The bank robbery analogy as a first approach for understanding basic concepts of synthesis, transport, and mechanism of action of hormones.

Learning endocrine physiology can be challenging. Some physiological concepts are abstract, making the process of learning more difficult for students. The comprehension of basic concepts, such as chemical hormone classification, is essential to understand the differences in synthesis, secretion, transport, and mechanism of action of hormones. To assist the students on this subject, we developed an analogy between the basic concepts of hormone synthesis, transport, and mechanism of action and a bank robbery as a first approach to engage and stimulate their learning process. In the analogy, the students are asked to help identify and characterize two bank robbery crews based on a set of evidence collected by the police. The goal is to identify the general profile of lipid- and water-soluble hormones synthesis, transport, and mechanism of action on target cells. When applying the activity, the students showed a great deal of interest in solving the crime and they seemed to understand the similarities between the analogy and the subject.NEW & NOTEWORTHY Two endocrine bank robbery crews are being searched by the police. As an endocrine system student, you have been summoned to help the police solve the robberies.

CASE FINDING FOR HYPOTHYROIDISM SHOULD INCLUDE TYPE 2 DIABETES AND METABOLIC SYNDROME PATIENTS: A LATIN AMERICAN THYROID SOCIETY (LATS) POSITION STATEMENT.

OBJECTIVE: Latin American Thyroid Society (LATS) Hypothyroidism Clinical Practice Guidelines recommend case finding of hypothyroid patients in multiple and different situations that agree with other Society guidelines. However, the detection of hypothyroidism in type 2 diabetes mellitus (T2DM) or metabolic syndrome (MetS) patients is not mentioned in particular. In the recent years, several basic and epidemiologic studies have appeared showing that a lower thyroid function and MetS/T2DM are associated. Hence, the aim of this review is to manifest the LATS position on the diagnosis of hypothyroidism in both MetS and T2DM patients. METHODS: A search was made in PubMed using the following terms: "hypothyroidism" AND "diabetes" OR "metabolic syndrome." The most relevant studies describing the prevalence and complications due to hypothyroidism in both MetS and T2DM patients were selected. RESULTS: The current document reviews new information from studies that have shown that the prevalence of hypothyroidism is higher in T2DM patients (odds ratio [OR], 3.45; 95% confidence interval [CI], 2.5 to 4.7) and that diabetic complications are more prevalent in subclinical hypothyroidism (ScH). The incidence of T2DM is 1.09-fold higher with each doubling of thyroid-stimulating hormone (TSH) mIU/L (95% CI, 1.06 to 1.12), and the incidence of prediabetes increases 15% (hazard ratio, 1.15; 95% CI, 1.04 to 1.26) in patients with TSH >5 mIU/L. Similarly, MetS is more prevalent in ScH compared to euthyroid individuals (OR, 1.31; 95% CI, 1.08 to 1.60). CONCLUSION: Thyroid function is affected in MetS and T2DM, and hypothyroidism is more common in these patients. Diabetic complications are more frequent in ScH patients. Therefore, LATS now recommends aggressive case finding of hypothyroidism in both MetS and T2DM patients. ABBREVIATIONS: CI = confidence interval; GLUT4 = glucose transporter 4; HOMA-IR = homeostatic model assessment for insulin resistance; HR = hazard ratio; LATS = Latin American Thyroid Society; MetS = metabolic syndrome; OR = odds ratio; ScH = subclinical hypothyroidism; T2DM = type 2 diabetes mellitus; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Evaluation of hypothalamus-pituitary-thyroid axis function by chronic perchlorate exposure in male rats.

Perchlorate is a widespread endocrine disruptor that was previously correlated with increased serum TSH levels and decreased thyroid hormones production both in animals and humans. Even so, the regulation of gene/protein expression in the hypothalamus, pituitary and thyroid by chronic perchlorate exposure was not completely elucidated. Therefore, this study aimed to investigate the underlying mechanisms involved in the disruption of hypothalamus-pituitary-thyroid axis by chronic perchlorate exposure. Male Wistar rats were treated or not with NaClO4 in the drinking water (35 mg/Kg/day) for 60 days. Thereafter, hormone/cytokines serum levels were measured through multiplex assays; genes/proteins expression were investigated by qPCR/Western Blotting and thyroid morphology was evaluated through histological analysis. Serum TSH levels were increased and serum T4 /T3 levels were decreased in perchlorate-treated animals. This treatment also altered the thyrotropin-releasing hormone mRNA/protein content in the hypothalamus. Additionally, the expression of both subunits of TSH were increased in the pituitary of perchlorate-treated rats, which also presented significant alterations in the thyroid morphology/gene expression. Furthermore, perchlorate exposure reduced liver Dio1 mRNA expression and increased the content of pro-inflammatory cytokines in the thyroid and the serum. In conclusion, our study adds novel findings about the perchlorate-induced disruption of the hypothalamus-pituitary-thyroid axis gene/protein expression in male rats. The data presented herein also suggest that perchlorate induces thyroid and systemic inflammation through the increased production of cytokines. Taken together, our results suggest that perchlorate contamination should be monitored, especially in the individuals most susceptible to the deleterious effects of reduced levels of thyroid hormones.

Iodide excess regulates its own efflux: a possible involvement of pendrin.

Adequate iodide supply and metabolism are essential for thyroid hormones synthesis. In thyrocytes, iodide uptake is mediated by the sodium-iodide symporter, but several proteins appear to be involved in iodide efflux. Previous studies demonstrated that pendrin is able to mediate apical efflux of iodide in thyrocytes. Acute iodide excess transiently impairs thyroid hormone synthesis, a phenomenon known as the Wolff-Chaikoff effect. Although the escape from this inhibitory effect is not completely understood, it has been related to the inhibition of sodium-iodide symporter-mediated iodide uptake. However, the effects of iodide excess on iodide efflux have not been characterized. Herein, we investigated the consequences of iodide excess on pendrin abundance, subcellular localization, and iodide efflux in rat thyroid PCCl3 cells. Our results indicate that iodide excess increases pendrin abundance and plasma membrane insertion after 24 h of treatment. Moreover, iodide excess increases pendrin half-life. Finally, iodide exposure also increases iodide efflux from PCCl3 cells. In conclusion, these data suggest that pendrin may have an important role in mediating iodide efflux in thyrocytes, especially under conditions of iodide excess.

Iron restriction increases myoglobin gene and protein expression in Soleus muscle of rats.

Iron is an important trace element for proper cell functioning. It is present in cytochromes, hemoglobin and myoglobin (Mb), where it binds to oxygen. It is also an electron acceptor in the respiratory chain. Mb is an 18 kDa heme-protein, highly expressed in skeletal muscle and heart. The expression of several genes involved in the metabolism of iron is post-transcriptionally regulated by this element. Iron was shown to interfere with the polyadenylation step, modifying their poly (A) tail length and, as a consequence, their stability and translation rate. The aim of this study was to investigate whether iron supplementation or long and short-term restriction affects Mb gene and protein expression, as well as Mb mRNA poly(A) tail length, in cardiac and skeletal muscles of rats. Long-term iron restriction caused an increase in Mb gene and protein expression in Soleus muscle. No changes were observed in extensor digitorum longus muscle and heart. Short-term iron supplementation after iron deprivation did not alter Mb gene expression and mRNA poly(A) tail length in all tissues studied. These results indicate that Mb gene and protein expression is upregulated in response to iron deprivation, an effect that is tissue-specific and seems to occur at transcriptional level.

Winter course in physiology: a successful example of continuing education for secondary school teachers in Brazil.

In international surveys, Brazilian students have been consistently ranking low in science. Continuing education for secondary school teachers is certainly a way to change this situation. To update teachers and provide teaching and learning experiences for graduate students, our department organized a "Winter Course in Physiology" where schoolteachers had the opportunity to attend lectures that were offered by graduate students and participate in discussions on teaching and learning strategies and their applicability, considering different schools and student age groups. This work evaluated the ways in which the Winter Course in Physiology improves continuing education for secondary school teachers. Graduate students prepared, presented, and discussed with the audience the concepts, content, and topics of the program, which were previously presented to the organizing committee and a supervising professor. Potential participants were recruited based on their curriculum vitae and a letter of intent. During the course, they completed a questionnaire that graded different aspects of course organization and lectures. The results indicated that the Winter Course was positively evaluated. Most topics received a grade of ≥4.0, considering a range of 1.0 (low) to 5.0 (high). In a followup, both the participants and instructors reported positive impacts on their overall knowledge in physiology. Schoolteachers reported improvements in the performance and participation of their students. In conclusion, the results suggested that the Winter Course is a good way to promote continuing education for schoolteachers and promote university outreach. It also provided an important experience for graduate students to develop teaching skills.

Therapeutical Potential of T3 as Adjuvant Therapy in Male Alloxan-induced Diabetic Rats.

Alloxan-induced diabetic rats present with hypothyroidism. When treated with triiodothyronine (T3), glycemia and proinflammatory cytokine expression are downregulated, improving insulin sensitivity. The effectiveness of associating T3 with insulin (replacement dose [6 U] and [3 U]) in controlling glycemia was investigated in this experimental model. Male Wistar rats were made diabetic by alloxan injection and sorted into groups treated or not with insulin (3 or 6 U) associated or not with T3 (1.5 µg 100 g-1 BW) for 28 days. Nondiabetic rats constituted the control group. Fasting glycemia, glucose decay rate, and thyrotropin (TSH) were measured in the blood/serum of all animals. Immunoblotting was used to assess total GLUT4 expression in skeletal muscles and epididymal white adipose tissue. Cytokine and nuclear factor-κB (NF-κB) expression were measured in these tissues and liver. Diabetic rats presented with increased fasting glycemia, inflammatory cytokines, and NF-κB expression, TSH levels, and insulin resistance. In diabetic rats treated with T3 and/or insulin, these parameters were decreased, whereas GLUT4 and anti-inflammatory cytokine expression were increased. T3 combined with 3-U insulin restored the parameters to values of the control group and was more effective at controlling glycemia than 6-U insulin. Thus, a combination of T3 and insulin might represent a promising strategy for diabetes management since it reduces the insulin requirement by half and improves glycemic control of diabetic rats, which could postpone insulin resistance that develops with chronic insulin administration. These findings open a perspective for using thyroid analogues that provide tissue-specific effects, which might result in a potentially more effective treatment of diabetes.

Glyphosate impairs male offspring reproductive development by disrupting gonadotropin expression.

Sexual differentiation in the brain takes place from late gestation to the early postnatal days. This is dependent on the conversion of circulating testosterone into estradiol by the enzyme aromatase. The glyphosate was shown to alter aromatase activity and decrease serum testosterone concentrations. Thus, the aim of this study was to investigate the effect of gestational maternal glyphosate exposure (50 mg/kg, NOAEL for reproductive toxicity) on the reproductive development of male offspring. Sixty-day-old male rat offspring were evaluated for sexual behavior and partner preference; serum testosterone concentrations, estradiol, FSH and LH; the mRNA and protein content of LH and FSH; sperm production and the morphology of the seminiferous epithelium; and the weight of the testes, epididymis and seminal vesicles. The growth, the weight and age at puberty of the animals were also recorded to evaluate the effect of the treatment. The most important findings were increases in sexual partner preference scores and the latency time to the first mount; testosterone and estradiol serum concentrations; the mRNA expression and protein content in the pituitary gland and the serum concentration of LH; sperm production and reserves; and the height of the germinal epithelium of seminiferous tubules. We also observed an early onset of puberty but no effect on the body growth in these animals. These results suggest that maternal exposure to glyphosate disturbed the masculinization process and promoted behavioral changes and histological and endocrine problems in reproductive parameters. These changes associated with the hypersecretion of androgens increased gonadal activity and sperm production.

Short-term creatine supplementation decreases reactive oxygen species content with no changes in expression and activity of antioxidant enzymes in skeletal muscle.

The effect of short-term creatine (Cr) supplementation upon content of skeletal muscle-derived-reactive oxygen species (ROS) was investigated. Wistar rats were supplemented with Cr (5 g/kg BW) or vehicle, by gavage, for 6 days. Soleus and extensor digitorum longus (EDL) muscles were removed and incubated for evaluation of ROS content using Amplex-UltraRed reagent. The analysis of expression and activity of antioxidant enzymes (superoxide dismutase 1 and 2, catalase and glutathione peroxidase) were performed. Direct scavenger action of Cr on superoxide radical and hydrogen peroxide was also investigated. Short-term Cr supplementation attenuated ROS content in both soleus and EDL muscles (by 41 and 33.7%, respectively). Cr supplementation did not change expression and activity of antioxidant enzymes. Basal TBARS content was not altered by Cr supplementation. In cell-free experiments, Cr showed a scavenger effect on superoxide radical in concentrations of 20 and 40 mM, but not on hydrogen peroxide. These results indicate that Cr supplementation decreases ROS content in skeletal muscle possibly due to a direct action of Cr molecule on superoxide radical.

Metabolic and functional effects of beta-hydroxy-beta-methylbutyrate (HMB) supplementation in skeletal muscle.

Beta-hydroxy-beta-methylbutyrate (HMB) is a metabolite derived from leucine. The anti-catabolic effect of HMB is well documented but its effect upon skeletal muscle strength and fatigue is still uncertain. In the present study, male Wistar rats were supplemented with HMB (320 mg/kg per day) for 4 weeks. Placebo group received saline solution only. Muscle strength (twitch and tetanic force) and resistance to acute muscle fatigue of the gastrocnemius muscle were evaluated by direct electrical stimulation of the sciatic nerve. The content of ATP and glycogen in red and white portions of gastrocnemius muscle were also evaluated. The effect of HMB on citrate synthase (CS) activity was also investigated. Muscle tetanic force was increased by HMB supplementation. No change was observed in time to peak of contraction and relaxation time. Resistance to acute muscle fatigue during intense contractile activity was also improved after HMB supplementation. Glycogen content was increased in both white (by fivefold) and red (by fourfold) portions of gastrocnemius muscle. HMB supplementation also increased the ATP content in red (by twofold) and white (1.2-fold) portions of gastrocnemius muscle. CS activity was increased by twofold in red portion of gastrocnemius muscle. These results support the proposition that HMB supplementation have marked change in oxidative metabolism improving muscle strength generation and performance during intense contractions.

Perchlorate, nitrate, and thiocyanate: Environmental relevant NIS-inhibitors pollutants and their impact on thyroid function and human health.

Thyroid disruptors are found in food, atmosphere, soil, and water. These contaminants interfere with the thyroid function through the impairment of thyroid hormone synthesis, plasma transport, peripheral metabolism, transport into the target cells, and thyroid hormone action. It is well known that iodide uptake mediated by the sodium-iodide symporter (NIS) is the first limiting step involved in thyroid hormones production. Therefore, it has been described that several thyroid disruptors interfere with the thyroid function through the regulation of NIS expression and/or activity. Perchlorate, nitrate, and thiocyanate competitively inhibit the NIS-mediated iodide uptake. These contaminants are mainly found in food, water and in the smoke of cigarettes. Although the impact of the human exposure to these anions is highly controversial, some studies indicated their deleterious effects in the thyroid function, especially in individuals living in iodine deficient areas. Considering the critical role of thyroid function and the production of thyroid hormones for growth, metabolism, and development, this review summarizes the impact of the exposure to these NIS-inhibitors on thyroid function and their consequences for human health.

Resistance training prevents damage to the mitochondrial function of the skeletal muscle of rats exposed to secondary cigarette smoke.

AIM: To analyze the consumption of oxygen and to quantify the mitochondrial respiratory chain proteins (OXPHOS) in the gastrocnemius muscle of rats exposed to cigarette smoke and/or RT practitioners. MAIN METHODS: Wistar rats were divided into groups: Control (C), Smoker (S), Exercise (E) and Exercise Smoker (ES). Groups F and ES were exposed to the smoke of 4 cigarettes for 30 min, 2× a day, 5× a week, for 16 weeks. Groups E and ES performed four climbs with progressive load, 1× per day, 5× per week, for 16 weeks. The gastrocnemius muscle was collected for analysis of OXPHOS content and oxygen consumption. Groups S (vs. C) and ES (vs. C and E) showed lower body weight gain when observing the evolution curve. KEY FINDINGS: The S rats showed a reduction in the NDUFB8 proteins of complex 1, SDHB of complex 2, MTC01 of complex 4 and ATP5A of complex 5 (ATP Synthase) compared to Group C. Additionally, S rats also showed increased consumption of O2 in Basal, Leak, Complex I and I/II combined measures compared to the other groups, suggesting that the activity of the mitochondria of these animals increased in terms of coupling and uncoupling parameters. SIGNIFICANCE: Our data suggest that exposure to cigarette smoke for 16 weeks is capable of causing impairment of mitochondrial function with reduced expression of respiratory chain proteins in skeletal muscle. However, the RT was effective in preventing impairment of mitochondrial function in the skeletal muscle of rats exposed to secondary cigarette smoke.

The case of thyroid hormones: how to learn physiology by solving a detective case.

Thyroid diseases are prevalent among endocrine disorders, and careful evaluation of patients' symptoms is a very important part in their diagnosis. Developing new pedagogical strategies, such as problem-based learning (PBL), is extremely important to stimulate and encourage medical and biomedical students to learn thyroid physiology and identify the signs and symptoms of thyroid dysfunction. The present study aimed to create a new pedagogical approach to build deep knowledge about hypo-/hyperthyroidism by proposing a hands-on activity based on a detective case, using alternative materials in place of laboratory animals. After receiving a description of a criminal story involving changes in thyroid hormone economy, students collected data from clues, such as body weight, mesenteric vascularization, visceral fat, heart and thyroid size, heart rate, and thyroid-stimulating hormone serum concentration to solve the case. Nevertheless, there was one missing clue for each panel of data. Four different materials were proposed to perform the same practical lesson. Animals, pictures, small stuffed toy rats, and illustrations were all effective to promote learning, and the detective case context was considered by students as inviting and stimulating. The activity can be easily performed independently of the institution's purchasing power. The practical lesson stimulated the scientific method of data collection and organization, discussion, and review of thyroid hormone actions to solve the case. Hence, this activity provides a new strategy and alternative materials to teach without animal euthanization.

Expression and Role of Thyrotropin Receptors in Proopiomelanocortin-Producing Pituitary Cells.

Background: Thyrotropin (TSH) is well known as the hormone of the anterior pituitary thyrotrophs responsible for acting in the thyroid gland, where it stimulates synthesis and release of thyroid hormones through Gs and Gq/11 protein coupled TSH receptors (TSHRs). Methods: In this study, we examined whether the functional TSHRs are also expressed in cultured rat pituitary cells, using double immunocytochemistry, quantitative reverse transcription-polymerase chain reaction analysis, cAMP and hormone measurements, and single-cell calcium imaging. Results: Double immunocytochemistry revealed the expression of TSHRs in cultured corticotrophs and melanotrophs, in addition to previously identified receptors in folliculostellate cells. The functional coupling of these receptors to the Gq/11 signaling pathway was not observed, as demonstrated by the lack of TSH activation of IP3-dependent calcium mobilization in these cells when bathed in calcium-deficient medium. However, TSH increased cAMP production in a time- and concentration-dependent manner and facilitated calcium influx in single corticotrophs and melanotrophs, indicating their coupling to the Gs signaling pathway. Consistent with these findings, TSH stimulated adrenocorticotropin and ß-endorphin release in male and female pituitary cells in a time- and concentration-dependent manner without affecting the expression of proopiomelanocortin gene. Conclusions: These results indicate that TSH is a potential paracrine modulator of anterior pituitary corticotrophs and melanotrophs, controlling the exocytotic but not the transcriptional pathway in a cAMP/calcium influx-dependent manner.

Resistance training mitigates hepato-cardiac changes and muscle mitochondrial protein reductions in rats with diet-induced obesity.

AIM: To investigate the effect of resistance training (RT) on hepatocardiovascular and muscle mitochondrial parameters in rats that were fed a high-calorie diet for 12 weeks. MAIN METHODS: The animals were divided into four groups: control (C), exercise (E), obese (O), and obese plus exercise (OE). Group E and OE rats performed resistance training by climbing on a vertical ladder with load attached to the end of the tail (1×/day, 3×/week, for 12 weeks). Group O and OE rats were fed a high-calorie diet containing chow and a cafeteria diet for 12 weeks. Under anesthesia, the heart and liver were removed for histopathological analysis, and the gastrocnemius muscle was removed for Western blotting. KEY FINDINGS: Group O rats were heavier, with increased fat mass, elevated fasting glycemia, and total triglycerides, and exhibited a significant number of Kupffer cells and diffuse steatosis in the liver. Group O rats also showed increased thickness of the right ventricle, septum, and pulmonary artery. All of these parameters were attenuated by RT. PGC1-α protein levels were increased in both exercise groups. The protein levels of OXPHOS complexes III, IV, and V were reduced in Group O, while RT prevented this alteration. SIGNIFICANCE: RT exerts a protective effect against hepato-cardiac alterations and prevents changes in the muscle mitochondrial protein profile induced by a high-calorie diet.

Posttranscriptional regulation of sodium-iodide symporter mRNA expression in the rat thyroid gland by acute iodide administration.

Iodide is an important regulator of thyroid activity. Its excess elicits the Wolff-Chaikoff effect, characterized by an acute suppression of thyroid hormone synthesis, which has been ascribed to serum TSH reduction or TGF-beta increase and production of iodolipids in the thyroid. These alterations take hours/days to occur, contrasting with the promptness of Wolff-Chaikoff effect. We investigated whether acute iodide administration could trigger events that precede those changes, such as reduction of sodium-iodide symporter (NIS) mRNA abundance and adenylation, and if perchlorate treatment could counteract them. Rats subjected or not to methylmercaptoimidazole treatment (0.03%) received NaI (2,000 microg/0.5 ml saline) or saline intraperitoneally and were killed 30 min up to 24 h later. Another set of animals was treated with iodide and perchlorate, in equimolar doses. NIS mRNA content was evaluated by Northern blotting and real-time PCR, and NIS mRNA poly(A) tail length by rapid amplification of cDNA ends-poly(A) test (RACE-PAT). We observed that NIS mRNA abundance and poly(A) tail length were significantly reduced in all periods of iodide treatment. Perchlorate reversed these effects, indicating that iodide was the agent that triggered the modifications observed. Since the poly(A) tail length of mRNAs is directly associated with their stability and translation efficiency, we can assume that the rapid decay of NIS mRNA abundance observed was due to a reduction of its stability, a condition in which its translation could be impaired. Our data show for the first time that iodide regulates NIS mRNA expression at posttranscriptional level, providing a new mechanism by which iodide exerts its autoregulatory effect on thyroid.

Impaired Gene Expression Due to Iodine Excess in the Development and Differentiation of Endoderm and Thyroid Is Associated with Epigenetic Changes.

Background: Thyroid hormone (TH) synthesis is essential for the control of development, growth, and metabolism in vertebrates and depends on a sufficient dietary iodine intake. Importantly, both iodine deficiency and iodine excess (IE) impair TH synthesis, causing serious health problems especially during fetal/neonatal development. While it is known that IE disrupts thyroid function by inhibiting thyroid gene expression, its effects on thyroid development are less clear. Accordingly, this study sought to investigate the effects of IE during the embryonic development/differentiation of endoderm and the thyroid gland. Methods: We used the murine embryonic stem (ES) cell model of in vitro directed differentiation to assess the impact of IE on the generation of endoderm and thyroid cells. Additionally, we subjected endoderm and thyroid explants obtained during early gestation to IE and evaluated gene and protein expression of endodermal markers in both models. Results: ES cells were successfully differentiated into endoderm cells and, subsequently, into thyrocytes expressing the specific thyroid markers Tshr, Slc5a5, Tpo, and Tg. IE exposure decreased the messenger RNA (mRNA) levels of the main endoderm markers Afp, Crcx4, Foxa1, Foxa2, and Sox17 in both ES cell-derived endoderm cells and embryonic explants. Interestingly, IE also decreased the expression of the main thyroid markers in ES cell-derived thyrocytes and thyroid explants. Finally, we demonstrate that DNA methyltransferase expression was increased by exposure to IE, and this was accompanied by hypermethylation and hypoacetylation of histone H3, pointing to an association between the gene repression triggered by IE and the observed epigenetic changes. Conclusions: These data establish that IE treatment is deleterious for embryonic endoderm and thyroid gene expression.

Effect of thyroid hormones on rat exocrine pancreas morphology and function.

AIM: The influence of thyroid hormones on exocrine pancreas function is poorly understood, and limited to the postnatal development period. Here, we evaluated the effects of hypo- and hyperthyroidism on the morphology and enzyme content of this tissue. MAIN METHODS: To induce hypothyroidism male Wistar rats were subjected to a thyroidectomy (Tx) or sham operated (SO). After 40 days, some of the Tx and SO rats were treated with T3 for 7 days. Following euthanization, the pancreas was removed and evaluated for morphology, as well as amylase, lipase and trypsin content, using histological and immunoreactive techniques analyses, respectively. Serum amylase levels were also evaluated. KEY FINDINGS: The pancreatic acinar cells of Tx rats were smaller, exhibited reduced Haematoxyllin stained areas, and contained lower amylase and lipase levels, indicative of low cell activity. Tx rats also presented higher collagen levels, and high trypsin content in pancreatic extracts. Interestingly, T3 administration reversed the observed acinar cell alterations and restored pancreatic enzyme content, by augmenting amylase and lipase and attenuating trypsin levels, but failed to change collagen content. Increased levels of lipase and decreased trypsin were also observed in T3-treated SO rats. SIGNIFICANCE: Thyroid hormones play an important role in acinar cell morphology and function. In the hypothyroid state there is a decrease in pancreatic enzyme levels that is restored with T3 treatment. In addition to participating in insulin sensitivity and glycemic control, THs also modulate enzyme expression and activity in the exocrine pancreas, consequently, delivering metabolic substrates to specific organs and tissues.

The insulin resistance is reversed by exogenous 3,5,3'triiodothyronine in type 2 diabetic Goto-Kakizaki rats by an inflammatory-independent pathway.

PURPOSE: Diabetes mellitus (DM) has a multifactorial etiology that imparts a particular challenge to effective pharmacotherapy. Thyroid hormone actions have demonstrated beneficial effects in diabetic as well as obese rats. In both conditions, inflammation status plays a crucial role in the development of insulin resistance. Taking this into consideration, the present study aimed to demonstrate another possible pathway of thyroid hormone action on insulin sensitivity in a spontaneous type 2 diabetic rat model: the Goto-Kakizaki (GK) rats. GK animals present all typical hallmarks of type 2 DM (T2DM), except the usual peripheric inflammatory condition, observed in the other T2DM animal models. METHODS: GK rats were treated or not with 3,5,3'triiodothyronine (T3). Insulin sensitivity, glucose tolerance, and proteins related to glucose uptake and utilization were evaluated in the skeletal muscle, white adipose tissue, and liver. RESULTS: GK rats T3-treated presented enhanced insulin sensitivity, increased GLUT-4 content in the white adipose tissue and skeletal muscle, and increased hexokinase and citrate synthase content in skeletal muscle. Both non-treated and T3-treated GK rats did not present alterations in cytokine content in white adipose tissue, skeletal muscle, liver, and serum. CONCLUSIONS: These results indicate that T3 improves insulin sensitivity in diabetic rats by a novel inflammatory-independent mechanism.

Disruption of the Pituitary Circadian Clock Induced by Hypothyroidism and Hyperthyroidism: Consequences on Daily Pituitary Hormone Expression Profiles.

BACKGROUND: The secretion of pituitary hormones oscillates throughout the 24-hour period, indicating that circadian clock-mediated mechanisms regulate this process in the gland. Additionally, pituitary hormone synthesis has been shown to be altered in hypo- and hyperthyroidism. Although thyroid hormones can modulate the other peripheral clocks, the interaction between thyroid hormone levels and circadian clock gene expression in the anterior pituitary has yet to be elucidated. METHODS: Male Wistar rats were divided into three groups: control, hypothyroid, and hyperthyroid. Following the experimental procedures, animals were euthanized every three hours over the course of a 24-hour period. The anterior pituitary glands were excised and processed for mRNA expression analysis by quantitative reverse transcriptase polymerase chain reaction. One- and two-way analysis of variance as well as cosinor analysis were used to evaluate the time-of-day-dependent differential expression for each gene in each experimental group and their interactions. RESULTS: Hyperthyroidism increased the mRNA expression of core clock genes and thyrotrophic embryonic factor (Tef), as well as the mesor and amplitude of brain and muscle Arnt-like protein-1 (Bmal1) and the mesor of nuclear receptor subfamily 1 (Nr1d1) group D member 1, when compared to euthyroid animals. Hypothyroidism disrupted the circadian expression pattern of Bmal1 and period circadian regulator 2 (Per2) and decreased the mesor of Nr1d1 and Tef. Furthermore, it was observed that the pituitary content of Dio2 mRNA was unaltered in hyperthyroidism but substantially elevated in hypothyroidism during the light phase. The upregulated expression was associated with an increased mesor and amplitude, along with an advanced acrophase. The gene expression of all the pituitary hormones was found to be altered in hypo- and hyperthyroidism. Moreover, prolactin (Prl) and luteinizing hormone beta subunit (Lhb) displayed circadian expression patterns in the control group, which were disrupted in both the hypo- and hyperthyroid states. CONCLUSION: Taken together, the data demonstrate that hypo- and hyperthyroidism alter circadian clock gene expression in the anterior pituitary. This suggests that triiodothyronine plays an important role in the regulation of pituitary gland homeostasis, which could ultimately influence the rhythmic synthesis and/or secretion of all the anterior pituitary hormones.