ratio Change from fasting value 4. A Insulin (CU./ml. ) 5. A Glucose (mg./lOO ml.) 6. A Insulin-to-AgIucose ratio * Significance levels determined by student’s t N.S.: not significant at 5 per cent level.
t value for unpaired
variables.
barely significant at 5 minutes for insulin but quite significant for glucose at all periods. The ratio of insulin-to-glucose was examined for absolute values and change from fasting values. Except for a slight difference in the absolute fasting ratio, there was no significant difference for any subsequent ratio between the control and stress-diabetes groups as shown in Table 1, lines 3 and 6. DJSCUSSION
In the group with steroid-provoked hyperglycemia, blood sugar levels rose higher than in the control group, despite higher insulin values after intravenous glucose loading. Thus, the ratio of insulin-to-glucose was almost identical in the stress-diabetics and controls. Evidently, the early insulin response of the stress group was not sufficient to control the blood sugar. One must conclude that the insulin release in the stress group is, in fact, suboptimal for maintenance of normoglycemia. These findings agree with current concepts of the evolution of the diabetic nor abnormal state.l” In normal subjects one finds neither hyperglycemia insulin levels. Next in sequence would come our steroid-stress subjects, who begin to show decreased glucose tolerance in spite of elevated insulin levels, and must therefore be considered relatively deficient in insulin, Next, one would place early decompensation of insulin secretion in a subject with a diabetic family history who, with a standard glucose tolerance test, still shows blood sugar levels within the normal range but has decreased insulin levels.2J3 It is of interest that the one subject in the stress group who had a diabetic parent did, in fact, show considerably lower insulin values, though not below control, and higher glucose levels than the group average. Finally in this sequence, one would have overt diabetics with both elevated blood glucose and depressed insulin levels, as commonly found in nonobese diabetics of all ages.14-16 From a practical point of view, patients who behave like the steroid-stress group should be retested yearly or every other year. If a gradual decompensation occurs, with insulin levels lower than those found in the present study,
EARLY
INSULIN
251
RESPONSE
this would confirm the postulated tion of the diabetic state.
place of steroid-stress diabetes in the evolu-
ACKNOWLEDGMENT The assistance of the Medical Department staff and of Messrs. Pacific Telephone Company is gratefully acknowledged.
Beaver
and Ardley of the
REFERENCES 1. YaIow, R. S., and Berson, S. A.: Plasma insulin concentrations in nondiabetic and early diabetic subjects: Deterrninations by a new sensitive immuno-assay technic. Diabetes 9:254-260, 1960. 2. Colwell, J. A., and Lein, A.: Diminished insulin response to hyperglycemia in prediabetes and diabetes. Diabetes l&560-565, 1967. 3. Yalow, R. S., Glick, S. M., Roth, J., and Berson, S. A.: Plasma insulin and growth hormone levels in obesity and diabetes. Ann. N. Y. Acad. Sci. 131:357373, 1965. 4. Grodsky, G. M., Karam, J. H., Pavlatos, F. Ch., and Forsham, P. H.: Seruminsulin response to glucose in prediabetic subjects. Lancet 1:290-291, 1965. 5. Ricketts, H. T., Cherry, R. A., and Kirsteins, L.: Biochemical studies of “prediabetes.” Diabetes 15:880-888, 1966. 6. Soeldner, J. S., Gleason, R. E., Williams, R. F., Garcia, M. J., Beardwood, D. M., and Marble, A.: Diminished serum insulin response to glucose in genetic prediabetic males with normal glucose tolerance. Diabetes 17: 17-26, 1968. 7. Simpson, R. G., Benedetti, A., Grodsky, G. M., Karam, J. H., and Forsham, P. H.: Early phase of insulin release. Diabetes 173684-692, 1968. 8. Alexander, R. W.: Detection of subclinical diabetes in industry using glucocorticoid provocation. J. Occup. Med. 10: 278-284, 1968. 9. 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 3: 296-304, 1954. 10. Nelson, N.: A photometric adaptation
of
the
Somogyi
method
for
the
de-
termination of glucose. J. Biol. Chem. 153: 375-380, 1944. 11. Grodsky, G. M., and Forsham, P. H.: An immunochemical assay of total extractable insulin in man. J. Clin. Invest. 39: 1070-1079, 1960. 12. Reaven, G., and Miller, R.: Study of the relationship between glucose and insulin responses to an oral glucose load in man. Diabetes 17:560-569, 1968. 13. Taylor, K. W., Sheldon, J., Pyke, D. A., and Oakley, W. G.: Glucose tolerance and serum insulin in the unaffected first-degree relatives of diabetics. Brit. Med. J. 4:22-24, 1967. 14. Perley, M., and Kipnis, D. M.: Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and nondiabetic subjects. Diabetes 15867874, 1966. 15. Karam, J. H., Grodsky, G. M., Pavlatos, F. Ch., and Forsham, P. H.: Critical factors in excessive serum-insulin response to glucose. Lancet 1:286-289, 1965. 16. Cerasi, E., and Luft, R.: “What is inherited-what pathogenesis 16:615-627,
is added” of diabetes 1967.
hypothesis for the melhtus. Diabetes
W.
ALEXANDER, PETER H. FORSHAM AND GEROLD M. GRODSKY
Ten healthy people were found to have an abnormal response to corticosteroidglucose tolerance test during an industrial survey designed to detect subclinical diabetes and were compared to 10 normal controls selected from the same survey. Although insulin-to-glucose ratios, after intravenous injection of glucose, were similar in both groups, blood glucose values subsequent to the fasting level
were significantly higher in the stressdiabetic group, indicating a suboptimal insulin response. Such subjects appear to represent the earliest stage in progressive decompensation of glucose tolerance due to relative insulin insufficiency in the presence of a mild peripheral block to glucose utilization. (Metabolism 18: No. 3, March, 248-251, 1969)
D
IMINISHED INSULIN SECRETION in response to an intravenous glucose load is seen in juvenile1 and maturity-onset diabetes, with a fasting blood sugar greater than 150 mg./lOO ml.2 or a two-hour postprandial blood sugar greater than 300 mg./lOO ml.3 Attempts to identify an abnormal secretion of insulin, occurring before the stage of such frank diabetes, have yielded contradictory results. Nondiabetic persons with immediate diabetic relatives are reported to have a normal’ and greater5 or lesser” than normal insulin response to a glucose load. Part of this discrepancy at least may be explained by relating the insulin concentration to the blood glucose level.s The early insulin response after a glucose load would appear to be the most important phase in detecting beginning abnormalities.7 The present study shows that a group of persons identified as having steroid-stress diabetes had suboptimal early release of insulin after glucose injection, but that this abnormality was not as great as reported for prediabetics, such as people with a strong family history of diabetes. METHODS During a voluntary survey for diabetes in employees of a utility company, 10 persons were classified as having stress diabetes (subclinical) by means of a dexamethasone-glucose F~mn the Medical Department, Pacific Telephone Company, San Francisco, Cakf., and the Metabolic Resemch Unit aw! Departments of Medicine and Biochemistry, University of California Medical Center, San Francisco, Calif. Received for publication December 12, 1968. RALPH W. ALEXANDER, M.D.: Assistant Clinical Professor of Medicine, Department of Medicine, University of California Medical Center, San Francisco, Calif., and Medical Director, Pa&c Telephone Company, San Francisco, Calif. PETER H. FORSHAM, M.D.: Director, Metabolic Research Unit and General Professor of Medicine and Pediatks; Clinical Research Center, University of Californiu Medical Center, San Francisco, Calif. GEROLD M. GRODSKY,PH.D.: Professor of Biochemistry and Research Biochemist, Metabolic Research Unit and Department of Biochemistry, Uniuersity of California Medical Center, San Francisco, Calif. 248
EARLY
INSULIN
349
RESPONSE
240
,. __-~
~~~
FAST 3 5
l.-Blood
L
15
MINUTES
Fig.
-I
AFTER
glucose
L
30 1”
L
FAST
GLUCOSE
and insulin
response
after
..l
1_._.._.____
3
5
L
~~_ ___J
15
30
MINUTES
AFTER
I”
GLUCOSE
25 Gm.
of intravenous
glucose.
tolerance test described by Fajans tolerance test,s modified after the cortisone-glucose and Conn.9 This otherwise healthy group was composed of seven men and three women, 31 to 59 years of age, with an average age of 45. One had a history of diabetes in a parent and two others in distant relatives. Body weight was more than 10 per cent ideal in one subject. One of the women was on estrogens. Another group of ten persons with a normal dexamethasone-glucose tolerance test, taken from the same voluntary survey, was identically studied. This group was composed of eight men and two women, age 30 to 50, with an average age of 39 years. None had a diabetic history in the immediate family and four had distant relatives with diabetes mellitus. One was more than 10 per cent ideal weight, and one woman was on an ovulation suppressant. All subjects were told to eat six slices of bread daily with regular meals for three days preceding blood collection. After an overnight fast, a blood sample was drawn after which 25 Cm. of glucose in a 50 per cent solution was given intravenously for 2 minutes. Blood specimens were obtained from the opposite arm at 3, 5, and 30 minutes after completing the injection. Blood samples were analyzed for glucose by the Somogyi-Nelson technique for whole blood,10 and for insulin by the immunochemical assay of Crodsky and Forsham. RESULTS
Figure 1 shows the mean values t one standard error of the mean for the control and stress-diabetic groups. Fasting glucose levels are the same in both groups, and fasting insulin levels are slightly but significantly higher in the stress-diabetic group (Table 1). Both groups have a significant elevation ( < 0.05 per cent significance level) of glucose and insulin levels from baseline three minutes after glucose injection. Levels decrease slightly at 5 minutes and continue to drop, but do not reach fasting values at 30 minutes. Absolute values for glucose and insulin concentration rise to and are maintained at higher than control group levels in stress-diabetics. This difference is much more notable for glucose concentrations, where significance levels reach < 0.05 per cent at 5 and 30 minutes, than it is for insulin (Table 1). The difference between the two groups for the change from fasting values is only
250 Table l.--Significance
ALEXANDER,
FORSHAM
AND GRODSKY
Levels* of Differences Between Normals and Stress Diabetics for Insulin and Glucose Fasting
3 min. 5 min. per cent
30 min.
<5.0 N.S.f <5.0
<5.0 <0.5 N.S.
(10 <0.05 N.S.
<5.0 <0.05 N.S.
N.S. <0.5 N.S.
<5.0 <0.05 N.S.
N.S.
Absolute values I. Insulin (aU./ml. ) 2. Glucose (mg./lOO ml.) 3. Insulin-to-glucose ratio Change from fasting value 4. A Insulin (CU./ml. ) 5. A Glucose (mg./lOO ml.) 6. A Insulin-to-AgIucose ratio * Significance levels determined by student’s t N.S.: not significant at 5 per cent level.
t value for unpaired
variables.
barely significant at 5 minutes for insulin but quite significant for glucose at all periods. The ratio of insulin-to-glucose was examined for absolute values and change from fasting values. Except for a slight difference in the absolute fasting ratio, there was no significant difference for any subsequent ratio between the control and stress-diabetes groups as shown in Table 1, lines 3 and 6. DJSCUSSION
In the group with steroid-provoked hyperglycemia, blood sugar levels rose higher than in the control group, despite higher insulin values after intravenous glucose loading. Thus, the ratio of insulin-to-glucose was almost identical in the stress-diabetics and controls. Evidently, the early insulin response of the stress group was not sufficient to control the blood sugar. One must conclude that the insulin release in the stress group is, in fact, suboptimal for maintenance of normoglycemia. These findings agree with current concepts of the evolution of the diabetic nor abnormal state.l” In normal subjects one finds neither hyperglycemia insulin levels. Next in sequence would come our steroid-stress subjects, who begin to show decreased glucose tolerance in spite of elevated insulin levels, and must therefore be considered relatively deficient in insulin, Next, one would place early decompensation of insulin secretion in a subject with a diabetic family history who, with a standard glucose tolerance test, still shows blood sugar levels within the normal range but has decreased insulin levels.2J3 It is of interest that the one subject in the stress group who had a diabetic parent did, in fact, show considerably lower insulin values, though not below control, and higher glucose levels than the group average. Finally in this sequence, one would have overt diabetics with both elevated blood glucose and depressed insulin levels, as commonly found in nonobese diabetics of all ages.14-16 From a practical point of view, patients who behave like the steroid-stress group should be retested yearly or every other year. If a gradual decompensation occurs, with insulin levels lower than those found in the present study,
EARLY
INSULIN
251
RESPONSE
this would confirm the postulated tion of the diabetic state.
place of steroid-stress diabetes in the evolu-
ACKNOWLEDGMENT The assistance of the Medical Department staff and of Messrs. Pacific Telephone Company is gratefully acknowledged.
Beaver
and Ardley of the
REFERENCES 1. YaIow, R. S., and Berson, S. A.: Plasma insulin concentrations in nondiabetic and early diabetic subjects: Deterrninations by a new sensitive immuno-assay technic. Diabetes 9:254-260, 1960. 2. Colwell, J. A., and Lein, A.: Diminished insulin response to hyperglycemia in prediabetes and diabetes. Diabetes l&560-565, 1967. 3. Yalow, R. S., Glick, S. M., Roth, J., and Berson, S. A.: Plasma insulin and growth hormone levels in obesity and diabetes. Ann. N. Y. Acad. Sci. 131:357373, 1965. 4. Grodsky, G. M., Karam, J. H., Pavlatos, F. Ch., and Forsham, P. H.: Seruminsulin response to glucose in prediabetic subjects. Lancet 1:290-291, 1965. 5. Ricketts, H. T., Cherry, R. A., and Kirsteins, L.: Biochemical studies of “prediabetes.” Diabetes 15:880-888, 1966. 6. Soeldner, J. S., Gleason, R. E., Williams, R. F., Garcia, M. J., Beardwood, D. M., and Marble, A.: Diminished serum insulin response to glucose in genetic prediabetic males with normal glucose tolerance. Diabetes 17: 17-26, 1968. 7. Simpson, R. G., Benedetti, A., Grodsky, G. M., Karam, J. H., and Forsham, P. H.: Early phase of insulin release. Diabetes 173684-692, 1968. 8. Alexander, R. W.: Detection of subclinical diabetes in industry using glucocorticoid provocation. J. Occup. Med. 10: 278-284, 1968. 9. 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 3: 296-304, 1954. 10. Nelson, N.: A photometric adaptation
of
the
Somogyi
method
for
the
de-
termination of glucose. J. Biol. Chem. 153: 375-380, 1944. 11. Grodsky, G. M., and Forsham, P. H.: An immunochemical assay of total extractable insulin in man. J. Clin. Invest. 39: 1070-1079, 1960. 12. Reaven, G., and Miller, R.: Study of the relationship between glucose and insulin responses to an oral glucose load in man. Diabetes 17:560-569, 1968. 13. Taylor, K. W., Sheldon, J., Pyke, D. A., and Oakley, W. G.: Glucose tolerance and serum insulin in the unaffected first-degree relatives of diabetics. Brit. Med. J. 4:22-24, 1967. 14. Perley, M., and Kipnis, D. M.: Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and nondiabetic subjects. Diabetes 15867874, 1966. 15. Karam, J. H., Grodsky, G. M., Pavlatos, F. Ch., and Forsham, P. H.: Critical factors in excessive serum-insulin response to glucose. Lancet 1:286-289, 1965. 16. Cerasi, E., and Luft, R.: “What is inherited-what pathogenesis 16:615-627,
is added” of diabetes 1967.
hypothesis for the melhtus. Diabetes