Roles of endothelin-1 and nitric oxide in the paracrine/autocrine regulation of the thyroid gland

The biological importance of the thyroid gland has been recognized for centuries. For instance, the discovery in the late 19th century that cretinism results from thyroid dysfunction led to the identification of thyroid hormones (T3 and T4) in early years of our century. Thyroid hormones play a vital role in fetal development, and throughout life, they influence major metabolic processes in almost all organs. Their synthesis depends primarily upon the regular availability of a trace element, iodine, present in the human body in minute amounts. The adequate uptake of iodide by the thyroid follicular cells represents not only a limiting step in the thyroid hormone synthesis, but also a prerequisite to insure the near constancy of the rate of thyroid hormone synthesis and secretion. To face wide fluctuations in the supply of iodine, adaptive autoregulatory mechanisms are activated within the gland. One may, thus, consider endemic goiter as an adaptive process that occurs in response to insufficient supply of dietary iodine. The thyroid enlargement characterized by the typical hyperplastic picture including all cellular compartments (epithelial and stromal), as it is observed at the early stages of goiter formation (before the appearance of nodules), represents an examples of a coordinated nonneoplastic growth. The proliferation of stromal cells is mainly reflected in increased vascularity and blood flow secondary to the expansion of the capillary bed. Besides the obvious influx of nutrients, changes in the thyroid micro-vasculature can also modulate the availability of iodide load to epithelial cells, hence their ability to synthesize thyroid hormones and highlights the role of the thyroid vascular compartment on the maintenance of the general thyroid hormone economy. The mechanisms underlying the integrated processes leading to the coordinated growth between parenchyma and stromal cells are being to be elucidated. Although TSH is classically considered as the main trophic factor of the gland, it clearly appeared during the last 10-15 years that growing processes imply local cross-talks between the different thyroid cell populations mediated by a highly intricated network of locally-released factors acting on a paracrine and/or autocrine mode of action. Although some factors were already identified when we started the project, other candidates appeared of interest. Thus, we hypothesized that newly discovered vasoactive factors; endothelins, and nitric oxide, could play an important role in the control of the thyroid microvasculature and secondarily on several aspects of thyroid function and growth. In the present thesis, we present evidences for their local production and propose potential roles in the thyroid gland. The first chapter contains background informations about thyroid hormones synthesis and peripheral mode of action, about TSH- and non TSH-dependent control of thyroid gland and function. The role of iodine is specifically emphasized, based on personal results. The main morphological and physiological aspects of vascular changes occurring during goiter formation and involution are reviewed. In the second chapter, the specific aims of the study are exposed, based on data of the literature available at the time we started the project, as well as on the rationale that led us to propose that endothelins and nitric oxide could be endogenously synthesized factors regulating the thyroid vasculature. In the third chapter, general informations related to the endothelins and their roles in endocrine organs other than the thyroid gland are reviewed. We also present our personal data related to the identification of endothelin-related proteins and gene expression in the rat thyroid gland and their modifications in an experimental model of goiter formation and involution. The involvement of endothelins in the maintenance of thyroid growth and function is then proposed. The fourth chapter is built on the same template than the third chapter (a review on the general properties of nitric oxide and on its roles in diverse endocrine organs), but we aim to present evidences for the local production of nitric oxide in the thyroid gland (human and rat) by locally active nitric oxide synthases. We then propose at the end of this chapter a theory based on the assumption that increased production of nitric oxide at the early stages or goiter formation could be the initial step leading to the expansion if the thyroid vasculature. In the last chapter, our main findings are summarized, and new perspectives for this project are presentedThèse d'agrégation de l'enseignement supérieur (faculté de médecine) -- UCL, 199

Diabète sucré comme manifestation inaugurale d’un phéochromocytome : à propos de deux cas cliniques

Le diabète sucré survient rarement dans le décours d’une autre endocrinopathie. Nous rapportons l’histoire clinique de deux patients non-obèses d’environ 50 ans ayant développé un diabète non-insulinodépendant. L’imagerie abdominale a débouché sur la découverte fortuite d’un phéochromocytome. Quoique ces tumeurs surrénaliennes se manifestent d’ordinaire par des céphalées, des palpitations, de la sudation profuse et de l’hypertension, les hormones catécholaminergiques peuvent aussi altérer le métabolisme glucidique à cause de leurs actions sur les récepteurs α- et β-adrénergiques du pancréas. L‘exérèse chirurgicale mène habituellement à la rémission du diabète. Ces cas cliniques permettent de rappeler l’importance d’un bilan étiologique exhaustif en cas de diabète atypique[Diabetes mellitus as the initial manifestation of pheochromocytoma: Report of two clinical cases] In rare cases, diabetes mellitus is actually secondary to another endocrinopathy. We report the clinical cases of two middle-aged, non-obese patients who developed non-insulin-dependent diabetes. Abdominal imaging led to the incidental discovery of a pheochromocytoma. These adrenal tumors usually manifest themselves by headaches, palpitations, sweating, and hypertension. Yet catecholamine hormones may also impact glucose metabolism due to their actions on pancreatic a- and p-adrenergic receptors. Surgical resection usually leads to diabetes remission. These clinical reports highlight the requirement for a full etiological investigation in alypical diabetes cases

Patient-Reported Outcomes with Insulin Glargine 300 U/mL in People with Type 2 Diabetes: The MAGE Multicenter Observational Study.

peer reviewedINTRODUCTION: MAGE was a Multicenter, single-Arm, observational 6-month (plus 6-month extension) study that aimed to assess treatment satisfaction, efficacy, and safety of insulin Glargine 300 U/mL (Gla-300) in people with type 2 diabetes (T2DM) receiving basal-bolus insulin in a rEal-world setting. MATERIALS AND METHODS: Participants were at least 18 years old, with T2DM for more than 1 year, HbA(1c) 7.0-10.0%. The primary endpoint was change in Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) total score (baseline to month 6). Secondary endpoints included reasons for starting Gla-300, changes in the DTSQ change version (DTSQc) total score, Hypoglycemia Fear Survey-II (HFS-II) total behavior and worry scores at months 6 and 12, HbA(1c) changes at months 3, 6, 9, and 12, and safety. RESULTS: MAGE included 87 adults (mean T2DM duration 17 years). The primary endpoint of DTSQs mean (standard deviation) total score improvement at month 6 was achieved (2.80 [5.46] points; p < 0.0001). The main reasons for Gla-300 initiation were to decrease HbA(1c) (89.7% of participants) and reduce the number of hypoglycemic events (35.6% of participants). Significant improvements were observed in the DTSQc total score and perceived hyperglycemia/hypoglycemia (baseline to month 6, p < 0.05). Significant changes in HFS-II behavior, worry, and total scores at 6 and 12 months were also observed (p < 0.05). There were no statistically significant changes in HbA(1c). Safety outcomes, including hypoglycemia, were comparable to previously reported trials. CONCLUSIONS: The MAGE study indicates that Gla-300, as part of a basal-bolus regimen, results in improved treatment satisfaction and reduced hypoglycemia fear in people with advanced T2DM

Effet du paracétamol sur la pression artérielle moyenne de patients hospitalisés en réanimation. Influence de la voie d'administration, orale ou intraveineuse

The aim of the study was to evaluate the consequences of the administration of paracetamol on the mean arterial pressure (MAP) of patients hospitalized in an intensive care unit, as well as the influence of the route of administration (oral vs. IV). This is an observational, prospective, and single center study that has been carried out in the medical and surgical intensive care unit (ICU) of the Centre Hospitalier de Jolimont, Haine Saint-Paul (Belgium). A cohort of 107 consecutive patients was collated over a period of three months. A group of 75 patients (group 1) received an unique dose of 1g of paracetamol intravenously and was compared to a group of 32 patients (group 2) who received the same dose orally (effervescent tablets). MAP was recorded either non-invasively (cuff), or with invasive means (arterial line), before (T0) and 15, 30, 45, 60, 90, and 120 min after administration of the drug. In both groups, the administration of paracetamol resulted in a drop of MAP of 10 to 20% in 30 patients (28% of the cohort), 20% to 40% in 23 patients (21%) and over 40% in 4 patients (3.7%). Six patients (5%) had to be treated by fluid replacement or vasopressors during the observation period. No significant difference in regard to the magnitude of the fall of MAP was noted between the two groups. The kinetics of the fall in blood pressure was essentially identical in both groups with a decrease of 5-6% occurring already at 30 min. Beyond 30 min, the MAP stabilized in group 1 with the blood pressure nadir observed at 30 min, whereas it tended to further decrease in group 2 with a delayed blood pressure nadir (-10% vs. T0) in the ninetieth minute. We believe that this observation is important as it draws the attention on the need for a strict hemodynamic monitoring in the many patients hospitalized in ICU and receiving paracetamol and on the anticipation it implies about the vigilance of the medical staff to quickly address these hemodynamic changes.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Recent insights into the cell biology of thyroid angiofollicular units.

In thyrocytes, cell polarity is of crucial importance for proper thyroid function. Many intrinsic mechanisms of self-regulation control how the key players involved in thyroid hormone (TH) biosynthesis interact in apical microvilli, so that hazardous biochemical processes may occur without detriment to the cell. In some pathological conditions, this enzymatic complex is disrupted, with some components abnormally activated into the cytoplasm, which can lead to further morphological and functional breakdown. When iodine intake is altered, autoregulatory mechanisms outside the thyrocytes are activated. They involve adjacent capillaries that, together with thyrocytes, form the angiofollicular units (AFUs) that can be considered as the functional and morphological units of the thyroid. In response to iodine shortage, a rapid expansion of the microvasculature occurs, which, in addition to nutrients and oxygen, optimizes iodide supply. These changes are triggered by angiogenic signals released from thyrocytes via a reactive oxygen species/hypoxia-inducible factor/vascular endothelial growth factor pathway. When intra- and extrathyrocyte autoregulation fails, other forms of adaptation arise, such as euthyroid goiters. From onset, goiters are morphologically and functionally heterogeneous due to the polyclonal nature of the cells, with nodules distributed around areas of quiescent AFUs containing globules of compact thyroglobulin (Tg) and surrounded by a hypotrophic microvasculature. Upon TSH stimulation, quiescent AFUs are activated with Tg globules undergoing fragmentation into soluble Tg, proteins involved in TH biosynthesis being expressed and the local microvascular network extending. Over time and depending on physiological needs, AFUs may undergo repetitive phases of high, moderate, or low cell and tissue activity, which may ultimately culminate in multinodular goiters

Iodine deficiency induces a VEGF-dependent microvascular response in salivary glands and in the stomach

Despite efforts to optimize iodine supply in iodine deficient countries, iodine deficiency (ID) remains a global problem worldwide. Activation of the local microvasculature by ID in the thyroid gland aims at improving the local supply of iodide. For this purpose, the thyrocytes secrete vascular endothelial growth factor (VEGF) that acts on adjacent capillaries, via a reactive oxygen species (ROS)/Hypoxia Inducible factor (HIF)- dependent pathway. Beside the thyroid, other organs including salivary glands and the stomach do express the sodium/iodide symporter (NIS) and are able to take iodide up, potentially rendering them sensitive to ID. To verify this hypothesis, ID-induced effects on the local microvasculature were studied in salivary glands and in the stomach. ID was induced by feeding young mice with an iodide-deficient diet and NIS inhibitor perchlorate in the drinking water. In salivary glands, ID induced a transient increase in HIF-1α protein expression accompanied by a transient, VEGFdependent increase in blood flow. In the gastric mucosa, ID transiently increased VEGF expression in the mucinsecreting epithelium and in ghrelin-secreting endocrine cells. These observations suggest that microvascular changes in response to ID occur in NIS-expressing tissues other than the thyroid. NIS expressing cells could be viewed as iodide sensors that respond to ID by inducing vascular changes, probably to optimize iodide bioavailability at regional or systemic levels