Association of Autoimmune Pancreatitis and Type 1 Diabetes Autoimmune exocrinopathy and endocrinopathy of the pancreas

Impaired glucose tolerance is frequent in patients with pheochromocytoma (1). A decreased insulin secretion is considered to be the main cause for pheochromocytoma-associated diabetes (2). Data from animal and circumstantial evidence from clinical studies suggest that catecholamines can induce insulin resistance. Previous studies characterized the glucose metabolism in patients with pheochromocytoma by fasting blood glucose levels (3), an intravenous insulin test (4), or an oral glucose tolerance test (OGTT) with corresponding insulin levels (1,5) before and after surgery. These studies primarily investigated the changes of insulin secretion and did not calculate the whole-body insulin sensitivity from euglycemic clamps. In animal studies, epinephrine was shown to induce insulin resistance in rat muscle (6). There is further evidence from clinical studies that insulin resistance can be induced by catecholamines via -adrenergic stimulation (7) or epinephrine (8). Therefore, it is very likely that catecholamine excess in patients with pheochromocytoma can induce insulin resistance. Hence, we investigated the extent of insulin resistance by means of the euglycemic-hyperinsulinemic clamp technique (9) in three patients (two women and one man) with pheochromocytoma and diabetes before and 5 weeks after adrenalectomy. To exclude glucose toxicity–induced insulin resistance, clamps were performed 2 weeks after normalization of hyperglycemia. All of the patients had a history of sustained hypertension, and one patient had a history of paroxysmal hypertension. The two women had a family history of type 2 diabetes and required insulin therapy before surgery; the man (no family history of diabetes) was treated with metformin before surgery. In each proband, wholebody glucose uptake (means ± SEM) significantly improved from 23.4 ± 4.1 before surgery to 36.2 ± 7.7 μmol kg 1 min 1 5 weeks after the adrenalectomy. The improved insulin sensitivity after surgery was confirmed in all of the subjects by a decrease in fasting hyperinsulinemia from 163 ± 19 before surgery to 102 ± 21 pmol/l after surgery. In contrast to previous studies, no inhibitory effect on fasting insulin secretion by high catecholamine levels was detected. In one patient, diabetes and hyperinsulinemia were reversed by the removal of the tumor. In the other two subjects, type 2 diabetes was known for 6 years and treated with insulin 2 and 3 years before the diagnosis of pheochromocytoma. Although diabetes was not reversible in these two patients, insulin treatment could be converted into oral antidiabetic treatment in one patient, and the daily insulin dose could be significantly reduced in the other patient. There was no change in BMIs or the concentrations of free fatty acids, triglycerides, and total, LDL, and HDL cholesterol after surgery compared with before surgery. Normalization of the 24-h urinary excretion of catecholamines after surgery was achieved in each of the patients. No patient took any drug that influenced the high-performance liquid chromatography analysis of the catecholamines. Previous studies showed an improvement of glucose metabolism as determined by fasting (3) or 2-h OGTT plasma glucose levels (1,5) after adrenalectomy in patients with pheochromocytoma. Because these studies (1,5) concentrated only on the assessment of insulin-secretory defects in patients with pheochromocytoma, the catecholamine-induced impaired glucose tolerance was explained by the detected decrease in the insulin secretion response during the OGTT (1). Although -receptor stimulation (catecholamines) can induce insulin resistance, as suggested by animal (6) and clinical studies (4,7,8), these studies did not investigate whether the improvement in glucose homeostasis after surgery is also the result of an improvement in insulin action. The threshold for insulin sensitivity (i.e., a normalization of whole-body glucose uptake determined by the euglycemic clamp) was only achieved in the male patient. In this patient, the insulin treatment could be stopped. Therefore, it is likely that, in this patient only, diabetes was induced by the high catecholamine plasma concentrations. In the two female patients, insulin resistance was most likely only exacerbated by the high catecholamine levels. Furthermore, in contrast to the male patient, the female patients had a family history of type 2 diabetes. In addition to insulin resistance, improvement of hyperinsulinemia could also be due to an insulin secretion–stimulating effect of catecholamines in these patients. Thus, in contrast to the previous findings indicating that reduced insulin secretion is the main cause for impaired glucose tolerance in pheochromocytoma (1,5). In our patients, impaired glucose metabolism was induced (in the male patient) or exacerbated (in the two female patients) by insulin resistance induced by catecholamine excess. Moreover, in contrast to these studies (1,5), even in the male patient with catecholamineinduced mildly impaired glucose tolerance, we observed a postoperative increase of insulin secretion. In conclusion, in the three patients with pheochromocytoma and diabetes, catecholamine overproduction led to increased insulin resistance. Insulin sensitivity improved after complete adrenalectomy. The previously described inhibitory effect of catecholamine excess on fasting insulin secretion was not detected in these patients.