Effect of Ghrelin on Glucose-Insulin Homeostasis: Therapeutic Implications

Ghrelin is a 28-amino-acid peptide that displays a strong growth hormone- (GH-) releasing activity through the activation of the growth hormone secretagogue receptor (GHSR). The first studies about role of ghrelin were focused on its orexigenic ability, but despite indisputable pharmacological data, the evidence for a physiological role for ghrelin in the control of appetite is much less clear. Mice with targeted deletion of either ghrelin or the GHSR exhibit an essentially normal metabolic phenotype when fed a regular chow diet, suggesting that ghrelin may have a redundant role in the regulation of food intake. RNAs for ghrelin as well as GHSR are expressed in the pancreas of rats and humans and several studies propose that ghrelin could have an important function in glucose homeostasis and insulin release, independent of GH secretion. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin. For this reason, at least theoretically, ghrelin and/or its signalling manipulation could be useful for the treatment or prevention of diseases of glucose homeostasis such as type 2 diabetes

Ghrelin and growth hormone secretagogues, physiological and pharmacological aspect

[Abstract] The first “growth hormone secretagogues” (GHSs) were discovered by Bowers et al. in 1977. In 1996 the GHSs receptor (GHS-R 1a) was cloned. The endogenous ligand for this receptor, ghrelin, was not identified until 1999. Synthetic molecules termed GHSs are substances that stimulate growth hormone (GH) release, via a separate pathway distinct from GH releasing hormone (GHRH)/somatostatin. Ghrelin displays strong GH-releasing activity through the activation of the GHS-R 1a. Apart from stimulating GH secretion, ghrelin and many synthetic GHSs: 1) stimulate prolactin and ACTH secretion; 2) negatively influence the pituitary-gonadal axis; 3) stimulate appetite and positive energy balance; 4) modulate pancreatic endocrine function and affect glucose levels; 5) have cardiovascular actions. The control of ghrelin secretion is not well established at present, although nutrition is an important regulator. Investigators have exploited the ability of GHSs and ghrelin to release GH by mechanisms different from GHRH as a diagnostic tool, which is the present main clinical use of some GHSs. As an alternative to GH, GH deficient conditions could be treated with any substance which would release endogenous GH, such as synthetic GHSs. It is likely that GHSs, acting as either agonists or antagonists on different pathophysiological processes, might have some other clinical impact and therapeutic potential. At least theoretically ghrelin receptor antagonists could be anti-obesity drugs, as blockers of the orexigenic signal from the gastrointestinal tract to the brain. Inverse agonists of the ghrelin receptor, by blocking the constitutive receptor activity, might lower the set-point for hunger between meals.Instituto de Salud Carlos III; PI021479Instituto de Salud Carlos III; PI051024Instituto de Salud Carlos III; PI050983Instituto de Salud Carlos III; PI070413Xunta de Galicia; PGIDT05PXIC91605PNXunta de Galicia; PS07/1

Análise dos resultados obtidos nos procesos de avaliación da materia de Fisioloxía Humana durante a COVID-19

[Resumo] Neste traballo presentamos unha análise dos resultados obtidos nos exames finais da materia de Fisioloxía Humana durante a COVID-19, materia impartida no grao de podoloxía da UDC. Estes resultados comparáronse cos obtidos en cursos anteriores en exames levados a cabo de xeito presencial. En todos os casos os resultados proceden de exames tipo test de resposta única. Para levar a cabo esta análise tivéronse en conta os cursos académicos 2017/2018 e 2018/2019, no que analizamos os resultados de 165 exames realizados de xeito presencial e comparámolos cos resultados de 46 exames realizados virtualmente no curso académico 2019/2020. Non se observaron diferencias na cualificación media obtida en ambas modalidades de exames. Non obstante, nos exames virtuais diminúe lixeiramente a porcentaxe de alumnos non presentados e a porcentaxe de suspensos e tres veces máis baixa, sen embargo, tamén diminúe o número de estudantes que obteñen sobresaínte. En base a estes resultados podemos concluír que os exames tipo test virtuais aumentan o número de estudantes que supera a materia, pero non así a nota global da mesma.[Abstract] In this work we present an analysis of the results obtained in the final exams of the Human Physiology subject during COVID-19, a subject taught in the podiatry degree at the UDC. These results were compared with those obtained in previous academic years in exams carried out face-to-face. In all cases, the results come from single-response multiple-choice tests. To carry out this analysis, the academic years 2017/2018 and 2018/2019 were taken into account, in which we analysed the results of 165 exams taken face-to-face and compared them with the results of 46 exams conducted online in the academic year 2019/2020. No differences were observed in the average qualification obtained in both exam modalities. However, in virtual exams the percentage of students not presented decreases slightly and the percentage of failures is three times lower, however, the number of students who obtain high marks also decreases. Based on these results, we can conclude that online exams increase the number of students who pass the subject, but not the overall mark.http://hdl.handle.net/2183/2879

Adaptación da docencia de Fisioloxía Humana ante a pandemia da Covid-19

[Resumo] A pandemia causada polo SARS-CoV-2 provocou un cambio no modelo educativo, principalmente polas medidas de seguridade adoptadas. O obxectivo do presente traballo é analizar os resultados da aprendizaxe a distancia na materia de Fisioloxía do grao en Podoloxía e Enfermería, pertencentes á UDC.[Abstract] The pandemic caused by SARS-CoV-2 has caused a change in the educational model, mainly due to the security measures adopted. The objective of this work is to analyze the results of distance learning in the Physiology subject of the degree in Podiatry and Nursing, belonging to the UDC.http://hdl.handle.net/2183/2879

Endocrine function in obesity

[Resumen] La obesidad se asocia con importantes anomalías en la función endocrina. La hiper insulinemia y la resistencia a la insulina son las dos alteraciones mejor conocidas, aunque sus mecanismos y su significado clínico no están claros. El tejido adiposo se considera un órgano endocrino con secreción hormonal; el aumento en la secreción de leptina, una señal de saciedad, por el adipocito es una alteración característica. En la obesidad hay una disminución en la secreción de hormona de crecimiento; esta alteración en la función somatotropa de la obesidad es funcional y se puede revertir en determinadas circunstancias. El mecanismo fisiopatológico responsable de la hiposecreción de GH en la obesidad es probablemente multifactorial. Existen muchos datos que sugieren que un estado crónico de hipersecreción de somatostatina resulta en una inhibición de la liberación de GH; el aumento de los ácidos grasos libres probablemente contribuye a esta alteración, así como un déficit en la secreción de ghrelina. En mujeres, la obesidad abdominal se asocia a hiperandrogenismo y a niveles disminuidos de proteína transportadora de hormonas sexuales. Los hombres obesos tienen niveles de testosterona y concentraciones de gonadotropinas disminuidos, especialmente en los casos de obesidad mórbida. La obesidad se asocia con un aumento en la tasa de producción de cortisol, que se compensa con un aumento del aclaramiento del mismo, lo cual resulta en niveles plasmáticos de cortisol libre que no se modifican con el aumento del peso corporal. Ghrelina es el único factor orexígeno circulante conocido y se ha visto que se encuentra disminuido en humanos obesos. En la obesidad hay también una tendencia a aumentar las concentraciones de TSH y T3 libre.[Abstract] Obesity is associated to significant disturbances in endocrine function. Hyper insulinemia and insulin resistance are the best known changes in obesity, but their mechanisms and clinical significance are not clearly established. Adipose tissue is considered to be a hormone-secreting endocrine organ; and increased leptin secretion from the adipocyte, a satiety signal, is a well-established endocrine change in obesity. In obesity there is a decreased GH secretion. Impairment of somatotropic function in obesity is functional and may be reversed in certain circumstances. The pathophysiological mechanism responsible for low GH secretion in obesity is probably multifactorial. There are many data suggesting that a chronic state of somatostatin hypersecretion results in inhibition of GH release. Increased FFA levels, as well as a deficient ghrelin secretion, probably contribute to the impaired GH secretion. In women, abdominal obesity is associated to hyperandrogenism and low sex hormone-binding globulin levels. Obese men, particularly those with morbid obesity, have decreased testosterone and gonadotropin levels. Obesity is associated to an increased cortisol production rate, which is compensated for by a higher cortisol clearance, resulting in plasma free cortisol levels that do not change when body weight increases. Ghrelin is the only known circulating orexigenic factor, and has been found to be decreased in obese people. In obesity there is also a trend to increased TSH and free T3 levels.Instituto de Salud Carlos III; PI070413Instituto de Salud Carlos III; PI10/00088Xunta de Galicia; PS07/12Xunta de Galicia; INCITE08ENA916110ESXunta de Galicia; INCITE09E1R91634ESXunta de Galicia; IN845B-2010/18

The Decreased Growth Hormone Response to Growth Hormone Releasing Hormone in Obesity Is Associated to Cardiometabolic Risk Factors

The aim of the present study was to evaluate the relationship between GHRH-induced GH secretion in obese premenopausal women and cardiovascular risk markers or insulin resistance. Premenopausal obese women, aged 35–52 years, were studied. GH secretion, IGF-I, serum cardiovascular risk markers, insulin, leptin, mid-waist and hip circumference, total body fat, and truncal fat were measured. Subjects were classified as meeting the criteria for GH deficiency (GHD) when peak GH after stimulation with GHRH was ≤3 μg/L. Mean total and LDL cholesterol, fasting insulin, and HOMA-IR were all higher, in subjects who would have been classified as GH-deficient compared with GH-sufficient. Peak GH secretion after stimulation was inversely associated with fasting insulin (R = −0.650, P = .012), HOMA-IR (R = −0.846, P = .001), total cholesterol (R = −0.532, P = .034), and LDL cholesterol (R = −0.692, P = .006) and positively associated with HDL cholesterol (R = 0.561, P = .037). These data strongly suggest a role for insulin resistance in the decreased GH secretion of obesity and that the blunted GH secretion of central obesity could be the pituitary expression of the metabolic syndrome

Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism

Ghrelin, a hormone whose levels increase during food deprivation, plays a pivotal role in the regulation of food intake, energy metabolism and storage, as well as in insulin sensitivity. Here, we investigated the effects of acyl-ghrelin neutralization with the acyl-ghrelin-binding compound NOX-B11(2) during the fasting-refeeding cycle. Our data demonstrate that ghrelin neutralization with NOX-B11(2) impairs recuperation of lost body weight after food deprivation. Analysis of enzymes involved in glucose and lipid metabolism in liver of fed, fasted and refed rats revealed that neutralization of acyl-ghrelin resulted in minor decreases in the enzymes of glycolytic and lipogenic pathways during fasting. However, during refeeding these enzymes as well as glycogen levels recovered more slowly when acyl-ghrelin was blocked. The high levels of ghrelin in response to food deprivation may contribute to an adequate decrease in hepatic glycolytic and lipogenic enzymes and aid in the recovery of body weight and energetic reserves once food becomes available after the fasting period

Thyroid Function Alteration in Obesity and the Effect of Bariatric Surgery

Review[Abstract] The most common endocrine disease in obesity is hypothyroidism and secondary endocrine alterations, including abnormal thyroid function, are frequent in obesity. It is unclear whether impaired thyroid function is the cause or the consequence of increased adiposity; furthermore, there are no clear data regarding the best way to dose levothyroxine for patients with both hypothyroidism and obesity, and the effect of bariatric surgery (BS). The aim of the present article is to review some controversial aspects of the relation between obesity and the thyroid: (1) Thyroid function in obesity and the effect of BS (2) Thyroid hormone treatment (THT) in obese patients with hypothyroidism and the effect of BS. In summary: In morbidly obese patients, TSH is moderately increased. Morbid obesity has a mild central resistance to the thyroid hormone, reversible with weight loss. In morbidly obese hypothyroid patients, following weight loss, the levothyroxine dose/kg of ideal weight did not change, albeit there was an increment in the levothyroxine dose/kg of actual weight. From a clinical practice perspective, in morbid obesity, diagnosing mild hypothyroidism is difficult, BS improves the altered thyroid function and THT can be adapted better if it is based on ideal weight.The results of this work have been funded by the Project Nº PI16/00884 to F.C. and S.S.-A.; integrated in the National Plan for Scientific Research, Development and Technological Innovation 2013–2016, Spain, and funded by the ISCIII (Instituto de Salud Carlos III)—General Subdirection of Assessment and Promotion of the Research—European Regional Development Fund (FEDER) “A way of making Europe

Perturbation of hypothalamic MicroRNA expression patterns in male rats after metabolic distress: impact of obesity and conditions of negative energy balance

[Abstract] The hypothalamus plays a crucial role in body weight homeostasis through an intricate network of neuronal circuits that are under the precise regulation of peripheral hormones and central transmitters. Although deregulated function of such circuits might be a major contributing factor in obesity, the molecular mechanisms responsible for the hypothalamic control of energy balance remain partially unknown. MicroRNAs (miRNAs) have been recognized as key regulators of different biological processes, including insulin sensitivity and glucose metabolism. However, the roles of miRNA pathways in the control of metabolism have been mostly addressed in peripheral tissues, whereas the potential deregulation of miRNA expression in the hypothalamus in conditions of metabolic distress remains as yet unexplored. In this work, we used high-throughput screening to define to what extent the hypothalamic profiles of miRNA expression are perturbed in two extreme conditions of nutritional stress in male rats, namely chronic caloric restriction and high-fat diet–induced obesity. Our analyses allowed the identification of sets of miRNAs, including let-7a, mir-9*, mir-30e, mir-132, mir-145, mir-200a, and mir-218, whose expression patterns in the hypothalamus were jointly altered by caloric restriction and/or a high-fat diet. The predicted targets of these miRNAs include several elements of key inflammatory and metabolic pathways, including insulin and leptin. Our study is the first to disclose the impact of nutritional challenges on the hypothalamic miRNA expression profiles. These data will help to characterize the molecular miRNA signature of the hypothalamus in extreme metabolic conditions and pave the way for targeted mechanistic analyses of the involvement of deregulated central miRNAs pathways in the pathogenesis of obesity and related disorders.Instituto de Salud Carlos III; PI10/00088Ministerio de Economia y Competitividad; IN845B-2010/187Instituto de Salud Carlos III; PI13/00322FISXunta de Galicia; 10CSA916014PRXunta de Galicia; EM2013/011Ministerio de Ciencia e Innovación; BFU 2011-2502

La expresión génica de FNDC5 en distintos tejidos, y los niveles circulantes de irisina, están modificados por la dieta y las condiciones hormonales

ResumenXunta de Galicia; EM2013/011Instituto de Salud Carlos III; PI13/0032