Case Report: Increased Insulin Sensitivity in Tumor Hypoglycemia in a Diabetic Patient: Glucose Metabolism in Tumor Hypoglycemia NIR BARZILAI,* PINCHAS COHEN,* NEIL McINTYRE,t EDDY KARNIELI*
RACHEL BAR-ILLAN,*
ABSTRACT: A 58-year-old man, with primary hemochromatosis, cirrhosis, and diabetes mellitus treated with insulin developed hepatoma. As the tumor grew, he lost his dependence on insulin therapy and experienced episodes of hypoglycemia. His response to infuse insulin was studied using the euglycemic clamp technique. Insulin was infused at rates of 1 and 10 IL/kg/ min. The insulin dose response curve was shifted to the left and at plasma insulin levels of 72 ILU/ mI, steady-state glucose consumption was 9.6 mg/kg/min, 50% more than in normals, and nearly three times greater than that in other cirrhotics. The insulin clearance rate was 4417 m1/ m2/min, almost five and six times more than in normals and cirrhotics, respectively. Basal hepatic glucose production was 3.6 mg/kg/min, two and three times higher than in normal and in cirrhotic subjects, respectively. The decrease in amino acid during hyperinsulinemia was more than 30% higher than in normal and other cirrhotics. IFG-I and II levels were not elevated in this patient. Increased insulin sensitivity and increased insulin clearance and serum amino acid decrease in response to insulin in vivo, suggest that insulin responsive tissues are at last partially responsible for tumor hypoglycemia. The increased glucose disposal rate probably accounted for the disappearance of the diabetes. KEY INDEXING TERMS: Glucose; insulin; insulin sensitivity; tumor; hypoglycemia; hepaFrom "'the Metabolic Unit, Rambam Medical Center and Facility of Medicine, Technion-Israel Institute of Technology, Haifa, Israel and t the Department of Medicine, Royal Free Hospital and School of Medicine, London, United Kingdom. The work was supported, in part, by a research grant from the U.S. National Institutes of Health, NIDDK, Grant No. AM 31489. The authors thank Dr. Ron G. Rosenfeld of the Department of Pediatrics, Stanford University for the IGF determinations. Correspondence: Nir Barzilai, MD, Division of Endocrinology, Department of Medicine, New York Hospital, CorneU University Medical School, 500 York Avenue, New York, NY 10021. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
toma; cirrhosis; IGF-II. [Am J Med Sci 1991; 302(4):229-234.]
M
uch controversy exists about the mechanism of hypoglycemia in extrapancreatic neoplasms. Hundreds of cases have been described and most of these tumors were mesenchymal in origin.I-4 Hepatoma is an established cause of hypoglycemia, and at least 37 cases were studied for various purposes in the last 2 years.5-7 In the past, elevations peptides with insulinlike activity (NSILA-S) were noted in less than half of the cases of neoplastic hypoglycemia, yet a role of insulin growth factor II (IGF-II), secreted by tumors, such as leiomyosarcoma and hepatoma, has lately been suggested.5,8 Other mechanisms have also been suggested, for example, inhibition of glycogenolysis and gluconeogenesis; destruction of the liver by tumor metastases; suppression of counter regulatory hormones; and glucose consumption by the tumor itself.4 Lately Stuart et al IO have studied a case of tumor hypoglycemia due to colon carcinoma, and observed a marked increase in insulin receptor number in liver, muscle and ' monocytes. 9 A study by Pun et al7 had demonstrated an improvement in glucose tolerance tests in patients with hepatoma compared to cirrhotics. This paper describes metabolic studies on a diabetic patient with hemochromatosis and hepatoma who completely lost his dependence on 72 units/day of insulin concomitantly with tumor growth and development of hypoglycemia. We studied whether in vivo there is an increase in insulin sensitivity, clearance, and amino acid disposal which would support the hypothesis that tumor hypoglycemia is at last partially related to changes in the insulin response of peripheral tissues. Case Report A 58·year-old man with a IS-year history of primary hemochromatosis and cirrhosis, established by biopsy and appropriate biochemical tests, was studied. He was found to be diabetic 10 years
229
Increased Insulin Sensitivity
prior to this study and was treated with daily glibenclamide. Later that same year, he required insulin therapy, and 3 years later,. 72 units of insulin per day were necessary for good control (fastmg glucose < 140 mg/dl). Two years prior to this. study, he seem~d.w~ll with no change in liver function tests, and WIth a serum ferntm m the low-normal range. Subsequently, his urine glucose tests became consistently negative and he developed episodes of early morning wakening, headaches, and sweating, which were found to be due to hypoglycemia (glucose < 40 mg/dl, requiring intravenous glucose). His insulin dosage was reduced to 28 units/day. A year later, he was readmitted after 4-5 months of anorexia, weight loss, lethargy, and malaise. Computed tomography examination revealed several areas of low attenuation in the liver. A liver biopsy was performed and revealed active cirrhosis with grade 3 siderosis and fragments ofhepatoma. Later, he was found to have a serum glucose of 20 mg/dl and his daily insulin was reduced to 10 units and insulin therapy was stopped. Three weeks after insulin was stopped, he had anot.he~ episode of hypoglycemia with glucose levels of 45 mg/dl. At this time, insulin levels were 5 mg/ml and cortisol was 24 mg/dl. With an increase in carbohydrate intake, he was successful in maintaining glucose levels of above 60 mg/dl. His fasting blood glucose level ~he morning of the study while measuring his hepatic glucose production was averaged at 64 mg/dl, his insulin level was 7 IlU/ml and Cpeptide was 0.46 ng/ml. A month later he died, and his tumor was estimated at autopsy to be 1 kg in weight (Table 1).
Materials and Methods Subjects. Clinical and biochemical characteristics of
the patient with hepatoma, cirrhotics, and normal controls are presented in Table 2. All subjects gave informed consent prior to the studies, which were approved by the Rambam Medical Center Human Rights Board and the Royal Free Hospital ethical committee. Normal subjects had no history of liver or metabolic disease and cirrhosis was proven by biopsy. Euglycemic Insulin Clamp Technique. Studies were performed after an overnight fast, as previously described. l1 The infusate was given via an antecubital vein. A dorsal hand vein was canulated and kept in a warming box (55 0 C) to arterialize the venous samples. After the measurement of hepatic glucose production, a bolus of insulin was given, followed by a continuous infusion for 2 hours at each insulin infusion rate. Rates of insulin infusion were 1 and 10 mU/kg/min in all subjects. Serum glucose was maintained between 85
Table 1. Dates of Diagnoses and Treatment for Diabetes in the Hepatoma Patient Date
Diagnosis
1/71 Primary hemochromatosis Cirrhosis 2/76 Diabetes 4/76 5/79 10/84 Hepatoma Hypoglycemia 1/85 2/85 Hypoglycemia 3/85 Death
230
Treatment for Diabetes (not diabetic) Glibenclamide,5 mg Insulin, 10 U regular +8U NPH Insulin, 44 U regular +28U NPH Insulin, 16 U regular +12U NPH Insulin, 10 U NPH No treatment for diabetes Metabolic studies
Table 2. Clinical and Biomedical Characteristics of the Hepatoma Patient, Hepatocellular Cirrhotics, and Normal Controls
Hepatoma Patient Age (yrs) % of Ideal body weight Total bilirubin (IlmollL) Albumin (gIL) Total protein (giL) Alkaline phosphatase (lUlL) SGOT(IU/L) Pasting plasma glucose (mg/dl) Pasting plasma insulin (llU/mi) C-peptide (ng/ml) Cortisol (llg/dL) Epinephrine (Ilg/L) Growth hormone (ng/ml)
58 73 25 30 60 352 1026 64
7 0.46 18 0.08
RACHEL BAR-ILLAN,*
ABSTRACT: A 58-year-old man, with primary hemochromatosis, cirrhosis, and diabetes mellitus treated with insulin developed hepatoma. As the tumor grew, he lost his dependence on insulin therapy and experienced episodes of hypoglycemia. His response to infuse insulin was studied using the euglycemic clamp technique. Insulin was infused at rates of 1 and 10 IL/kg/ min. The insulin dose response curve was shifted to the left and at plasma insulin levels of 72 ILU/ mI, steady-state glucose consumption was 9.6 mg/kg/min, 50% more than in normals, and nearly three times greater than that in other cirrhotics. The insulin clearance rate was 4417 m1/ m2/min, almost five and six times more than in normals and cirrhotics, respectively. Basal hepatic glucose production was 3.6 mg/kg/min, two and three times higher than in normal and in cirrhotic subjects, respectively. The decrease in amino acid during hyperinsulinemia was more than 30% higher than in normal and other cirrhotics. IFG-I and II levels were not elevated in this patient. Increased insulin sensitivity and increased insulin clearance and serum amino acid decrease in response to insulin in vivo, suggest that insulin responsive tissues are at last partially responsible for tumor hypoglycemia. The increased glucose disposal rate probably accounted for the disappearance of the diabetes. KEY INDEXING TERMS: Glucose; insulin; insulin sensitivity; tumor; hypoglycemia; hepaFrom "'the Metabolic Unit, Rambam Medical Center and Facility of Medicine, Technion-Israel Institute of Technology, Haifa, Israel and t the Department of Medicine, Royal Free Hospital and School of Medicine, London, United Kingdom. The work was supported, in part, by a research grant from the U.S. National Institutes of Health, NIDDK, Grant No. AM 31489. The authors thank Dr. Ron G. Rosenfeld of the Department of Pediatrics, Stanford University for the IGF determinations. Correspondence: Nir Barzilai, MD, Division of Endocrinology, Department of Medicine, New York Hospital, CorneU University Medical School, 500 York Avenue, New York, NY 10021. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
toma; cirrhosis; IGF-II. [Am J Med Sci 1991; 302(4):229-234.]
M
uch controversy exists about the mechanism of hypoglycemia in extrapancreatic neoplasms. Hundreds of cases have been described and most of these tumors were mesenchymal in origin.I-4 Hepatoma is an established cause of hypoglycemia, and at least 37 cases were studied for various purposes in the last 2 years.5-7 In the past, elevations peptides with insulinlike activity (NSILA-S) were noted in less than half of the cases of neoplastic hypoglycemia, yet a role of insulin growth factor II (IGF-II), secreted by tumors, such as leiomyosarcoma and hepatoma, has lately been suggested.5,8 Other mechanisms have also been suggested, for example, inhibition of glycogenolysis and gluconeogenesis; destruction of the liver by tumor metastases; suppression of counter regulatory hormones; and glucose consumption by the tumor itself.4 Lately Stuart et al IO have studied a case of tumor hypoglycemia due to colon carcinoma, and observed a marked increase in insulin receptor number in liver, muscle and ' monocytes. 9 A study by Pun et al7 had demonstrated an improvement in glucose tolerance tests in patients with hepatoma compared to cirrhotics. This paper describes metabolic studies on a diabetic patient with hemochromatosis and hepatoma who completely lost his dependence on 72 units/day of insulin concomitantly with tumor growth and development of hypoglycemia. We studied whether in vivo there is an increase in insulin sensitivity, clearance, and amino acid disposal which would support the hypothesis that tumor hypoglycemia is at last partially related to changes in the insulin response of peripheral tissues. Case Report A 58·year-old man with a IS-year history of primary hemochromatosis and cirrhosis, established by biopsy and appropriate biochemical tests, was studied. He was found to be diabetic 10 years
229
Increased Insulin Sensitivity
prior to this study and was treated with daily glibenclamide. Later that same year, he required insulin therapy, and 3 years later,. 72 units of insulin per day were necessary for good control (fastmg glucose < 140 mg/dl). Two years prior to this. study, he seem~d.w~ll with no change in liver function tests, and WIth a serum ferntm m the low-normal range. Subsequently, his urine glucose tests became consistently negative and he developed episodes of early morning wakening, headaches, and sweating, which were found to be due to hypoglycemia (glucose < 40 mg/dl, requiring intravenous glucose). His insulin dosage was reduced to 28 units/day. A year later, he was readmitted after 4-5 months of anorexia, weight loss, lethargy, and malaise. Computed tomography examination revealed several areas of low attenuation in the liver. A liver biopsy was performed and revealed active cirrhosis with grade 3 siderosis and fragments ofhepatoma. Later, he was found to have a serum glucose of 20 mg/dl and his daily insulin was reduced to 10 units and insulin therapy was stopped. Three weeks after insulin was stopped, he had anot.he~ episode of hypoglycemia with glucose levels of 45 mg/dl. At this time, insulin levels were 5 mg/ml and cortisol was 24 mg/dl. With an increase in carbohydrate intake, he was successful in maintaining glucose levels of above 60 mg/dl. His fasting blood glucose level ~he morning of the study while measuring his hepatic glucose production was averaged at 64 mg/dl, his insulin level was 7 IlU/ml and Cpeptide was 0.46 ng/ml. A month later he died, and his tumor was estimated at autopsy to be 1 kg in weight (Table 1).
Materials and Methods Subjects. Clinical and biochemical characteristics of
the patient with hepatoma, cirrhotics, and normal controls are presented in Table 2. All subjects gave informed consent prior to the studies, which were approved by the Rambam Medical Center Human Rights Board and the Royal Free Hospital ethical committee. Normal subjects had no history of liver or metabolic disease and cirrhosis was proven by biopsy. Euglycemic Insulin Clamp Technique. Studies were performed after an overnight fast, as previously described. l1 The infusate was given via an antecubital vein. A dorsal hand vein was canulated and kept in a warming box (55 0 C) to arterialize the venous samples. After the measurement of hepatic glucose production, a bolus of insulin was given, followed by a continuous infusion for 2 hours at each insulin infusion rate. Rates of insulin infusion were 1 and 10 mU/kg/min in all subjects. Serum glucose was maintained between 85
Table 1. Dates of Diagnoses and Treatment for Diabetes in the Hepatoma Patient Date
Diagnosis
1/71 Primary hemochromatosis Cirrhosis 2/76 Diabetes 4/76 5/79 10/84 Hepatoma Hypoglycemia 1/85 2/85 Hypoglycemia 3/85 Death
230
Treatment for Diabetes (not diabetic) Glibenclamide,5 mg Insulin, 10 U regular +8U NPH Insulin, 44 U regular +28U NPH Insulin, 16 U regular +12U NPH Insulin, 10 U NPH No treatment for diabetes Metabolic studies
Table 2. Clinical and Biomedical Characteristics of the Hepatoma Patient, Hepatocellular Cirrhotics, and Normal Controls
Hepatoma Patient Age (yrs) % of Ideal body weight Total bilirubin (IlmollL) Albumin (gIL) Total protein (giL) Alkaline phosphatase (lUlL) SGOT(IU/L) Pasting plasma glucose (mg/dl) Pasting plasma insulin (llU/mi) C-peptide (ng/ml) Cortisol (llg/dL) Epinephrine (Ilg/L) Growth hormone (ng/ml)
58 73 25 30 60 352 1026 64
7 0.46 18 0.08
