thyronines and Hyperglycemia

Thyronamines (TAMs) are a newly identified class of endogenous signaling compounds. Their structure is identical to that of thyroid hormone and deiodinated thyroid hormone derivatives, except that TAMs do not possess a carboxylate group. Despite some initial publications dating back to the 1950s, TAMs did not develop into an independent area of research until 2004, when they were rediscovered as potential ligands to a class of G protein-coupled receptors called trace-amine associated receptors. Since this discovery, two representatives of TAMs, namely 3-iodothyronamine (3-T(1)AM) and thyronamine (T(0)AM), have been detected in vivo. Intraperitoneal or central injection of 3-T(1)AM or T(0)AM into mice, rats, or Djungarian hamsters caused various prompt effects, such as metabolic depression, hypothermia, negative chronotropy, negative inotropy, hyperglycemia, reduction of the respiratory quotient, ketonuria, and reduction of fat mass. Although their physiological function remains elusive, 3-T(1)AM and T(0)AM have already revealed promising therapeutic potential because they represent the only endogenous compounds inducing hypothermia as a prophylactic or acute treatment of stroke and might thus be expected to cause fewer side effects than synthetic compounds. This review article summarizes the still somewhat scattered data on TAMs obtained both recently and more than 20 yr ago to yield a complete and updated picture of the current state of TAM research.

Topics: Adiposity; Animals; Cricetinae; Heart Rate; Humans; Hyperglycemia; Hypothermia; Ketosis; Male; Mice; Rats; Receptors, G-Protein-Coupled; Receptors, Thyroid Hormone; Signal Transduction; Stroke; Thyronines

BACKGROUND AND PURPOSE Preclinical pharmacology of 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, indicates that it is a rapid modulator of rodent metabolism and behaviour. Since T1AM undergoes rapid enzymatic degradation, particularly by MAO, we hypothesized that the effects of T1AM might be altered by inhibition of MAO. EXPERIMENTAL APPROACH We investigated the effects of injecting T1AM (i.c.v.) on (i) feeding behaviour, hyperglycaemia and plasma levels of thyroid hormones and (ii) T1AM systemic bioavailability, in overnight fasted mice, under control conditions and after pretreatment with the MAO inhibitor clorgyline. T1AM (1.3, 6.6, 13, 20 and 26 µg·kg(-1) ) or vehicle were injected i.c.v. in fasted male mice not pretreated or pretreated i.p. with clorgyline (2.5 mg·kg(-1) ). Glycaemia was measured by a glucorefractometer, plasma triiodothyronine (fT3) by a chemiluminescent immunometric assay, c-fos activation immunohistochemically and plasma T1AM by HPLC coupled to tandem-MS. KEY RESULTS T1AM, 1.3 µg·kg(-1) , produced a hypophagic effect (-24% vs. control) and reduced c-fos activation. This dose showed systemic bioavailability (0.12% of injected dose), raised plasma glucose levels and reduced peripheral insulin sensitivity (-33% vs. control) and plasma fT3 levels. These effects were not linearly related to the dose injected. Clorgyline pretreatment strongly increased the systemic bioavailability of T1AM and prevented the hyperglycaemia and reduction in fT3 induced by T1AM. CONCLUSIONS AND IMPLICATIONS T1AM induces central and peripheral effects including hyperglycaemia and a reduction in plasma fT3 levels in fasted mice. These effects critically depend on the concentration of T1AM or its metabolites in target organs.

Topics: Animals; Blood Glucose; Clorgyline; Eating; Exenatide; Fasting; Hyperglycemia; Hypoglycemic Agents; Hypothalamus; Insulin Resistance; Male; Mice; Monoamine Oxidase Inhibitors; Pancreas; Peptides; Proto-Oncogene Proteins c-fos; Thyroid Gland; Thyroid Hormones; Thyronines; Venoms

The effect of propylthiouracyl (PTU)-induced low thyroid function on insulin responsiveness to glucose and glucose responsiveness to insulin in sheep was studied by performing hyperglycemic and euglycemic clamp experiments. All sheep were maintained at a level of 125% daily metabolizable energy intake and were housed in an environmental room that was maintained at 20 degrees C with a 16-hr lighting period. In the first study, eight female Suffolk sheep were divided equally into two groups and were subjected to oral PTU treatments of 4 mg/kg body weight (BW) per day for 7 d (low PTU) and 8 mg/kg BW per day for 14 d (high PTU). A hyperglycemic clamp experiment was conducted in each group on both control and PTU treatment periods. Plasma concentrations of triiodothyronine and thyroxine decreased (P < 0.05) in high PTU-treated sheep compared with those of low PTU-treated and control sheep. Both PTU treatments did not significantly influence basal insulin and glucose levels. Results of the hyperglycemic clamp experiment indicated that the mean plasma insulin increment and the ratio of mean plasma insulin increment to glucose infusion rate were significantly higher (P < 0.01) in high PTU-treated sheep than in low PTU-treated and control sheep. In the second study, the PTU treatment (8 mg/kg BW per day) was applied for 17 d in four male Suffolk sheep. A euglycemic clamp experiment with two insulin infusion rates (1.0 and 10.0 mU/kg per minutes) for two sequential periods of 2 hr each and thyroid hormone responses to intrajugular injection of thyrotropin-releasing hormone (1 microgram/kg BW) were performed in each sheep on both control and PTU treatment periods. In the euglycemic clamp experiment, the glucose infusion rate and the ratio of glucose infusion rate to mean plasma insulin increment were significantly reduced (P < 0.05) during the PTU treatment period for 10.0 mU/kg BW per minute of insulin infusion rate. The response areas of plasma thyroxine and triiodothyronine to thyrotropin-releasing hormone injection were blunted (P < 0.01) in PTU-treated sheep compared with those of control sheep. The high PTU treatment induced low thyroid function, enhanced insulin secretion response, and impaired insulin action in sheep.

Topics: Animals; Blood Glucose; Female; Glucose; Glucose Clamp Technique; Hyperglycemia; Hypothyroidism; Insulin; Male; Propylthiouracil; Sheep; Sheep Diseases; Thyroid Gland; Thyroid Hormones; Thyronines; Thyrotropin-Releasing Hormone; Triiodothyronine