methimazole and Insulin-Resistance

Insulin-like growth factor binding-protein-1 (IGFBP-1) has a role in glucose homeostasis and is present at high concentrations in hyperthyroidism. We have investigated the relationship between IGFBP-1 concentration and glucose homeostasis in hyperthyroidism.. Patients and controls had intravenous glucose tolerance tests (IVGTT) and/or oral glucose tolerance tests (OGTT). Patients were tested when hyperthyroid and when euthyroid whilst the controls were tested once. The IVGTT was used to assess insulin sensitivity and the OGTT to establish that the study group had abnormal glucose tolerance. The hyperthyroid patients were treated with methimazole to restore euthyroidism.. Ten patients (9 females) and 13 healthy controls (9 females) consented to the study. Ten patients and nine controls (7 females) had IVGTT. Six patients (5 females) and six controls (4 females) had OGTT.. Glucose, insulin, glucagon, GH and IGFBP-1 were measured during GTT. IGF-I, free thyroid hormones, and TSH concentrations were measured basally.. Hyperthyroid subjects were insulin resistant and 67% had impaired glucose tolerance. Fasting IGFBP-1 levels were doubled in hyperthyroid subjects compared to healthy controls and correlated positively with free T4 (r = 0.84, P < 0.0001), with peak glucose during the OGTT (r = 0.68, P < 0.005) with peak insulin during the IVGTT (r = 0.51, P < 0.005) and negatively with glucose disappearance constant (r = - 0.52, P < 0.005). IGFBP-1 was highly phosphorylated in hyperthyroid and control subjects. Fasting insulin and IGFBP-1 levels were unrelated but IGFBP-1 suppressed acutely during GTT in all groups. GH levels fell less in patients with hyperthyroidism than in normals during GTTs.. We conclude that in hyperthyroidism thyroid hormones directly increase fasting IGFBP-1 concentration but acute regulation of IGFBP-1 by insulin is normal and that elevated fasting phosphorylated IGFBP-1 concentration is associated with insulin resistance.

Topics: Adult; Antithyroid Agents; Area Under Curve; Blood Glucose; Case-Control Studies; Female; Glucose Tolerance Test; Human Growth Hormone; Humans; Hyperthyroidism; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Male; Methimazole; Thyroxine

Abdominal pain is a common chief complaint that encompasses a broad differential diagnosis at emergency department (ED), ranging from general discomfort to life-threatening disease. Abdominal pain induced by a metabolic disorder should also be considered. Diabetic ketoacidosis (DKA) is a common complication of new-onset type 1 diabetes mellitus in young patients. Although DKA that presented to the ED with complaint of abdominal pain is not uncommon, it is precipitated by hyperthyroidism, which is rare and more complicated. Herein, we present a case of a 20-year-old women who came to our ED with the chief complaint of abdominal pain, which was actually the result of DKA caused by hyperthyroidism without underlying disease.

Topics: Antithyroid Agents; Biomarkers; Diabetic Ketoacidosis; Diagnosis, Differential; Diagnostic Imaging; Electrocardiography; Emergency Service, Hospital; Female; Humans; Hyperthyroidism; Insulin Resistance; Methimazole; Young Adult

We previously reported that serum interleukin-18 (IL-18) levels were significantly increased in hyperthyroid Graves' disease patients. The development of insulin resistance in hyperthyroidism has been documented. We investigated the relationship between IL-18 and insulin resistance in patients with hyperthyroid Graves' disease and in experimental hyperthyroid mice. Then, we examined whether IL-18 induces insulin resistance in mice injected with IL-18 for a week. A significant positive correlation was observed between serum IL-18 levels and parameters such as thyroid functions and homeostasis model assessment for insulin resistance in hyperthyroid Graves' disease. In experimental hyperthyroid mice, IL-18 was significantly elevated. Insulin resistance increased in experimental hyperthyroid mice and IL-18-injected mice. These findings suggest IL-18 to be an important factor inducing insulin resistance in hyperthyroidism.

Topics: Adolescent; Adult; Animals; Antithyroid Agents; Blood Glucose; Female; Graves Disease; Humans; Hyperthyroidism; Injections, Intraperitoneal; Insulin; Insulin Resistance; Interleukin-18; Male; Methimazole; Mice; Mice, Inbred C57BL; Middle Aged; Recombinant Proteins; Young Adult

Visceral adipocytes and associated macrophages produce and release excessive amounts of biologically active inflammatory cytokines via the portal and systemic vascular system, which induce insulin resistance in insulin target tissues such as fat, liver, and muscle. Free fatty acids (FFAs) absorbed via the portal system or released from adipocytes also induce insulin resistance. In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin-stimulated AKT signaling. In addition, C10 inhibits palmitate-induced IL6 and iNos up-regulation in both 3T3L1 adipocytes and RAW 264.7 macrophages, LPS-induced NF-κB and IFN-β activation in 3T3L1 cells, and LPS-induced iNos, Ifn-β, Il1β, Cxcl10, and Il6 expression in RAW 264.7 macrophages. C10 also blocks palmitate-induced Socs-3 up-regulation and insulin receptor substrate-1 (IRS-1) serine 307 phosphorylation in 3T3L1 adipocytes. Additionally, we show for the first time that although palmitate increases IRS-1 serine 307 phosphorylation in 3T3L1 adipocytes, AKT serine 473 phosphorylation is enhanced, not reduced, by palmitate. These results suggest that through inhibition of FFA-mediated signaling in adipocytes and associated macrophages, as well as possibly other insulin target cells/tissues (i.e. non-immune cells), C10 might be efficacious to prevent or reverse cytokine-induced insulin resistance seen in obesity-related insulin resistance and type 2 diabetes mellitus.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Chemokine CXCL10; Inflammation Mediators; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Interferon-beta; Interleukin-1beta; Interleukin-6; Leptin; Lipopolysaccharides; Macrophages; Methimazole; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Palmitates; Phosphorylation; Proto-Oncogene Proteins c-akt; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thiones; Up-Regulation

This experimental study was designed to examine whether hyperuricemia in hypothyroidism is associated with insulin resistance. For induction of hypothyroidism, rabbits (n = 12) were administered methimazole orally (75 mg/100 g food) for 30 days. T3, T4 and TSH values measured in plasma prior to and at the end of the experimentation period revealed the establishment of hypothyroidism. In the euthyroid and hypothyroid states of rabbits, crystalline porcine insulin was administered (0.1 unit/kg body weight) intraperitoneally and plasma glucose was measured at 0, 15, 30, 45 and 60 minutes. Sum of post insulin infusion glucose values was considered to reflect insulin resistance. Creatinine clearance (GFR) and uric acid clearance (CuA) were determined. Additionally, triglycerides were measured in plasma and Mg2+ both in erythrocytes and in plasma. Due to hypothyroidism: i) The glycemic response to insulin was not altered. ii) GFR and CuA were both decreased but CuA/GFR unchanged. iii) Triglycerides in plasma decreased. iv) Mg2+ concentration increased in plasma whereas decreased in erythrocytes. Several associations were observed between the variables on correlation analysis. On the basis of our data, it could be suggested that insulin resistance does not exist in hypothyroidism. Hyperuricemia observed in hypothyroidism should be considered to be secondary to decreased renal excretion but not as an indicator of insulin resistance.

Topics: Animals; Antithyroid Agents; Creatinine; Erythrocytes; Humans; Hyperuricemia; Hypothyroidism; Insulin; Insulin Resistance; Kidney; Magnesium; Methimazole; Rabbits; Thyrotropin; Thyroxine; Time Factors; Triglycerides; Triiodothyronine; Uric Acid

Insulin autoimmune syndrome is characterized by spontaneous hypoglycemia, glucose intolerance, hyperinsulinemia and insulin-binding antibodies in serum without previous immunization. A 31-year-old man with Graves' disease developed insulin autoantibodies after therapy with methimazole. The patient was unique in that persistent hyperglycemia with polyuria and polydipsia had continued for several days before frequent hypoglycemic attacks appeared. We were able to extract a huge amount of immunoreactive insulin (116,000 microU/ml) with acid-ethanol from his serum obtained in the diabetic stage, and serum C-peptide immunoreactivity was as high as 268 ng/ml. The insulin-binding activity of his serum was quite potent, and when 1:5,000 diluted serum was incubated with 125I-porcine insulin, 71.2% of the label could be precipitated by polyethylene glycol. The insulin-binding protein was identified as mainly IgG with kappa light chains. Insulin-binding activity was not detected in serum obtained before methimazole therapy, suggesting that the drug was responsible for the induction of antibodies in this patient. The antibodies recognized porcine, sheep, bovine and horse insulins as well as human insulin. The mechanisms by which the antibodies produced hyper- and hypoglycemia have also been discussed.

Topics: Adult; Autoantibodies; Glucose Tolerance Test; Graves Disease; Humans; Hypoglycemia; Insulin Antibodies; Insulin Resistance; Male; Methimazole