methimazole and Hyperinsulinism

Topics: Autoantibodies; Autoimmune Diseases; Diagnosis, Differential; HLA Antigens; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Insulin Antibodies; Methimazole; Syndrome; Tiopronin

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies and fasting or late postprandial hypoglycemia. The number of reports on the association of long-term follow-up of IAS in China is limited. We herein report a case of drug-induced IAS in a 44-year-old Chinese woman. She had been taking methimazole for Graves' disease and had subsequently presented with recurrent hypoglycemic episodes. Laboratory assessments on admission revealed that her serum insulin level was significantly elevated (>1000 µIU/mL) and that she was positive for serum insulin autoantibody, leading to a diagnosis of IAS. Human leukocyte antigen DNA typing identified *04:06/*09:01:02, an immunogenetic determinant associated with IAS. After treatment with prednisone for 2 months, the hypoglycemic episodes disappeared, her serum insulin level gradually declined, and her insulin antibody levels became negative. Clinicians should be aware of the potential for methimazole to trigger autoimmune hypoglycemia in people with a genetic predisposition.

Topics: Adult; Autoimmune Diseases; Female; Follow-Up Studies; Graves Disease; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulin; Methimazole

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by high levels of blood insulin autoantibodies. It has been documented that drugs containing sulfhydryl groups may result in IAS. In this study, we present two cases of IAS induced by methimazole, along with their corresponding treatments and a long-term follow-up after hospitalization.. We report two patients with Grave's disease (GD), carrying the HLA-DRB1 04:06 genotype, who experienced hypoglycemic episodes after taking methimazole. Inpatient treatments helped return their blood glucose levels to normal. Although no recurrences of hypoglycemia were present in the two cases studied, insulin autoantibodies remained positive for the previous follow-up sessions, which turned negative only three years after discharge.. GD patients who carry the HLA-DRB1 04:06 genotype are prone to IAS if they take drugs containing sulfhydryl groups. It may take time for the elimination of insulin autoantibodies after the recovery from the hypoglycemic episode in IAS patients.

Topics: Autoantibodies; Autoimmune Diseases; Follow-Up Studies; Graves Disease; HLA-DRB1 Chains; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulins; Methimazole; Patient Discharge; Sulfhydryl Compounds

Hypoglycemia is an emergent condition with many causes, including underlying diabetes mellitus either with the use of insulin or oral anti-diabetic medications for glucose control, and organ (heart, hepatic, or renal) failure. Insulin autoimmune syndrome (IAS) can also cause hypoglycemia, however it is relatively difficult to diagnose as it is rare clinically. Although uncommon, IAS can be life threatening in patients with persistent hypoglycemia.. We report the case of a 27-year-old female with underlying Graves' disease who was treated with methimazole (MTZ). After 6 weeks of treatment, she developed hypoglycemia symptoms accompanied by dizziness and cold sweating. We excluded underlying diabetes mellitus, the use of insulin or oral anti-diabetic medications, and organ failure.. Laboratory data showed elevated insulin and C-peptide levels. Therefore, insulinoma and IAS were suspected. Abdominal computed tomography and magnetic resonance imaging ruled out insulinoma, and MTZ-induced IAS was finally diagnosed.. The hypoglycemia symptoms resolved after MTZ was switched to propylthiouracil, confirming the diagnosis of IAS.. This case emphasizes the significance of life-threatening MTZ-induced IAS. IAS should be suspected in patients who develop spontaneous hypoglycemia, especially in those with underlying Graves' disease receiving MTZ who present with hyperinsulinism.

Topics: Adult; Autoimmune Diseases; Diabetes Mellitus; Female; Graves Disease; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Methimazole; Pancreatic Neoplasms

The older of a pair of sisters experienced hypoglycemia after the start of thiamazole (MMI) treatment. Based on a high insulin antibody level, she was diagnosed with insulin autoimmune syndrome (IAS). HLA-DNA typing identified DRB1*04:06. Although a 75-g oral glucose tolerance test (OGTT) showed biphasic insulin secretion, the secretion pattern became monophasic after discontinuation of the MMI. The younger sister was diagnosed with IAS after the start of MMI treatment. HLA-DNA typing identified DRB1*04:06. The 75-g OGTT showed biphasic insulin secretion, but it became monophasic after discontinuation of the MMI. According to the similar insulin secretion kinetics in the two sisters with IAS, we suspect that a genetic predisposition may be associated with the features of anti-insulin antibodies.

Topics: Adult; Antithyroid Agents; Autoimmune Diseases; Female; Genetic Predisposition to Disease; Glucose Tolerance Test; Graves Disease; HLA-DRB1 Chains; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Insulin Secretion; Methimazole; Siblings

We developed an ultrasensitive enzyme immunoassay (ICT-EIA) for insulin autoantibody (IAA) measurements to better understand the pathophysiology of diabetes.. We developed ICT-EIA for IAA and measured IAA in 24 patients with type 1 diabetes, 30 patients with type 2 diabetes, 30 patients with methimazole-treated Graves' disease, 20 patients with Hashimoto's disease, 9 patients with hyperinsulinemia, and 73 healthy control subjects.. The conventional ELISA identified 3 patients with type 1 diabetes and 2 patients with type 2 diabetes as IAA positive, whereas 15 patients with type 1 diabetes, 7 patients with type 2 diabetes, and 4 patients with methimazole-treated Graves' disease were identified as IAA positive using ICT-EIA.. The ICT-EIA is an ultrasensitive and specific assay for IAA, and its use may provide a better understanding of the role of IAA in diabetes onset and progression.

Topics: Autoantibodies; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Progression; Graves Disease; Hashimoto Disease; Humans; Hyperinsulinism; Immunoenzyme Techniques; Insulin; Insulin Antibodies; Methimazole; Sensitivity and Specificity

Thyrotoxicosis is known to induce a broad range of changes in carbohydrate metabolism. Recent studies have identified the sympathetic and parasympathetic nervous system as major regulators of hepatic glucose metabolism. The present study aimed to investigate the pathogenesis of altered endogenous glucose production (EGP) in rats with mild thyrotoxicosis. Rats were treated with methimazole in drinking water and l-thyroxine (T(4)) from osmotic minipumps to either reinstate euthyroidism or induce thyrotoxicosis. Euthyroid and thyrotoxic rats underwent either a sham operation, a selective hepatic sympathetic denervation (Sx), or a parasympathetic denervation (Px). After 10 days of T(4) administration, all animals were submitted to a hyperinsulinemic euglycemic clamp combined with stable isotope dilution to measure EGP. Plasma triiodothyronine (T(3)) showed a fourfold increase in thyrotoxic compared with euthyroid animals. EGP was increased by 45% in thyrotoxic compared with euthyroid rats and correlated significantly with plasma T(3). In thyrotoxic rats, hepatic PEPCK mRNA expression was increased 3.5-fold. Relative suppression of EGP during hyperinsulinemia was 34% less in thyrotoxic than in euthyroid rats, indicating hepatic insulin resistance. During thyrotoxicosis, Sx attenuated the increase in EGP, whereas Px resulted in increased plasma insulin with unaltered EGP compared with intact animals, compatible with a further decrease in hepatic insulin sensitivity. We conclude that chronic, mild thyrotoxicosis in rats increases EGP, whereas it decreases hepatic insulin sensitivity. Sympathetic hepatic innervation contributes only to a limited extent to increased EGP during thyrotoxicosis, whereas parasympathetic hepatic innervation may function to restrain EGP in this condition.

Topics: Animals; Autonomic Denervation; Blood Glucose; Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Kinetics; Liver; Male; Methimazole; Parasympathectomy; Phosphoenolpyruvate Carboxykinase (GTP); Rats; Rats, Wistar; RNA, Messenger; Sympathectomy; Thyroid Hormones; Thyrotoxicosis; Thyroxine

Hyperthyroidism is characterized by increased levels of circulating free fatty acids (FFA) and increased lipid oxidation, but it is uncertain which regional fat depots contribute. The present study was designed to define the participation of femoral and abdominal fat stores in the overall stimulation of lipolysis in hyperthyroidism in the basal state and during insulin stimulation. We studied nine women with newly diagnosed hyperthyroidism (HT) and after (euthyroidism, ET) medical treatment with methimazol and compared with eight control subjects (CTR). All subjects were studied in the postabsorptive state and during a 3-h hyperinsulinemic euglycemic clamp with microdialysis catheters sc in the abdominal and femoral adipose tissue. Before treatment, patients had elevated circulating concentrations of triiodthyronine, FFA, and glycerol. Levels of interstitial glycerol ( micro mol/liter) in abdominal adipose tissue [485 +/- 24 (HT), 226 +/- 20 (ET) (P < 0.001), 265 +/- 34 (CTR) (P < 0.001)] and in femoral adipose tissue [468 +/- 41(HT), 245 +/- 29 (ET) (P < 0.01), 278 +/- 31(CTR) (P < 0.005)] were elevated in the basal hyperthyroid state, and these differences prevailed during the glucose clamp [230 +/- 23 (HT), 113 +/- 13 (ET) (P < 0.01), 132 +/- 22(CTR) (P < 0.01) and 303 +/- 39 (HT), 122 +/- 15 (ET) (P < 0.01), 166 +/- 21(CTR) (P < 0.01)]. These results suggest that femoral and abdominal adipose tissue contribute equally to the excessive rate of lipolysis in hyperthyroidism and that both tissues are resistant to the actions of insulin.

Topics: Abdomen; Adipose Tissue; Adult; Antithyroid Agents; Blood Flow Velocity; Energy Metabolism; Fatty Acids, Nonesterified; Female; Femur; Food; Glucose Clamp Technique; Glycerol; Humans; Hyperinsulinism; Hyperthyroidism; Lipolysis; Methimazole; Microdialysis; Middle Aged; Triiodothyronine

In 1986, a 26-year-old female had been diagnosed as having Graves' disease and had been treated with methimazole for four months. After the treatment with propylthiouracil for another four months, she had been treated with methimazole once again. She was in complete remission for two years. She again experienced symptoms of hyperthyroidism, and treatment with methimazole was started again. On the thirteenth day after treatment, she experienced hypoglycemic attacks with skin eruption. The plasma glucose was 57 mg/dl, 125I-Insulin binding 69%, free IRI 196 microU/ml. The patient had the HLA-DRB1*0406.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Female; Graves Disease; Humans; Hyperinsulinism; Hypoglycemia; Insulin Antibodies; Methimazole

Some patients with the insulin autoimmune syndrome have circulating insulin that is heterogeneous. We used reverse phase high performance liquid chromatographic analysis to identify the forms of plasma insulin in patients with this syndrome and compared the results with those in patients with insulin-treated diabetes and patients with hyperinsulinism. Under acidic conditions, free insulin dissociated from insulin antibodies eluted from Bio-Gel P-30 columns as a single peak. When such insulin fractions were applied to reverse phase high performance liquid chromatography, a major insulin peak emerged with the same retention time as standard human insulin in all six patients with the syndrome. In addition, a minor insulin peak was consistently found at relatively high acetonitrile concentrations. However, this hydrophobic insulin also was found in two of four insulin-treated diabetic patients and in one of two hyperinsulinemic patients who did not have insulin antibodies. Preliminary characterization of the variant insulin revealed that it has a molecular size between those of proinsulin and insulin and retains the immunoreactivity of insulin, but not C-peptide. It may be an aggregate of insulin molecule or proinsulin intermediates. Since the variant insulin was not found only in patients with the insulin autoimmune syndrome, it seems unlikely that an altered endogenously produced insulin induces the generation of autoantibodies to insulin in this syndrome.

Topics: Adult; Aged; Autoimmune Diseases; Chromatography, High Pressure Liquid; Diabetes Mellitus; Female; Humans; Hyperinsulinism; Insulin; Male; Methimazole; Middle Aged; Molecular Weight; Proinsulin