SCIENTIFIC PAPERS
Mesenchymal Tumor Hypoglycemia The Effect of a Tumor Tissue Extract on the Insulin and Glucagon Secretion from the Isolated Perfused Porcine Pancreas S. Lindkaer Jensen, MD, Copenhagen, Denmark C. Kiihl, MD, Copenhagen, Denmark K. B. Lauritsen, MD, Copenhagen, Denmark A. J. Moody, MD, Copenhagen, Denmark
Severe fasting hypoglycemia has occasionally been reported in patients harboring nonpancreatic tumors of mesenchymal origin [I]. Recently, Silbert et al [2] reported a case of mesenchymal tumor hypoglycemia, which seemed to be due to a deficient splanchnic glucose output, a deficient pancreatic glucagon secretion and/or hepatic glycogenolysis. On the basis of these observations, we decided to study the effect of a mesenchymal tumor from a patient with severe fasting hypoglycemia on the secretion of insulin and glucagon from the isolated perfused porcine pancreas. Case Report The patient, a sixty-six year old woman, had a three month history of several attacks in the morning of sweating, pallor, trembling, dizziness, weakness, palpitation, apprehensiveness, and sometimes syncope. The symptoms were relieved by food intake, and the attacks tended to occur 4 to 5 hours after meals. She was admitted to another hospital in June 1976. Fasting blood glucose concentrations were low (1.0 to 1.2 mmol/l). Pancreatic scanning aroused suspicion of a process of the body of the pancreas and she was referred to the Department of Surgical Gastroenterology C, Rigshospitalet, Copenhagen for surgical treatment. FromtheDepartment of Surgical Gastroenterology C, Rigshospitalet, University of tipenhagen; the Department of Internal Medicine T. Bispebjarg Hospital. Cwenfxigan: and the Novo Research InstiMe. Copenhagen, Denmark. Reprint requests should be addressed to S. Lindkaer Jensen, MO, Department of Surgical Gastroenterology C. Rigshospitalet, Blegdamsvej 9. DK-2100 Copanhagen 0. Denmark.
192
Preoperatively, the fasting plasma glucose levels were low, as well as the corresponding insulin levels (0 to 3 rU/ml). Selective celiac axis and superior mesenteric arteriography demonstrated hepatomegaly and tumor vessels in the right upper part of the liver. At operation a tumor measuring 10 X 15 cm in the right liver lobe with several satellite tumors scattered all over the liver was found. The pancreas, the other abdominal organs, and the retroperitoneal space were palpated carefully without finding any abnormalities. Biopsies from the pancreas were all normal at microscopy, whereas microscopy of the biopsies from the hepatic tumors demonstrated a benign tumor built up of broad intertwining bands of spindled fibroblasts. Scattered areas of adenomatous structures were found within the tumors. Five weeks after laparotomy the patient was discharged.
Methods
A lOO-gm oral glucose tolerance test (OGTT) and a 25-gm intravenous glucose tolerance test (IVGTT) were carried out three and four weeks after the laparotomy, respectively. Blood samples were drawn from a permanent canulla inserted into an antecubital vein at the times indicated in Figures 1 and 2. After separation plasma was stored at -25OC until assayed for content of glucose, insulin [3], pancreatic glucagon [4] and gastric inhibitory polypeptide (GIB) [51. Extracts from the tumor were prepared with acidified ethanol [6], evaporated to dryness and redissolved in the perfusate buffer (Krebs-Ringer solution containing 5 per cent dextran and 0.1 per cent
The American Journal of Surgery
Mesenchymal Tumor Hypoglycemia
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Figure 1. Plasma levels of glucose, pancreatic glucagon, InsuMn, and GIP of patient w/th a mesenchymal tumor associated with fasting hypoglycemia after a 700 gm oral glucose load. MINUTES
human serum albumin) used in the isolated perfused porcine pancreas [7]. The solution contained 70 pg protein per ml and was added to the perfusate by means of a constant infusion syringe pump adjusted to deliver 0.41 ml per minute during three 10 minute periods separated by resting periods of 20 minutes. The extract was added to the perfusate during perfusion with either glucose (5.0 or 7.5 mmol/l) or arginine (1.0 mmol/l). The entire experimental period was 120 minutes. Effluent samples were collected every minute for analysis of insulin and glucagon. The viability of the pancreas was confirmed by a high oxygen consumption (0.008 ml 02 per minute per gm pancreatic tissue v/w), a constant perfusion flow (30 ml per minute), and a constant perfusion pressure (35 mm Hg). During the last 10 minutes, glucose was added to the perfusate to a final concentration of 20 mmol/l to ensure a sufficient endocrine pancreatic response [ 71. Results Postoperatively the plasma insulin levels were still low (0 to 3 pU/ml) as were the fasting plasma glucose levels (1.0 to 1.2 mmol/l). The fasting plasma glucagon levels ranged between 75 and 80 pg/ml (low-
vohme135.
Fabruary 1979
Figure 2. Plasma levels of glucose, pancreatic glucagon, insulin, and G/P of a patient with a mesenchymal tumor associated w/th fast/ng hypoglycemia after a 25 gm intravenous glucose load.
normal) and the GIP leveis were from 0.4 to 0.5 ng/ml (normal). The OGTT disclosed an impaired glucose tolerance test. (Figure 1.) Plasma insulin increased slowly from 2 FLU/ml to a peak value of 40 pU/ml after 120 minutes, pancreatic glucagon levels remained unchanged, while GIP increased from 0.4 to 3.85 ng/ml at 160 minutes (maximum in normal subjects, 0.8 ng at 40 minutes). The IVGTT indicated that the patient had a normal glucose disappearance rate of 1.71. (Figure 2.) Plasma insulin increased from 2 pU/ml basically to a peak value of 23 pU/ml at 5 minutes. No changes in plasma glucagon levels were observed, and as expected the plasma GIP levels were also unchanged. The effects of the tumor extract on the secretion of insulin and glucagon from the isolated perfused porcine pancreas were (Figure 3): (a) a marked suppression of the arginine-induced glucagon release; in contrast the insulin response to arginine was unaf-
193
Lindkaer Jensen et al
I
20
I
Extract
LO
60
80
100
120 min.
Flgure 3. Effects of a mesenchymal tumor extract on the secnrtton of insulin and glucagon from the Isolated pertbed porcine pancreas during perfusion with glucose concentratbns of 5.0 and 7.5 mmoU/ and an arginine concentration of 1.0 mmoUI.
fected by the extract; (b) a paradoxical glucagon response (increase in glucagon concentrations instead of suppression of glucagon as seen normally [7]) to 20 mmol/l of glucose. No effect of the extract on the insulin and glucagon secretion was observed during perfusion with glucose concentrations of 5.0 and 7.5 mmol/l. The extract did not contain measurable amounts of insulin or glucagon immunoreactivity. Comments
The present study showed that an extract from a mesenchymal tumor from a patient suffering from severe fasting hypoglycemia significantly influenced the glucagon secretion from the isolated perfused porcine pancreas. The arginine-induced glucagon secretion was abolished, and a paradoxical glucagon response to hyperglycemia was observed after the infusions of the extract. These observations are of potential clinical relevance, since they support the theory recently advanced by Silbert et al [2] that mesenchymal tumor hypoglycemia not associated with hyperinsulinemia in some cases is due to a still unknown factor secreted from the tumor. This factor is supposed to inhibit pancreatic glucagon secretion and thereby also splanchnic glucose production.
194
Silbert et al [2] reported a case of a patient with a mesothelioma. The serum insulin was low, the nonsuppressible insulin-like and somatomedin-like activities of serum were not elevated, and the tumor did not contain somatostatin. The principal cause of hypoglycemia was suggested to be a marked decrease in splanchnic glucose output associated with a decrease in glycogenolysis at least partly due to a deficient glucagon secretion. The most important metabolic and endocrinologic data noted in our patient were severe fasting hypoglycemia and hypoinsulinemia, thus excluding excessive secretion of insulin as a cause of the hypoglycemia. The basal glucagon concentrations were normal. It is evident from a recent investigation [8] that the basal glucagon level plays an important role in the maintenance of basal splanchnic glucose production in man. In low insulin hypoglycemia produced experimentally glucagon levels are greatly enhanced [9]. Therefore, our finding of a low-normal basal level of glucagon together with a plasma glucose concentration of 1.0 mmol/l supports the theory that the fasting hypoglycemia might be due to a deficient glycogenolysis at least partly due to a relative deficiency in pancreatic secretion. The lack of suppression of glucagon secretion by hyperglycemia is a characteristic of the diabetic state [IO] but has also been noted in patients with multiple adenomatosis [II]. The lack of suppression of glucagon during orally or intravenously administered glucose in our patient could be explained by the low insulin levels [IO], but the possibility exists that the lack of glucagon suppression was due to the tumor, since a paradoxical glucagon response to hyperglycemia was observed in the isolated perfused porcine pancreas after the infusions of the extract. The GIP response to glucose ingestion was high, suggesting that the low insulin levels noted were not caused by reduction in the function of the enteroinsular axis. The nature of the substance secreted from the tumor is not known. It is probably not somatostatin since both insulin and glucagon are suppressed by this hormone in the isolated perfused porcine pancreas [12]. The hypoglycemia found in patients with mesenchymal tumors has also been attributed to excessive uptake of glucose by the tumor [I]. Excessive glucose uptake by the tumor in the present patient cannot be excluded, since the glucose disappearance constant was normal. Nevertheless, the results obtained in this study support the theory that these tumors are capable of secreting a factor which directly inhibits pancreatic glucagon secretion.
The American Journal of Surgery
Mesenchymal
Summary Severe fasting hypoglycemia and hypoinsulinemia occurred in a sixty-six year old woman with an intrahepatic mesenchymal tumor. An extract from the tumor was potent in inhibiting the arginine-induced glucagon secretion from the isolated perfused porcine pancreas. This observation supports the theory recently advanced that mesenchymal tumor hypoglycemia in some cases is due to a still unknown factor secreted from the tumor, which directly inhibits pancreatic glucagon secretion. References
4. Hoist JJ, Christiansen J, Kuhi C: The enterogiucagon response to intrajejunal infusion of glucose, triglycerides, and sodium chloride, and its relation to jejunai inhibltion of gastric acid in man. ScandJ Gastroenterol 11: 297, 1976. 5. Moody AJ, Lauritsen KB, Sundby F: Radioimmunoassay for GIP and gut GLI-1. Diabetobgia (In press.) 6. Kuhl C. Lindkaer Jensen S, Vagn Nielsen 0: Porcine gastric insulin. fndccrinology 99: 1667, 1976. 7. Lindkaer Jensen S, Kuhi C, Vagn Nielsen 0, Hoist JJ: Isolation and perfusion of the porcine pancreas. &anti J Gasfmenteml Suppl37: 57, 1976. 6. Liljenquist JE, Mueller GL, Cherrington AD, Keller U, Chiasson JL, Perry JM, Lacy WW, Rabinowitz D: Evidence for an important role of glucagon in the regulation of hepatic glucose production in man. J C/in Invest 59: 369, 1977. 9. Muller WA, Faloona GR, Unger RH: The effect of experimental insulin deficiency on glucagon secretion. J C/in /west 50:
1992, 1970.
1. Laurent J, Debry A, Floquet J: Hypoglycaemic-inducing mesenchymal tumours: Doege-Potter syndrome. Hypoglycaemic Turnours. Amsterdam, Excerpta Medica, 197 1. 2. Siiberl CK, Rossini AA, Ghazvinian S, Widrich WC, Marks W, Sawin CT: Tumour hypoglycemia: deficient splanchnic glucose output and deficient giucagon secretion. Diebefes 25: 202, 1976. 3. Kuhl C: Glucose metabolism during and after pregnancy in ncrmai and gestational diabetic women. Acta Endocrno/ 79: 709, 1975.
Vokmw 135, Fokuay
Tumor Hypoglycemia
1978
10. Miiller WA, Faloona GR, Aquilar-Parada E, Unger RH: Abnormal alpha-cell function in diabetes. N Engl J Med 263: 109, 1970. 11. Tiengo A, Fedele D, Marchiori E, Nosadini R, Muggeo M: Suppression and stimulation mechanisms controlling glucagon secretion in a case of islet-cell tumor producing glucagon, insulin, and gastrin. Diabetes 25: 406, 1976. 12. Larsson L-l. Hirch MA. Holst JJ. lnoemansson S. Kuhi C. Lindkaer Jensen S, Lundquist G, Rehfeid JF, Schwartz TW: Pancreatic somatistatinoma. Clinical features and physiological implications Lancet 1: 666, 1977.
195
Mesenchymal Tumor Hypoglycemia The Effect of a Tumor Tissue Extract on the Insulin and Glucagon Secretion from the Isolated Perfused Porcine Pancreas S. Lindkaer Jensen, MD, Copenhagen, Denmark C. Kiihl, MD, Copenhagen, Denmark K. B. Lauritsen, MD, Copenhagen, Denmark A. J. Moody, MD, Copenhagen, Denmark
Severe fasting hypoglycemia has occasionally been reported in patients harboring nonpancreatic tumors of mesenchymal origin [I]. Recently, Silbert et al [2] reported a case of mesenchymal tumor hypoglycemia, which seemed to be due to a deficient splanchnic glucose output, a deficient pancreatic glucagon secretion and/or hepatic glycogenolysis. On the basis of these observations, we decided to study the effect of a mesenchymal tumor from a patient with severe fasting hypoglycemia on the secretion of insulin and glucagon from the isolated perfused porcine pancreas. Case Report The patient, a sixty-six year old woman, had a three month history of several attacks in the morning of sweating, pallor, trembling, dizziness, weakness, palpitation, apprehensiveness, and sometimes syncope. The symptoms were relieved by food intake, and the attacks tended to occur 4 to 5 hours after meals. She was admitted to another hospital in June 1976. Fasting blood glucose concentrations were low (1.0 to 1.2 mmol/l). Pancreatic scanning aroused suspicion of a process of the body of the pancreas and she was referred to the Department of Surgical Gastroenterology C, Rigshospitalet, Copenhagen for surgical treatment. FromtheDepartment of Surgical Gastroenterology C, Rigshospitalet, University of tipenhagen; the Department of Internal Medicine T. Bispebjarg Hospital. Cwenfxigan: and the Novo Research InstiMe. Copenhagen, Denmark. Reprint requests should be addressed to S. Lindkaer Jensen, MO, Department of Surgical Gastroenterology C. Rigshospitalet, Blegdamsvej 9. DK-2100 Copanhagen 0. Denmark.
192
Preoperatively, the fasting plasma glucose levels were low, as well as the corresponding insulin levels (0 to 3 rU/ml). Selective celiac axis and superior mesenteric arteriography demonstrated hepatomegaly and tumor vessels in the right upper part of the liver. At operation a tumor measuring 10 X 15 cm in the right liver lobe with several satellite tumors scattered all over the liver was found. The pancreas, the other abdominal organs, and the retroperitoneal space were palpated carefully without finding any abnormalities. Biopsies from the pancreas were all normal at microscopy, whereas microscopy of the biopsies from the hepatic tumors demonstrated a benign tumor built up of broad intertwining bands of spindled fibroblasts. Scattered areas of adenomatous structures were found within the tumors. Five weeks after laparotomy the patient was discharged.
Methods
A lOO-gm oral glucose tolerance test (OGTT) and a 25-gm intravenous glucose tolerance test (IVGTT) were carried out three and four weeks after the laparotomy, respectively. Blood samples were drawn from a permanent canulla inserted into an antecubital vein at the times indicated in Figures 1 and 2. After separation plasma was stored at -25OC until assayed for content of glucose, insulin [3], pancreatic glucagon [4] and gastric inhibitory polypeptide (GIB) [51. Extracts from the tumor were prepared with acidified ethanol [6], evaporated to dryness and redissolved in the perfusate buffer (Krebs-Ringer solution containing 5 per cent dextran and 0.1 per cent
The American Journal of Surgery
Mesenchymal Tumor Hypoglycemia
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.
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./'--'
-10
I
-5
.h 0
60 MINUTES
120
$ .
180
Figure 1. Plasma levels of glucose, pancreatic glucagon, InsuMn, and GIP of patient w/th a mesenchymal tumor associated with fasting hypoglycemia after a 700 gm oral glucose load. MINUTES
human serum albumin) used in the isolated perfused porcine pancreas [7]. The solution contained 70 pg protein per ml and was added to the perfusate by means of a constant infusion syringe pump adjusted to deliver 0.41 ml per minute during three 10 minute periods separated by resting periods of 20 minutes. The extract was added to the perfusate during perfusion with either glucose (5.0 or 7.5 mmol/l) or arginine (1.0 mmol/l). The entire experimental period was 120 minutes. Effluent samples were collected every minute for analysis of insulin and glucagon. The viability of the pancreas was confirmed by a high oxygen consumption (0.008 ml 02 per minute per gm pancreatic tissue v/w), a constant perfusion flow (30 ml per minute), and a constant perfusion pressure (35 mm Hg). During the last 10 minutes, glucose was added to the perfusate to a final concentration of 20 mmol/l to ensure a sufficient endocrine pancreatic response [ 71. Results Postoperatively the plasma insulin levels were still low (0 to 3 pU/ml) as were the fasting plasma glucose levels (1.0 to 1.2 mmol/l). The fasting plasma glucagon levels ranged between 75 and 80 pg/ml (low-
vohme135.
Fabruary 1979
Figure 2. Plasma levels of glucose, pancreatic glucagon, insulin, and G/P of a patient with a mesenchymal tumor associated w/th fast/ng hypoglycemia after a 25 gm intravenous glucose load.
normal) and the GIP leveis were from 0.4 to 0.5 ng/ml (normal). The OGTT disclosed an impaired glucose tolerance test. (Figure 1.) Plasma insulin increased slowly from 2 FLU/ml to a peak value of 40 pU/ml after 120 minutes, pancreatic glucagon levels remained unchanged, while GIP increased from 0.4 to 3.85 ng/ml at 160 minutes (maximum in normal subjects, 0.8 ng at 40 minutes). The IVGTT indicated that the patient had a normal glucose disappearance rate of 1.71. (Figure 2.) Plasma insulin increased from 2 pU/ml basically to a peak value of 23 pU/ml at 5 minutes. No changes in plasma glucagon levels were observed, and as expected the plasma GIP levels were also unchanged. The effects of the tumor extract on the secretion of insulin and glucagon from the isolated perfused porcine pancreas were (Figure 3): (a) a marked suppression of the arginine-induced glucagon release; in contrast the insulin response to arginine was unaf-
193
Lindkaer Jensen et al
I
20
I
Extract
LO
60
80
100
120 min.
Flgure 3. Effects of a mesenchymal tumor extract on the secnrtton of insulin and glucagon from the Isolated pertbed porcine pancreas during perfusion with glucose concentratbns of 5.0 and 7.5 mmoU/ and an arginine concentration of 1.0 mmoUI.
fected by the extract; (b) a paradoxical glucagon response (increase in glucagon concentrations instead of suppression of glucagon as seen normally [7]) to 20 mmol/l of glucose. No effect of the extract on the insulin and glucagon secretion was observed during perfusion with glucose concentrations of 5.0 and 7.5 mmol/l. The extract did not contain measurable amounts of insulin or glucagon immunoreactivity. Comments
The present study showed that an extract from a mesenchymal tumor from a patient suffering from severe fasting hypoglycemia significantly influenced the glucagon secretion from the isolated perfused porcine pancreas. The arginine-induced glucagon secretion was abolished, and a paradoxical glucagon response to hyperglycemia was observed after the infusions of the extract. These observations are of potential clinical relevance, since they support the theory recently advanced by Silbert et al [2] that mesenchymal tumor hypoglycemia not associated with hyperinsulinemia in some cases is due to a still unknown factor secreted from the tumor. This factor is supposed to inhibit pancreatic glucagon secretion and thereby also splanchnic glucose production.
194
Silbert et al [2] reported a case of a patient with a mesothelioma. The serum insulin was low, the nonsuppressible insulin-like and somatomedin-like activities of serum were not elevated, and the tumor did not contain somatostatin. The principal cause of hypoglycemia was suggested to be a marked decrease in splanchnic glucose output associated with a decrease in glycogenolysis at least partly due to a deficient glucagon secretion. The most important metabolic and endocrinologic data noted in our patient were severe fasting hypoglycemia and hypoinsulinemia, thus excluding excessive secretion of insulin as a cause of the hypoglycemia. The basal glucagon concentrations were normal. It is evident from a recent investigation [8] that the basal glucagon level plays an important role in the maintenance of basal splanchnic glucose production in man. In low insulin hypoglycemia produced experimentally glucagon levels are greatly enhanced [9]. Therefore, our finding of a low-normal basal level of glucagon together with a plasma glucose concentration of 1.0 mmol/l supports the theory that the fasting hypoglycemia might be due to a deficient glycogenolysis at least partly due to a relative deficiency in pancreatic secretion. The lack of suppression of glucagon secretion by hyperglycemia is a characteristic of the diabetic state [IO] but has also been noted in patients with multiple adenomatosis [II]. The lack of suppression of glucagon during orally or intravenously administered glucose in our patient could be explained by the low insulin levels [IO], but the possibility exists that the lack of glucagon suppression was due to the tumor, since a paradoxical glucagon response to hyperglycemia was observed in the isolated perfused porcine pancreas after the infusions of the extract. The GIP response to glucose ingestion was high, suggesting that the low insulin levels noted were not caused by reduction in the function of the enteroinsular axis. The nature of the substance secreted from the tumor is not known. It is probably not somatostatin since both insulin and glucagon are suppressed by this hormone in the isolated perfused porcine pancreas [12]. The hypoglycemia found in patients with mesenchymal tumors has also been attributed to excessive uptake of glucose by the tumor [I]. Excessive glucose uptake by the tumor in the present patient cannot be excluded, since the glucose disappearance constant was normal. Nevertheless, the results obtained in this study support the theory that these tumors are capable of secreting a factor which directly inhibits pancreatic glucagon secretion.
The American Journal of Surgery
Mesenchymal
Summary Severe fasting hypoglycemia and hypoinsulinemia occurred in a sixty-six year old woman with an intrahepatic mesenchymal tumor. An extract from the tumor was potent in inhibiting the arginine-induced glucagon secretion from the isolated perfused porcine pancreas. This observation supports the theory recently advanced that mesenchymal tumor hypoglycemia in some cases is due to a still unknown factor secreted from the tumor, which directly inhibits pancreatic glucagon secretion. References
4. Hoist JJ, Christiansen J, Kuhi C: The enterogiucagon response to intrajejunal infusion of glucose, triglycerides, and sodium chloride, and its relation to jejunai inhibltion of gastric acid in man. ScandJ Gastroenterol 11: 297, 1976. 5. Moody AJ, Lauritsen KB, Sundby F: Radioimmunoassay for GIP and gut GLI-1. Diabetobgia (In press.) 6. Kuhl C. Lindkaer Jensen S, Vagn Nielsen 0: Porcine gastric insulin. fndccrinology 99: 1667, 1976. 7. Lindkaer Jensen S, Kuhi C, Vagn Nielsen 0, Hoist JJ: Isolation and perfusion of the porcine pancreas. &anti J Gasfmenteml Suppl37: 57, 1976. 6. Liljenquist JE, Mueller GL, Cherrington AD, Keller U, Chiasson JL, Perry JM, Lacy WW, Rabinowitz D: Evidence for an important role of glucagon in the regulation of hepatic glucose production in man. J C/in Invest 59: 369, 1977. 9. Muller WA, Faloona GR, Unger RH: The effect of experimental insulin deficiency on glucagon secretion. J C/in /west 50:
1992, 1970.
1. Laurent J, Debry A, Floquet J: Hypoglycaemic-inducing mesenchymal tumours: Doege-Potter syndrome. Hypoglycaemic Turnours. Amsterdam, Excerpta Medica, 197 1. 2. Siiberl CK, Rossini AA, Ghazvinian S, Widrich WC, Marks W, Sawin CT: Tumour hypoglycemia: deficient splanchnic glucose output and deficient giucagon secretion. Diebefes 25: 202, 1976. 3. Kuhl C: Glucose metabolism during and after pregnancy in ncrmai and gestational diabetic women. Acta Endocrno/ 79: 709, 1975.
Vokmw 135, Fokuay
Tumor Hypoglycemia
1978
10. Miiller WA, Faloona GR, Aquilar-Parada E, Unger RH: Abnormal alpha-cell function in diabetes. N Engl J Med 263: 109, 1970. 11. Tiengo A, Fedele D, Marchiori E, Nosadini R, Muggeo M: Suppression and stimulation mechanisms controlling glucagon secretion in a case of islet-cell tumor producing glucagon, insulin, and gastrin. Diabetes 25: 406, 1976. 12. Larsson L-l. Hirch MA. Holst JJ. lnoemansson S. Kuhi C. Lindkaer Jensen S, Lundquist G, Rehfeid JF, Schwartz TW: Pancreatic somatistatinoma. Clinical features and physiological implications Lancet 1: 666, 1977.
195
