510 Horm. Metab. Res. 9 (1977) 510-512 © Georg Thieme Verlag Stuttgart
Hyperinsulinemic Hypoglycemia: Effect of Epinephrine Suppression P.C. Kansal, B.R. Boshell, J. Buse*, M.S. Bandisode, R.F. Roddam and Maria G. Buse* Department of Medicine, University of Alabama In Birmingham, Birmingham, Alabama, "Medical University of South Carolina, Charleston, South Carolma, U.S.A.
The inhibitory effect of epinephrine on basal and tolbutamide-stimulated insulin release was studied in 5 patients with hyperinsulinemic hypoglycemia. Epinephrine inhibited both basal and tolbutamide-induced insulin release in patients with ß-ceU adenoma and hyperplasia, but failed to inhibit insulin release in a patient with ß-cell carcinoma. The inhibition of basal insulin with epinephrine was maximum in patients with ß-cell hyperplasia. This differential inhibitory effect of epinephrine on insulin release may prove to be a useful screening test in the preoperative diagnosis of the nature of the lesion producing hyperinsulinemia. Key-Words: Tolbutamide - Epinephrine - Insulin Response
Introduction Patients with insulinomas usually have increased fasting plasma insulin in relation to plasma glucose (Turner, Oakley and Naba"o 1971). The diagnosis of insulinoma is usually confirmed by demonstrating excessive insulin secretion in response to tolbutamide (Khurana, Dhawer, Klayton, Co"edor, Jung, Sieracki, Gonzales and Danowski 1971), glucagon (Marks and Samols 1969), leucine (Floyd, Fazans, Knopf and Conn 1964) or prolonged fasting (Scholz, Remine and Priestly 1960). About 10 percent of the pancreatic insulinomas are malignant. None of the tests mentioned above discriminate between the benign and malignant nature of the lesions.
While this study was in progress, a paper describing the effect of intravenous infusion of epinephrinePropranolol in two patients with pancreatic ß-cell adenoma has been published (Shen 1975). Material and Methods Five patients with hyperinsulinemie hypoglyeemia were studied at the Medieal University of South Carolina (patients land 5) and at the University of Alabama in Birmingham (patients 2, 3 and 4). The elinical data is given in Table I. All the subjects were explained about the nature of the procedures to be carried out and an informed consent was obtained. Table 1. Clinical characteristics of patients with hyperinsulinemic hypoglycemia No.
Age
Sex
1
55 32 52 53 62
F F F F M
2 3 4
5
Fasting Fasting Pathological Diablood glu- immunognosis cose reactive (mgl insulin 100 ml)
50 50 70 80 50
44
27 8 18 27
ß-eell ß-cell ß-cell ß-cell ß-cell
adenoma adenoma hyperplasia hyperplasia carcinoma
Tolbutamide test (IV I Gm - IVTTj was carried out before and during epinephrine infusion on different days in patients Catecholamines modulate insulin secretion by the be- No. 1 and 5, and on the same day in patients No. 3 and 4. IVTT before and during epinephrine infusion were also perta cells of the pancreas (Porte, Graber, Kuzuya and formed on the same day in two normal subjects. Epinephrine Williams 1966). Epinephrine inhibits plasma insulin (diluted in normal saline) was infused at the rate of 6/pgl levels in the basal state (Robertson and Porte 1973) ml/min. The infusion was started 30 minutes before the IV as weil as in response to intravenous glucose, glucagon injection of tolbutamide and was continued for 60 minutes following the tolbutamide injection. Patient No. 2 was suband tolbutamide (Porte et al. 1966). Autonomous Jitjtted to epinephrine suppression test without tolbutamide. endocrine function is more easily diagnosed by sup-
pressive rather than by stimulatory tests such as dexamethasone suppression test in hypercorticism, triiodothyronine test in hyperthyroidism and glucose in acromegaly. Moreover, dexamethasone suppression test is also used to differentiate between adrenal hyperplasia, adenoma and carcinoma as a cause of hypercorticism. Based on this background, the present investigation was undertaken to determine the effect of epinephrine infusion on basal levels of insulin and insulin release in response to tolbutamide in patients with hypoglycemia caused by hyperinsulinism. Received: 20 Oet. 1976
Aeeepted: 23 May 1977
Frequent blood sampies were draWn in heparinized tubes which were kept on ice until centrifuged. Plasma insulin levels were determined by a double-antibody method as described by Morgan and Lazarow (196·3). All sampies from one patient were assayed in the same batch.
Results Surgical exploration followed by histopathological study of the pancreas of 5 patients who underwent epinephrine suppression tests revealed that patients No. 1 and 2 had pancreatic ß-cell adenomas, No. 3 and 4 had ß-cell hyperplasia and No. 5 had ß-cell carcinoma.
Downloaded by: Boston University. Copyrighted material.
Summary
_
Hyperp/oSlo
The maximum insulin secretion in response to IV tolbutamide occurred within the first 10 minutes. The total insulin increment above the basal levels during the first 30 minutes was compared in tests without epinephrine and during epinephrine infusion. Each patient served as his or her own contro!. During epinephrine infusion, the insulin response to tolbutamide increased by 71 and 66% in two normal volunteers; by 97% in patient No. 1; 80% in No. 3 and 32% in patient No. 4. In patient No. I, the blood sampie for insulin level at 30 minutes was not drawn but insulin level in response to tolbutamide during epinephrine infusion at 60 minutes was the same as at 0 minutes. Epinephrine did not suppress the insulin secretory response to tolbutamide in patient No. 5 who had carcinoma of the ß-cells (Fig. 2). In fact, in this patient there was a paradoxical increase in insulin levels in response to tolbutamide du ring epinephrine infusion. In this patient, insulin levels at 30 and 60 minutes, in response to tolbutamide without epinephrine infusion, were 165 and 72 J..LU/ml and during epinephrine infusion 330 and 170 J..LU/ml respectively.
-Ad.nomo
125
~CtJ,c;nomQ
~ ~ 100
-' ~ o-' a::
I-
z
o
75
U
-' ~
I-
~
\5
50
IZ LU U
a::
LU
0..
25
0~
________L -________L-______--J 10
20
30
Fig. 1. Effect of epinephrine (6 pg/minute) on circulating irnmunoreactive insulin (IRI).
The effect of epinephrine infusion on the insulin levels in the basal state and in response to IV tolbutamide is shown in Figures 1 and 2 respectively. The basal insulin levels during epinephrine infusion decreases by 32 and 23ro in patients with f3-cell adenomas (No. 1 and 2 respectively), but 62% each in patients with ß-cell hyperplasia (No. 3 and 4) but paradoxically increased by 20% in the patient with ß-cell carcinoma (Fig. 1). 210
TOlBUTAMIDE BEFORE EPINEPHRINE
CD
200
TOLBUTAMIOE WITH EPINEPHR/NE
~
511
Discussion Fasting hypoglycemia with endogenous hyperinsulinemia is usually due to pancreatic tumors in adults and ninety percent of these tumors are benign. Extrapancreatic tumor is a rare cause of hyperinsulinemic hypoglycemia (Lyall, Marieb, Wise, Cornog, Neville and Felig 1975). Hyperinsulinemia due to hyperplasia of ß-cells of the pancreas is commonly seen in infants. However, in the study reported here,
.---.
®
200
Jj
i
oS
200
®
"ö :>
"-
___________ -11 0
5
10 15 20 (/J-cell o.,.".""o)
0
30
30 10 20 (Co 0' /J-c.II,)
0 0
~
2
20 30 NORMALS(Meon 0' 7wo) !5
10
i
,
"ö
:>
"0
2
!5
10
20
(/J-c.1I hyperplollo)
0
30
M/NUTES
20 2 5 10 (J3-c.1I hyp.rplos,o)
•
30
Fig. 2. Plasma insulin levels in response to infusion of tolbutamide, with or without epinephrine, in two normals and four patients with hyperinsulinemia.
Downloaded by: Boston University. Copyrighted material.
Hyperinsulinemic Hypoglycemia: Effect of Epinephrine Suppression
P.c. KansaJ, B.R. Boshell, J. Buse, M.S. Bandisode, R.F. Roddam, Maria G. Buse
there were 2 cases of ß-cell hyperplasia in adults. In the majority of the cases, the diagnosis of excessive endogenous insulin may be made by the classical tests mentioned in the introduction (Turner et al. 1971, Khurana et a1. 1971, Marks et al. 1969, Floyd et al. 1964, Scholz et a1. 1960, Porte et a1. 1966). The role of insulin suppression by fish insulin (Turner and Ha"is 1974) or by Somatostatin (Lorenzi, Gerich, Karam and Forsham 1975) in the diagnosis of insulinoma remains to be determined. Moreover, fish insulin and Soroatostatin are not available as yet for clinical use. However, none of these tests discriminate between the causes of endogenous hyperinsulinemia. Somatostatin inhibited insulin release in response to glucose both in malignant (Curnow, Carey, Tay/or, Johanson and Murad 1975) and non-malignant (Christen sen, Hanse, Lundbaek, Orskov and Seyer-Hanse 1975) insulinomas.
adenomas and hyperplasia. We have no explanation for this discrepancy except the difference in experimental procedures in the two studies. During epinephrine infusion, the degree of inhibition of basal insulin was greater in patients with ß-cell hyperplasia (62% in each) than in those patients with ß-cel1 adenoma (32 and 23%)_ However, with the dose of epinephrine used in this study, the suppression of insulin following administration of tolbutamide was not different in these two groups of patients. Epinephrine did not inhibit insulin either basal or in response to tolbutamide in a patient with ß-cell carcinoma. In fact, in this patient during epinephrine infusion, there was a paradoxical rise both in the basal insulin and in response to tolbutamide. The preliminary data presented here suggests that epinephrine suppression of insulin both in the basal state and/or in response to tolbutamide may discriminate between benign and malignant lesion of ßcells of the pancreas.
In contrast to the previous study (Shen 1975) where combined infusion of epinephrine and Propranolol did not decrease basal insulin levels in two patients Acknowledgement with insulinomas; in the study reported here, epimephrine inhibited insulin both basal and in response We wish to thank Mr. George Duckworth for technical assistance, Miss Marilyn Parsons for secretarial help and Mr. to intravenous tolbutamide in patients with ß-cell Rod Powers for medical illustration.
References Bennett, L.L., D.L. Curry, K. Curry: Differences in insulin release in response to glucose and tolbutarnide stimulation. Proc.Soc.Exp.BioI.Med. 144: 436-439 (1973) Christensen, S.E., A.P. Hansen, K. Lundbaek, H. Orskov, K. Seyer-Hanse: Somatostatin and insulinoma. The Lancet I: 1426 (1975) Curnow, R.T., R.M. Carey, A. Taylor, A. Johanson, F. Murad: Somatostatin inhibition of insulin and gastrin hypersecretion in pancreatic islet-cell carcinoma. New Eng1.J. Med. 292: 1385-1386 (1975) Floyd, J. e., Jr., S.S. Fazans, R.F. Knopf, J. W. Conn: Plasma insulin in organic hyperinsulinism. Comparative effects of tolbutamide, leucine and glucose. J.Clin.Endocr. 24: 747760 (1964) Gaeke, R.F., E.L. KapIlln, A. Rubenstein, J. Starr, G. Burke: Insulin and proinsulin release during calcium infusion in a patient with islet-cell tumor. Metabolism 9: 1029-1034 (1975) Khurana, R.C., V.P.S. Dhawer, R. Killyton, D.G. Co"edor, Y. Jung, J.e. Sieracki, A.R. Gonzales, T.S. Danowski: Insulin and glucose patterns in control subjects and in proved insulinoma. Am.J.Med.Sci. 262: 115-128 (1971) Lorenzi, M., J.E. Gerich, J.H. Karam, P.H. Forsham: Failure of somatostatin to inhibit tolbutamide-induced insulin secretion in patients with insulinomas: A possible diagnostic tool. J.Clin.Endocr.Metab. 40: 1121-1124 (1975) Lyall, S.S., N.J. Marieb, J.K. Wise, J.L. Cornog, E.e. Neville,
P. Felig: Hyperinsulinemic hypoglycemia associated with a neurofibrosarcoma. Arch.lntern.Med. 135: 865-867 (1975) Marks, v., E. Samols: Diagnostic tests for evaluating hypoglycemia. In: Diabetes (Proceedings of the Sixth Congress of the International Diabetes Federation), Ostman, J., R.D.G. Milner (eds.). Excerpta Medica Foundation, Amsterdam 1969, p. 864-872 Morgan, e.R., A.L. Lazarow: Immunoassay of insulin: Twoantibody system. Plasma levels of normal, subdiabetic and diabetic rats. Diabetes 12: 115-126 (1963) Porte, D., Jr.. A.L. Graber, T. Kuzuya, R.H. Williams: The effect of epinephrine on immunoreactive insulin levels in man. J .Clin.lnvest. 45: 228-236 (\ 966) Robertson, R.P., D. Porte, Jr.: Adrenergic modulation of basal insulin secretion in man. Diabetes 22: 1-8 (\ 973) Scholz, DA., w.H. Remine, J. T. Priestley: Clinics of endocrine and metabolie disease. Hyperinsulinism: Review of 95 cases of functioning pancreatic islet-cell tumors. Proc.Staff Med.Mayo Clin. 35: 545-550 (1960) Shen, Shiao- Wei: Disordered glucose and insulin metabolism in patients with insulinoma. Arch.lntern.Med. 135: 668672 (1975) Turner, R.e., E. Ha"is: Diagnosis of insulinomas by suppression tests. Lancet : 188-190 (\ 974) Turner, R.e., N. W. Oakley, J.D.N. Nabarro: Control of basal insulin secretion, with special reference to the diagnosis of insulinomas. Brit.Med.J. 2: 132-135 (1971)
Requests for reprints should be addressed to: P.c. Kansal, M.D., Diabetes Research and Education Hospital, 1808 7th Avenue South, Birmingharn, Alabama 35294 (V.S.A.)
Downloaded by: Boston University. Copyrighted material.
512
Hyperinsulinemic Hypoglycemia: Effect of Epinephrine Suppression P.C. Kansal, B.R. Boshell, J. Buse*, M.S. Bandisode, R.F. Roddam and Maria G. Buse* Department of Medicine, University of Alabama In Birmingham, Birmingham, Alabama, "Medical University of South Carolina, Charleston, South Carolma, U.S.A.
The inhibitory effect of epinephrine on basal and tolbutamide-stimulated insulin release was studied in 5 patients with hyperinsulinemic hypoglycemia. Epinephrine inhibited both basal and tolbutamide-induced insulin release in patients with ß-ceU adenoma and hyperplasia, but failed to inhibit insulin release in a patient with ß-cell carcinoma. The inhibition of basal insulin with epinephrine was maximum in patients with ß-cell hyperplasia. This differential inhibitory effect of epinephrine on insulin release may prove to be a useful screening test in the preoperative diagnosis of the nature of the lesion producing hyperinsulinemia. Key-Words: Tolbutamide - Epinephrine - Insulin Response
Introduction Patients with insulinomas usually have increased fasting plasma insulin in relation to plasma glucose (Turner, Oakley and Naba"o 1971). The diagnosis of insulinoma is usually confirmed by demonstrating excessive insulin secretion in response to tolbutamide (Khurana, Dhawer, Klayton, Co"edor, Jung, Sieracki, Gonzales and Danowski 1971), glucagon (Marks and Samols 1969), leucine (Floyd, Fazans, Knopf and Conn 1964) or prolonged fasting (Scholz, Remine and Priestly 1960). About 10 percent of the pancreatic insulinomas are malignant. None of the tests mentioned above discriminate between the benign and malignant nature of the lesions.
While this study was in progress, a paper describing the effect of intravenous infusion of epinephrinePropranolol in two patients with pancreatic ß-cell adenoma has been published (Shen 1975). Material and Methods Five patients with hyperinsulinemie hypoglyeemia were studied at the Medieal University of South Carolina (patients land 5) and at the University of Alabama in Birmingham (patients 2, 3 and 4). The elinical data is given in Table I. All the subjects were explained about the nature of the procedures to be carried out and an informed consent was obtained. Table 1. Clinical characteristics of patients with hyperinsulinemic hypoglycemia No.
Age
Sex
1
55 32 52 53 62
F F F F M
2 3 4
5
Fasting Fasting Pathological Diablood glu- immunognosis cose reactive (mgl insulin 100 ml)
50 50 70 80 50
44
27 8 18 27
ß-eell ß-cell ß-cell ß-cell ß-cell
adenoma adenoma hyperplasia hyperplasia carcinoma
Tolbutamide test (IV I Gm - IVTTj was carried out before and during epinephrine infusion on different days in patients Catecholamines modulate insulin secretion by the be- No. 1 and 5, and on the same day in patients No. 3 and 4. IVTT before and during epinephrine infusion were also perta cells of the pancreas (Porte, Graber, Kuzuya and formed on the same day in two normal subjects. Epinephrine Williams 1966). Epinephrine inhibits plasma insulin (diluted in normal saline) was infused at the rate of 6/pgl levels in the basal state (Robertson and Porte 1973) ml/min. The infusion was started 30 minutes before the IV as weil as in response to intravenous glucose, glucagon injection of tolbutamide and was continued for 60 minutes following the tolbutamide injection. Patient No. 2 was suband tolbutamide (Porte et al. 1966). Autonomous Jitjtted to epinephrine suppression test without tolbutamide. endocrine function is more easily diagnosed by sup-
pressive rather than by stimulatory tests such as dexamethasone suppression test in hypercorticism, triiodothyronine test in hyperthyroidism and glucose in acromegaly. Moreover, dexamethasone suppression test is also used to differentiate between adrenal hyperplasia, adenoma and carcinoma as a cause of hypercorticism. Based on this background, the present investigation was undertaken to determine the effect of epinephrine infusion on basal levels of insulin and insulin release in response to tolbutamide in patients with hypoglycemia caused by hyperinsulinism. Received: 20 Oet. 1976
Aeeepted: 23 May 1977
Frequent blood sampies were draWn in heparinized tubes which were kept on ice until centrifuged. Plasma insulin levels were determined by a double-antibody method as described by Morgan and Lazarow (196·3). All sampies from one patient were assayed in the same batch.
Results Surgical exploration followed by histopathological study of the pancreas of 5 patients who underwent epinephrine suppression tests revealed that patients No. 1 and 2 had pancreatic ß-cell adenomas, No. 3 and 4 had ß-cell hyperplasia and No. 5 had ß-cell carcinoma.
Downloaded by: Boston University. Copyrighted material.
Summary
_
Hyperp/oSlo
The maximum insulin secretion in response to IV tolbutamide occurred within the first 10 minutes. The total insulin increment above the basal levels during the first 30 minutes was compared in tests without epinephrine and during epinephrine infusion. Each patient served as his or her own contro!. During epinephrine infusion, the insulin response to tolbutamide increased by 71 and 66% in two normal volunteers; by 97% in patient No. 1; 80% in No. 3 and 32% in patient No. 4. In patient No. I, the blood sampie for insulin level at 30 minutes was not drawn but insulin level in response to tolbutamide during epinephrine infusion at 60 minutes was the same as at 0 minutes. Epinephrine did not suppress the insulin secretory response to tolbutamide in patient No. 5 who had carcinoma of the ß-cells (Fig. 2). In fact, in this patient there was a paradoxical increase in insulin levels in response to tolbutamide du ring epinephrine infusion. In this patient, insulin levels at 30 and 60 minutes, in response to tolbutamide without epinephrine infusion, were 165 and 72 J..LU/ml and during epinephrine infusion 330 and 170 J..LU/ml respectively.
-Ad.nomo
125
~CtJ,c;nomQ
~ ~ 100
-' ~ o-' a::
I-
z
o
75
U
-' ~
I-
~
\5
50
IZ LU U
a::
LU
0..
25
0~
________L -________L-______--J 10
20
30
Fig. 1. Effect of epinephrine (6 pg/minute) on circulating irnmunoreactive insulin (IRI).
The effect of epinephrine infusion on the insulin levels in the basal state and in response to IV tolbutamide is shown in Figures 1 and 2 respectively. The basal insulin levels during epinephrine infusion decreases by 32 and 23ro in patients with f3-cell adenomas (No. 1 and 2 respectively), but 62% each in patients with ß-cell hyperplasia (No. 3 and 4) but paradoxically increased by 20% in the patient with ß-cell carcinoma (Fig. 1). 210
TOlBUTAMIDE BEFORE EPINEPHRINE
CD
200
TOLBUTAMIOE WITH EPINEPHR/NE
~
511
Discussion Fasting hypoglycemia with endogenous hyperinsulinemia is usually due to pancreatic tumors in adults and ninety percent of these tumors are benign. Extrapancreatic tumor is a rare cause of hyperinsulinemic hypoglycemia (Lyall, Marieb, Wise, Cornog, Neville and Felig 1975). Hyperinsulinemia due to hyperplasia of ß-cells of the pancreas is commonly seen in infants. However, in the study reported here,
.---.
®
200
Jj
i
oS
200
®
"ö :>
"-
___________ -11 0
5
10 15 20 (/J-cell o.,.".""o)
0
30
30 10 20 (Co 0' /J-c.II,)
0 0
~
2
20 30 NORMALS(Meon 0' 7wo) !5
10
i
,
"ö
:>
"0
2
!5
10
20
(/J-c.1I hyperplollo)
0
30
M/NUTES
20 2 5 10 (J3-c.1I hyp.rplos,o)
•
30
Fig. 2. Plasma insulin levels in response to infusion of tolbutamide, with or without epinephrine, in two normals and four patients with hyperinsulinemia.
Downloaded by: Boston University. Copyrighted material.
Hyperinsulinemic Hypoglycemia: Effect of Epinephrine Suppression
P.c. KansaJ, B.R. Boshell, J. Buse, M.S. Bandisode, R.F. Roddam, Maria G. Buse
there were 2 cases of ß-cell hyperplasia in adults. In the majority of the cases, the diagnosis of excessive endogenous insulin may be made by the classical tests mentioned in the introduction (Turner et al. 1971, Khurana et a1. 1971, Marks et al. 1969, Floyd et al. 1964, Scholz et a1. 1960, Porte et a1. 1966). The role of insulin suppression by fish insulin (Turner and Ha"is 1974) or by Somatostatin (Lorenzi, Gerich, Karam and Forsham 1975) in the diagnosis of insulinoma remains to be determined. Moreover, fish insulin and Soroatostatin are not available as yet for clinical use. However, none of these tests discriminate between the causes of endogenous hyperinsulinemia. Somatostatin inhibited insulin release in response to glucose both in malignant (Curnow, Carey, Tay/or, Johanson and Murad 1975) and non-malignant (Christen sen, Hanse, Lundbaek, Orskov and Seyer-Hanse 1975) insulinomas.
adenomas and hyperplasia. We have no explanation for this discrepancy except the difference in experimental procedures in the two studies. During epinephrine infusion, the degree of inhibition of basal insulin was greater in patients with ß-cell hyperplasia (62% in each) than in those patients with ß-cel1 adenoma (32 and 23%)_ However, with the dose of epinephrine used in this study, the suppression of insulin following administration of tolbutamide was not different in these two groups of patients. Epinephrine did not inhibit insulin either basal or in response to tolbutamide in a patient with ß-cell carcinoma. In fact, in this patient during epinephrine infusion, there was a paradoxical rise both in the basal insulin and in response to tolbutamide. The preliminary data presented here suggests that epinephrine suppression of insulin both in the basal state and/or in response to tolbutamide may discriminate between benign and malignant lesion of ßcells of the pancreas.
In contrast to the previous study (Shen 1975) where combined infusion of epinephrine and Propranolol did not decrease basal insulin levels in two patients Acknowledgement with insulinomas; in the study reported here, epimephrine inhibited insulin both basal and in response We wish to thank Mr. George Duckworth for technical assistance, Miss Marilyn Parsons for secretarial help and Mr. to intravenous tolbutamide in patients with ß-cell Rod Powers for medical illustration.
References Bennett, L.L., D.L. Curry, K. Curry: Differences in insulin release in response to glucose and tolbutarnide stimulation. Proc.Soc.Exp.BioI.Med. 144: 436-439 (1973) Christensen, S.E., A.P. Hansen, K. Lundbaek, H. Orskov, K. Seyer-Hanse: Somatostatin and insulinoma. The Lancet I: 1426 (1975) Curnow, R.T., R.M. Carey, A. Taylor, A. Johanson, F. Murad: Somatostatin inhibition of insulin and gastrin hypersecretion in pancreatic islet-cell carcinoma. New Eng1.J. Med. 292: 1385-1386 (1975) Floyd, J. e., Jr., S.S. Fazans, R.F. Knopf, J. W. Conn: Plasma insulin in organic hyperinsulinism. Comparative effects of tolbutamide, leucine and glucose. J.Clin.Endocr. 24: 747760 (1964) Gaeke, R.F., E.L. KapIlln, A. Rubenstein, J. Starr, G. Burke: Insulin and proinsulin release during calcium infusion in a patient with islet-cell tumor. Metabolism 9: 1029-1034 (1975) Khurana, R.C., V.P.S. Dhawer, R. Killyton, D.G. Co"edor, Y. Jung, J.e. Sieracki, A.R. Gonzales, T.S. Danowski: Insulin and glucose patterns in control subjects and in proved insulinoma. Am.J.Med.Sci. 262: 115-128 (1971) Lorenzi, M., J.E. Gerich, J.H. Karam, P.H. Forsham: Failure of somatostatin to inhibit tolbutamide-induced insulin secretion in patients with insulinomas: A possible diagnostic tool. J.Clin.Endocr.Metab. 40: 1121-1124 (1975) Lyall, S.S., N.J. Marieb, J.K. Wise, J.L. Cornog, E.e. Neville,
P. Felig: Hyperinsulinemic hypoglycemia associated with a neurofibrosarcoma. Arch.lntern.Med. 135: 865-867 (1975) Marks, v., E. Samols: Diagnostic tests for evaluating hypoglycemia. In: Diabetes (Proceedings of the Sixth Congress of the International Diabetes Federation), Ostman, J., R.D.G. Milner (eds.). Excerpta Medica Foundation, Amsterdam 1969, p. 864-872 Morgan, e.R., A.L. Lazarow: Immunoassay of insulin: Twoantibody system. Plasma levels of normal, subdiabetic and diabetic rats. Diabetes 12: 115-126 (1963) Porte, D., Jr.. A.L. Graber, T. Kuzuya, R.H. Williams: The effect of epinephrine on immunoreactive insulin levels in man. J .Clin.lnvest. 45: 228-236 (\ 966) Robertson, R.P., D. Porte, Jr.: Adrenergic modulation of basal insulin secretion in man. Diabetes 22: 1-8 (\ 973) Scholz, DA., w.H. Remine, J. T. Priestley: Clinics of endocrine and metabolie disease. Hyperinsulinism: Review of 95 cases of functioning pancreatic islet-cell tumors. Proc.Staff Med.Mayo Clin. 35: 545-550 (1960) Shen, Shiao- Wei: Disordered glucose and insulin metabolism in patients with insulinoma. Arch.lntern.Med. 135: 668672 (1975) Turner, R.e., E. Ha"is: Diagnosis of insulinomas by suppression tests. Lancet : 188-190 (\ 974) Turner, R.e., N. W. Oakley, J.D.N. Nabarro: Control of basal insulin secretion, with special reference to the diagnosis of insulinomas. Brit.Med.J. 2: 132-135 (1971)
Requests for reprints should be addressed to: P.c. Kansal, M.D., Diabetes Research and Education Hospital, 1808 7th Avenue South, Birmingharn, Alabama 35294 (V.S.A.)
Downloaded by: Boston University. Copyrighted material.
512
