propylthiouracil and Insulin-Resistance

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.

Topics: Adipocytes, Brown; Adipocytes, White; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Coumarins; Diet, High-Fat; Energy Metabolism; Fatty Liver; Glucose Intolerance; Insulin Resistance; Maillard Reaction; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Propylthiouracil; Thermogenesis; Triiodothyronine; Weight Gain

During pregnancy, maternal metabolic disease and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offspring remains poorly understood.. We investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation.. Here, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals.. Therefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals.

Topics: Animals; Antithyroid Agents; Blood Glucose; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Female; Glucose Intolerance; Hyperinsulinism; Hypothyroidism; Insulin Resistance; Insulin-Secreting Cells; Iodine; Islets of Langerhans; Mice; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Stress, Physiological

The present study was undertaken to evaluate the change of circulating visfatin, C-reactive protein (CRP) concentrations, and insulin sensitivity in patients with hyperthyroidism. We studied 19 adult patients (14 women and 5 men aged 32.6 +/- 1.8 years) with hyperthyroidism due to Graves disease and 19 age- and sex-matched euthyroid controls (17 women and 2 men aged 36.7 +/- 2.7 years). All hyperthyroid patients were treated with 1 of 2 antithyroid drugs and were reevaluated after thyroid function normalized. Before antithyroid treatment, the hyperthyroid group had significantly higher visfatin plasma concentration (mean +/- standard error of the mean, 20.7 +/- 1.8 ng/mL) than the control group (16.2 +/- 1.3 ng/mL, P = .044); but the visfatin level dropped significantly after treatment (12.0 +/- 1.4 ng/mL, P < .001). The reciprocal index of homeostasis model assessment of insulin resistance (HOMA-IR) in the hyperthyroid group was higher before treatment (2.06 +/- 0.26 mmol mU/L*L) than after treatment (1.21 +/- 0.16 mmol mU/L*L, P = .027). There was no significant difference in serum glucose, high-sensitivity CRP, and insulin levels between hyperthyroid and control groups and in the hyperthyroid group before and after treatment. Body mass index-adjusted visfatin levels were significantly elevated in the hyperthyroid group. Pearson correlation revealed that visfatin, glucose, insulin, and HOMA-IR values positively correlated with triiodothyronine and free thyroxine levels. However, visfatin did not correlate with insulin and HOMA-IR levels. The results indicated that plasma visfatin concentration was elevated in hyperthyroidism due to Graves disease, but serum CRP levels were not. Plasma visfatin levels were not associated with indicators of insulin resistance in hyperthyroid patients.

Topics: Adult; Antithyroid Agents; Blood Glucose; C-Reactive Protein; Carbimazole; Cytokines; Female; Graves Disease; Humans; Insulin; Insulin Resistance; Male; Nicotinamide Phosphoribosyltransferase; Propylthiouracil; Statistics, Nonparametric; Thyrotropin; Thyroxine; Triiodothyronine

The aims of this work were to determine the effect of hypothyroidism on insulin-stimulated glucose turnover and to unravel the potential mechanisms involved in such an effect.. Hypothyroidism was induced by administration of propylthiouracil, with partial T4 substitution. Euglycaemic-hyperinsulinaemic clamps, associated with the labelled 2-deoxy-D-glucose technique for measuring tissue-specific glucose utilisation, were used. To assess a possible involvement of leptin in the modulation of glucose metabolism by hypothyroidism, leptin was infused intracerebroventricularly for 6 days. A group of leptin-infused rats was treated with rT3 to determine a potential role of T3 in mediating the leptin effects.. Compared with euthyroid rats, hypothyroid animals exhibited decreased overall glucose turnover and decreased glucose utilisation indices in skeletal muscle and adipose tissue. Leptinaemia in hypothyroid rats was lower while resistin mRNA expression in adipose tissue was higher than in euthyroid animals. Intracerebroventricular leptin infusion in hypothyroid rats partially restored overall, muscle and adipose tissue insulin-stimulated glucose utilisation and improved the reduced glycaemic response observed during insulin tolerance tests. The leptin effects were due neither to the observed increase in plasma T3 levels nor to changes in the high adipose tissue resistin expression of hypothyroid rats. The administration of leptin to hypothyroid animals was accompanied by increased expression of muscle and adipose tissue carnitine palmitoyl transferases, decreased plasma NEFA levels and reduced muscle triglyceride content.. Hypothyroidism is characterised by decreased insulin responsiveness, partly mediated by an exaggerated glucose-fatty acid cycle that is partly alleviated by intracerebroventricular leptin administration.

Topics: Adipose Tissue; Animals; Blood Glucose; Carnitine O-Palmitoyltransferase; Energy Metabolism; Fatty Acids, Nonesterified; Gene Expression; Glucose; Glucose Clamp Technique; Hormones, Ectopic; Hyperthyroidism; Insulin; Insulin Resistance; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Leptin; Male; Muscle, Skeletal; Propylthiouracil; Rats; Rats, Wistar; Resistin; Thyrotropin; Thyroxine; Triglycerides; Triiodothyronine; Triiodothyronine, Reverse

Low serum paraoxonase (PON) activity is thought to be a risk factor for the development of atherosclerosis. The present study was designed to evaluate PON1 activity and its relationship with preatherosclerotic markers such as lipid peroxidation and insulin resistance in hyperthyroid patients before and after propylthiouracil (PTU) treatment and in subjects with iatrogenic subclinical hyperthyroidism.. Twenty patients with hyperthyroidism, 20 patients with euthyroid multinodular goiter (MNG) and 20 age- and sex-matched healthy controls were enrolled in the study. Insulin sensitivity index, PON activity and lipid peroxidation were measured at baseline and 2 months after achieving euthyroidism or subclinical hyperthyroidism. Levothyroxine was given as a part of TSH suppression therapy in multinodular goitre patients.. Insulin sensitivity was determined by an oral glucose tolerance test (OGTT) based on the insulin sensitivity index (ISI) formula, serum paraoxonase activity was determined with a spectrophotometric method. Lipid peroxidation was measured by the formation of thiobarbituric acid reactive substances (TBARs).. ISI was significantly lower in the hyperthyroid group than baseline levels in MNG patients and controls (P < 0.001). While ISI increased after treatment in the hyperthyroid group (P < 0.01), it significantly decreased with L-T4 treatment in the MNG group (P < 0.01). Serum paraoxonase activity was significantly lower in the hyperthyroid group before treatment than baseline and final measurements of other groups (P < 0.05). While PON activity increased after restoration of the euthyroid state in the hyperthyroid group (P < 0.05), it decreased with L-T4 treatment in the MNG group (P < 0.05). Lipid peroxidation was significantly higher in hyperthyroid group compared to baseline levels of other groups (P < 0.05). It decreased after treatment in the hyperthyroid group (P < 0.05) but a significant increase was observed following L-T4 treatment in the MNG group (P < 0.05). Serum paraoxonase activity was found to be negatively correlated with serum TT4 (r = -0.32, P = 0.003), TT3 levels (r = -0.31, P = 0.004), TBARs levels (r = 0.32, P = 0.003) and positively correlated with ISI (r = 0.35, P = 0.001) and high-density lipoprotein (HDL) cholesterol levels (r = 0.35, P = 0.0011) in the hyperthyroid and MNG groups.. Iatrogenic thyroid hormone excess seems to mimic the effects of endogenous thyroid hormone excess on paraoxonase activity, insulin sensitivity and oxidative stress. These findings suggest that TSH suppression with levothyroxine may increase oxidative stress and LDL oxidation and thereby promote atherogenesis.

Topics: Adult; Analysis of Variance; Antithyroid Agents; Arteriosclerosis; Aryldialkylphosphatase; Case-Control Studies; Female; Goiter, Nodular; Humans; Hyperthyroidism; Insulin Resistance; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Propylthiouracil; Thyroid Function Tests