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III. Medical Department, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
Address all correspondence and requests for reprints to: Prof. Dr. Med. R. Paschke, University of Leipzig III. Medical Department, Philipp-Rosenthal-Strasse 27, D-04103 Leipzig, Germany. E-mail: pasr{at}fmedizin.uni-leipzig.de.
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Abstract |
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Introduction |
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2-receptor mediated (6). Moreover, stimulation of the ß-adrenergic receptor by catecholamines results in stimulation of insulin secretion (7, 8, 9, 10). Catecholamine effects on peripheral glucose uptake have been reported to be of less importance in this context (11). Reduced insulin secretion has repeatedly been reported in patients with pheochromocytoma (1, 12). Therefore, the development of diabetes associated with pheochromocytoma is assumed to be mainly due to decreased insulin secretion. However, hyperinsulinemia in patients with pheochromocytoma has also been reported (13), suggesting that ß-receptor-mediated stimulation of insulin secretion predominates in some patients. Moreover, high levels of norepinephrine have been reported to decrease insulin and ß-adreno-receptor binding in a patient with pheochromocytoma inducing a decrease in insulin sensitivity as determined by iv insulin tolerance test (9). Except from preliminary studies in our own group using the euglycemic hyperinsulinaemic clamp (14), previous studies characterized glucose metabolism in patients with pheochromocytoma either by fasting blood glucose levels (2), by iv insulin test (9) or by oral glucose tolerance test with corresponding insulin levels (1, 15) before and after surgery. These studies primarily investigated changes of insulin secretion and did not evaluate the whole-body insulin sensitivity from oral glucose tolerance test plasma glucose and insulin levels (16).
In animal studies, epinephrine has been shown to induce insulin resistance in rat muscle (7). Furthermore Raz et al. (17) studied the effect of epinephrine in eight healthy patients. They detected an inhibition of insulin-mediated glycogenesis because of an inactivation of glycogen synthase, suggesting that epinephrine inhibits insulin-mediated glucose utilization at the major site of insulin resistance: skeletal muscle. A study by Laakso et al. (18) showed that epinephrines causes a reduced effect of insulin to increase skeletal muscle glucose extraction. There is further evidence from clinical studies that insulin resistance can be induced by ß-adrenergic stimulation after stress induced by hypoglycemia (8), epinephrine (10), or by ß-blocker treatment (19). Recently Keijzers et al. (20) demonstrated that administration of caffeine decreases insulin sensitivity in healthy subjects as a effect of increased plasma epinephrine concentrations. Moreover, we have recently demonstrated inhibition of glucose uptake in muscle and fat by ß-adrenergic stimulation (21). Our hypothesis is, therefore, catecholamine excess in patients with pheochromocytoma can induce insulin resistance. To test this hypothesis, we investigated the extent of insulin resistance by the euglycemic hyperinsulinaemic clamp technique in patients with pheochromocytoma before and 5 wk after adrenalectomy.
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Patients and Methods |
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We studied 10 patients (6 women and 4 men) with pheochromocytoma recruited from our medical department. The median age was 51 yr ± 10.22 (male 49.5 yr ± 10.4; female 52.2 yr ± 10.9). After biochemical confirmation of the diagnosis by 24-h urine catecholamine excretion, the preoperative localization of pheochromocytoma was performed by magnetic resonance imaging scan. After a preoperative nonspecific -adrenergic receptor antagonist (phenoxybenzamine) therapy for at least 10 d before surgery adrenalectomy was performed in all patients. To exclude glucose toxicity-induced insulin resistance, euglycemic hyperinsulinemic clamp was performed 2 wk after normalization of hyperglycemia. Patients with pheochromocytoma and type 2 diabetes were treated with insulin 2 wk before the clamp to achieve a normalization of glucose metabolism. During the insulin treatment period, a stable glucose concentration between 5.1 and 8.7 mmol/liter during the course of the day and fasting glucose concentrations less than 5.5 mmol/liter as well as postprandial glucose concentrations of less than 7.8 mmol/liter were achieved. The daily insulin doses were adjusted to the plasma glucose concentrations and varied from patient to patient (between 10 IU and 90 IU/d). Insulin treatment was stopped only on the day before the clamp. No patient required adrenal hormone replacement after surgery, no complications were recorded.
Euglycemic hyperinsulinaemic glucose clamp
Insulin sensitivity was determined with the euglycemic hyperinsulinaemic clamp method (22) before preoperative -adrenergic receptor antagonist therapy. After an overnight fast and supine resting for 30 min, iv catheters were inserted into antecubital veins in both arms. One was used for the infusion of insulin and glucose, the other was used for frequent blood sampling. At baseline, samples were taken for the measurement of glucose, insulin, C peptide, free fatty acid, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides plasma concentration. After a priming dose of 1.2 nmol/m2 insulin the infusion with insulin (Actrapid 100 U/ml, NovoNordisk, Bagsvaerd, Denmark) was started with a constant infusion rate of 0.28 nmol/m2 body surface per minute and continued for 120 min. After 3 min, the variable 20% glucose infusion rate was added. The glucose infusion rate was adjusted during the clamp to maintain the blood glucose at 5.0 mmol/liter. Bedside blood glucose measurements were performed every 5 min using the glucose dehydrogenase technique with Hemocue B (Hemocue, Angelholm, Sweden). Our patients with pheochromocytoma underwent the same clamp conditions and were recruited from the same population as the previously studied patients from our group, which share the same population background (23, 24). Because we measured venous blood samples, we have to consider the effects of different glucose concentrations as confounding factor for the assessment of insulin sensitivity. Additional blood samples were taken during the steady state to determine of glucose, insulin, and C peptide.
Assays and calculations
Body mass index was calculated as weight divided by squared height. Waist and hip circumferences were measured. Blood samples were taken after an overnight fast, and after 30 min supine position to determine serum lipids and standard laboratory parameters. Plasma glucose was measured by the glucose oxidase method (ESAT 6660-2, Prüfgerätewerk Medingen, Dresden, Germany). Plasma insulin was determined in a two-site chemiluminescent enzyme immunometric assay for the IMMULITE automated analyzer (Diagnostic Products Corp., Los Angeles, CA). Plasma C peptide was determined in a solid phase, chemiluminescent enzyme immunoassay using the IMMULITE automated analyzer (Diagnostic Products Corp.). For the quantification of serum-free fatty acids, an in vitro enzymatic colorimetric method was used (nonesterified fatty acids (NEFA) kit, acyl-coenzyme A synthetase (ACS)-acyl-coenzyme A oxydase (ACOD) method, Wako Chemikals, Neuss, Germany). Urinary excretion of catecholamines was determined by HPLC analysis (Chromosystems, München, Germany).
Statistical analysis
The calculation of insulin sensitivity in the steady-state during h 2 of the euglycemic clamp was performed as described (16). Insulin sensitivity was determined as glucose infusion rate during the steady state of the clamp divided by the steady-state insulin concentration as described (22). All calculations and statistics were performed with SPSS for Windows (SPSS Inc., Chicago, IL). The differences between the groups were tested by Student’s t test.
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Results |
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. To exclude multiple endocrine neoplasia 2, thyroid ultrasound was performed and the plasma concentrations of calcitonin and calcium parathyroid hormone were determined. All patients had unilateral intraadrenal pheochromocytoma. All patients had a history of sustained hypertension, and three patients had a history of paroxysmal hypertension. Sweating and headaches were reported by two patients, one patient had palpitations. All patients had significantly increased preoperative catecholamines levels in 24-h urine. After surgery, normal catecholamine excretion in 24-h urine was detected in all patients (Fig. 1). Glucose infusion rate required to maintain euglycemia during the clamp (micromoles/kilogram/minute) and the plasma glucose concentrations during the euglycemic hyperinsulinemic clamp are shown in Fig. 2. Postoperative glucose uptake was determined 5 wk after surgery in all cases. After adrenalectomy, insulin resistance determined by euglycemic hyperinsulinaemic clamp improved in all subjects (Fig. 3, A and B). In five patients, with diabetes mellitus glucose infusion rate required to maintain euglycemia during the clamp (mean ± SEM) significantly improved from 27.5 ± 6.5 µmol/kg·min before surgery to 44.6 ± 12.3 µmol/kg·min 5 wk after adrenalectomy (P < 0.05) (Fig. 3A). In five individuals without diabetes, glucose infusion rate required to maintain euglycemia during the clamp improved from 105 ± 13.6 to 130 ± 11.2 (P < 0.05) (Fig. 3B). The five patients with diabetes mellitus required insulin therapy or oral antidiabetics (metformin) before surgery. Two diabetic patients returned to a normal fasting blood glucose without antidiabetic treatment. In three patients, diabetes was still overt after adrenalectomy; however, the daily insulin dose could be significantly decreased from 90 IU/d to 36 IU/d in one patient or replaced by metformin in the other two patients, respectively. The improvement of insulin resistance was also reflected by the decrease in fasting plasma C peptide and fasting insulin concentrations, fasting hyperinsulinemia decreased from 210 ± 74 pmol/liter (patients with diabetes mellitus) and 69 ± 9 pmol/liter (patients without diabetes mellitus) before to 134 ± 56 pmol/liter and 54 ± 8 after surgery respectively (P < 0.01) after adrenalectomy (Fig. 3, C and D). There was no change in the body mass index or the concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, free fatty acids, or triglycerides after surgery compared with the preoperative situation. Blood pressure before surgery was measured in the morning before the euglycemic clamp at least 8 h after the last dose of phenoxybenzamine. Blood pressure after surgery was measured before the clamp without antihypertensive drug therapy. In all subjects, a decrease in systolic blood pressure was achieved after surgery, whereas the changes in diastolic blood pressure were only marginal (Table 1). Normalization of 24 h urinary excretion of catecholamines after surgery was achieved in all patients. No patient used any drug influencing biochemical tests for catecholamines.
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Discussion |
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In all patients, complete removal of the pheochromocytoma was achieved. The reduction in systolic blood pressure, the normalization of symptoms and 24-h urinary catecholamine excretion after surgery indicated the cure of the catecholamine excess. All subjects with type 2 diabetes were insulin resistant before surgery and needed insulin therapy or oral antidiabetic treatment. To exclude the influence of glucose toxicity on insulin resistance euglycemic hyperinsulinemic clamps were performed after a 2-wk period of normalization of glucose metabolism. The extent of insulin resistance was quantified by glucose infusion rate required to maintain euglycemia during the euglycemic hyperinsulinemic clamp. Lowering of plasma catecholamines after removal of adrenal tumors resulted in an improvement of insulin sensitivity in all patients. However, a normalization of the glucose infusion rate required to maintain euglycemia during the clamp as determined by euglycemic hyperinsulinemic clamp was only achieved in two patients. In these patients, insulin treatment could be stopped. It is, therefore, likely that in these patients diabetes was induced by high catecholamine plasma concentrations. In the other three patients with diabetes, insulin resistance was most likely only aggravated by high catecholamine levels. Furthermore, in contrast to the two patients without insulin therapy after surgery patients with ongoing antidiabetic therapy had a family history of type 2 diabetes. In two patients, insulin treatment could be converted into oral antidiabetic treatment (metformin) after surgery and in another patient the daily insulin dose could be significantly decreased. The improvement of insulin action is further supported by decreased hyperinsulinemia in all patients after adrenalectomy. Because patients with pheochromocytoma and normal glucose tolerance were in the same metabolic state (as determined by fasting insulin and glucose concentrations) before and after surgery, a potential influence of factors, which could have improved insulin action after surgery, such as changes in nutrition, activity or medication, at least in these patients could be excluded.
Previous studies reported an inhibitory effect of high catecholamine levels on fasting insulin levels (1, 5, 6, 11, 12). However, we did not measure insulin secretion by acute insulin response to glucose or an insulin secretagogue like arginine. Therefore, we cannot draw conclusions regarding the effects of the high serum catecholamine concentrations on insulin secretion in our patients with phaeochromocytoma. However, in our patients with phaeochromocytoma impaired glucose metabolism was induced or exacerbated by insulin resistance induced by the catecholamine excess. We cannot exclude that, in addition to the increased insulin resistance caused by the catecholamine excess, defects in insulin secretion contribute to the alterations in glucose metabolism in patients with pheochromocytoma-associated insulin resistance.
In conclusion, catecholamine overproduction in patients with pheochromocytoma leads to increased insulin resistance. Insulin sensitivity, as determined by the glucose infusion rate required to maintain euglycemia during the euglycemic hyperinsulinemic clamp, improves after complete adrenalectomy both in patients with pheochromocytoma and type 2 diabetes and in patients with pheochromocytoma and normal glucose tolerance.
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Footnotes |
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Abbreviations: HDL, High-density lipoprotein; LDL, low-density lipoprotein.
Received February 3, 2003.
Accepted April 10, 2003.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-adrenergic pathways. Diabetes 27:554–562[Medline]
2 receptors inhibit insulin release in man. Clin Endocrinol (Oxf) 18:37–41[Medline]
, angiotensin II, growth hormone, and IGF-I are not elevated in insulin-resistant obese individuals with impaired glucose tolerance. Diabetes Care 24:328–334This article has been cited by other articles:
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  N. Kanaan, A. Persu, G. Van Ingelgem, J. Malaise, and E. Goffin Recurrent pulmonary oedema and severe hypertension after renal transplantation: other reasons than renal artery stenosis Nephrol. Dial. Transplant., January 1, 2008; 23(1): 397 - 399. [Full Text] [PDF]
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 E. ZAPANTI and I. ILIAS Pheochromocytoma: Physiopathologic Implications and Diagnostic Evaluation Ann. N.Y. Acad. Sci., November 1, 2006; 1088(1): 346 - 360. [Abstract] [Full Text] [PDF]
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