Flavia Prodam

Baseline glucose homeostasis predicts the new onset of diabetes during statin therapy: A retrospective study in real life

OBJECTIVEWe evaluated the risk of altered glucose levels and new-onset diabetes (NOD) associated with statins according to glucose levels at baseline in a population treated for dyslipidemia on primary prevention for >5 years. DESIGN. The retrospective study included 308 subjects (265 on statins and 43 controls on diet) with a follow-up of 5–15 years. The cohort was classified according to glucose tolerance at both baseline and follow-up.RESULTSThe cumulative incidence of NOD was 13.6% (9.3% in controls and 13.5% in treated patients). NOD was diagnosed after 3.4±1.8 years. In the group with normal glucose levels at baseline, a family history of diabetes (OR: 3.4, 95% CI 1.3–8.9), BMI >30 kg/m2 (OR: 8.5, 95% CI 2.0–35.8), treatment with thiazide (OR: 21.9, 95% CI 1.2–384.2) and no alcohol consumption (OR: 0.3, 95% CI 0.1–0.8) reduced the risk of developing altered glucose levels or NOD. No effects of statins were seen. In the group with altered glucose levels at baseline, hypertension (OR: 5.0, 95% CI 1.0–25.3) and hypertriglyceridemia (OR: 3.5, 95% CI 1.0–11.8) increased the risk of remaining with altered glucose levels or developing NOD. Treatment with statins (OR: 7.5, 95% CI 1.5–37.4), in particular atorvastatin, was associated with an increased risk. In the whole population, statin therapy (OR: 4.0, 95% CI 1.1–14.1, p<0.020), and in particular simvastatin and atorvastatin, was associated with increased risk of altered glucose levels or NOD. Patients who developed or maintained altered glucose levels or NOD had a poor metabolic phenotype at baseline.CONCLUSIONSStatins were associated with an increased risk of NOD or altered glucose levels, mainly in subjects with altered glucose levels before the beginning of therapy. Poor metabolic phenotype and unhealthy behaviors or family history of diabetes contributed to that risk.

Etiology of Congenital Hypothyroidism

Congenital hypothyroidism (CH) is a condition of thyroid hormone deficiency present at birth. According to the duration of thyroid hormone deficiency, it may be classified into permanent and transient CH. According to the anatomic location of the pathogenic defect, CH may be further classified into primary, secondary (or central), and peripheral CH. The most frequent cause of permanent primary CH is thyroid dysgenesis, which includes thyroid ectopy, agenesis, and hypoplasia. Thyroid dysgenesis is generally sporadic in occurrence, but in about 2 % of cases, mutations in genes PAX8, TTF-2, NKX2.1, and NXK2.5 may be detected. Dyshormonogenesis is the second most common cause and may be caused by mutations in genes encoding the sodium-iodide symporter, thyroperoxidase, hydrogen peroxide generation factors, thyroglobulin, iodothyronine deiodinase, and pendrin. Rare causes of CH include resistance to TSH binding or signaling, central CH, and peripheral CH caused by thyroid hormone syndrome or defects in thyroid hormone transport and metabolism.

Children Obesity, Glucose Tolerance, Ghrelin, and Prader-Willi Syndrome

Abstract Prader Willi syndrome (PWS) is caused by a genomic imprinting disorder. Its major manifestations include childhood-onset hyperphagia and morbid obesity with specific fat distribution, relative hypoinsulinemia, preserved insulin sensitivity, growth hormone (GH) deficiency, hypogonadism, and mild mental retardation. Hyperghrelinemia is a common feature of the syndrome preceding obesity in infancy, with a different pattern of acylated (AG) and unacylated ghrelin (UAG) secretion across PWS nutritional phases. Alterations in the ghrelin system have been investigated in the context of PWS, such as uncontrolled eating, fat accrual, and specific glucose metabolism, probably as compensatory mechanisms. This chapter discusses findings on the role of ghrelin and obestatin in these PWS clinical features, paying particular attention to the regulation of insulin secretion and sensitivity from childhood to adulthood. The regulation of the ghrelin system by new treatments for hyperphagia and obesity in PWS has been also addressed.

Growth hormone deficiency in children.

Growth hormone deficiency (GHD) is a stimulating area of clinical research and discussion, which has rapidly evolved over the past 40 years. Both medical and scientific interests have focused on recognising that psychological, developmental and unhealthy aspects of paediatric GHD may affect lifespan, thereby leaving patients at risk of long-term health concerns. Research on genetic characterization of uncommon and syndromic forms of GHD has been progressively advantaged by growing molecular methodologies, and advances in diagnostic procedures and precise profiling of clinical outcomes has markedly contributed to tailoring therapeutic strategies to suit the needs of children and adolescents transitioning into adulthood and compliance to treatment. Therefore, recognising the key role of replacement growth hormone therapy in childhood is important for optimizing health later in life. GHD and treatmentwith growth hormones in children and adolescents is a broad discipline, and this collection of reviews from leading endocrinologists with different areas of expertise reflects this. Authors were asked to include novel insights from current research, as well as to provide concrete recommendations for practical application though inclusion of practice points and research agendas to facilitate reading. The first chapter by Mara Giordano describes advances in our understanding of genetic causes of isolated GHD and combined pituitary hormone deficiency, and focuses attention on the impending ability of novel molecular tools to clarify genetic mechanisms that are still poorly understood. The second chapter by Manuel Gahete and colleagues illustrates the prominent aspects of growth hormone biology and highlights research on transgenic and naturally occurring GHD animal models used to investigate the origin, phenotype and consequences of GHD. In the third chapter, Natascia Di Iorgi and colleagues provide an extensive review of the clinical phenotypes of classical and non-classical forms of paediatric GHD, and shed light on advanced imaging tools capable of aiding current and future diagnostic procedures. Amish Chinoy and Phillip G. Murray discuss current evidence on the interacting roles of clinical, biochemical and radiological tools used to diagnose GHD in childhood, while emphasizing the need for caution in interpreting results owing to many potential pitfalls. In the next chapter, Erik Richmond and Alan D. Rogol deal with issues relating to developmental influences of proper growth hormone secretion on later health risks and examine strategies and recommendations for growth hormone treatment of GHD in children and patients in the transition to adult care. In chapter six, Juliane Rothermel and Thomas Reinehr highlight the role and mechanisms through which GHD and treatment with growth hormones can positively and negatively influence themanifold metabolic features associated with the disease.

Diabetes in Growth Hormone Deficiency

Growth hormone (GH) deficiency (GHD) is a complex disease with a constellation of symptoms and signs which involve metabolism at several levels. Particular attention has been paid to glucose and insul

Hormones and Gastrointestinal Function

Development is a continuous process. Nutrition, environment and stress modulate development through gene expression in an epigenetic manner. Prenatal and perinatal nutrition can be imprinting factors and turn on different genes that provide different phenotypes, such as the thrifty phenotype [1]. Indeed, the nutritional support of gastrointestinal growth and function is an important tool in the clinical care of newborn babies, in particular preterm neonates. Before birth, although amniotic fluid is not the main source of nutrition for the fetus, it contributes up to 15% of fetal nutritional requirements and plays a key role in its development and maturation [2, 3]. Accordingly, by 20 weeks of gestation, the anatomy of the fetal gut resembles that of the term neonate. However, the process of intestinal absorption is only partially mature before 26 weeks of gestation: gastro-entero-pancreatic peptides are secreted at a basal rate and can be completely stimulated or inhibited after delivery, in particular through contact with nutrients [4, 5]. At the age of 2 years, the intestine is fully functional [6]. Gut hormones, peptides, and growth factors clearly have a role in gut growth after birth and directly and indirectly mediate the trophic actions of enteral nutrition in a manner that is still incompletely understood [5]. By contrast, hormones and growth factors, which are present in breast milk, also seem to exert trophic activities on gut development and immune function. The interplay is complex [1, 3]. Little is known about the development of these regulatory systems in the human neonate and, as a consequence, premature infants experience significant morbidity and mortality associated with feeding problems [6]. Present clinical nutritional support for preterm babies consists of enteral and parenteral nutrition but both have associated complications [6, 7]. Since enteral feeding is important for gut development, acute or chronic gastrointestinal diseases could be caused by feeding with formula rather than human breast milk. Formula milks contain higher amounts of proteins and lack many endogenous hormones and growth factors [5, 6, 8]. A better understanding of factors linked to gastrointestinal function and energy metabolism could result in improved strategies for supporting nutrition of preterm newborns as well as their later development.

Ghrelin Regulation in Epilepsy

Epilepsy is one of the most common neurological problems worldwide affecting approximately 1% of the population (Browne & Holmes, 2000; Chang & Lowenstein, 2003). It is characterized by recurrent unprovoked behavioural seizures (Beck & Elger, 2008). In recent decades, the relationship between epilepsy and the neuroendocrine system has gained a great deal of interest and many researchers as neurologists, endocrinologists and basic scientists have investigated it. The main issue is whether hormonal changes in relation to epilepsy are due to seizures activity per se or to consequential effects of antiepileptic drugs. To understand the far-reaching effects of epilepsy and antiepileptic medications on hormonal system and vice versa, several studies have been recently performed. Their results are interesting but still controversial and the neuroendocrine regulation of epilepsy is far to be clearly explained. However, considering that a role of hormones in epilepsy is known and in part well described, this chapter would firstly review the endocrine regulation mediated by sex hormones, prolactin (PRL), growth hormone (GH), thyrotropin-releasing hormone (TRH), adrenocortical axis and neuropeptide Y (NPY). More recently, also other new hormones have been investigated in this field, bringing to light ghrelin. Ghrelin is a 28 amino acid peptide predominantly produced by the stomach (Kojima et al., 1999). It was discovered as the first natural ligand of the orphan growth hormone segretagogues receptor 1a (GHS-R1a), which exerts, through its activation, a strong GH-releasing activity (Arvat et al., 2001; Howard et al., 1996; Kojima et al., 1999; Kojima & Kangawa, 2005; van der Lely et al., 2004). It also influences glucose and insulin metabolism and controls food and energy intake through many neuroendocrine systems (van der Lely et al., 2004). Furthermore, several evidences suggest that ghrelin not only plays a metabolic role but it is also involved in sleepwake regulation, affective status, learning and memory processes (Steiger et al., 2011; van der Lely et al., 2004). Besides, the recent discovery of ghrelin has also provided an important insight to the neuroendocrine knowledge in epilepsy. In fact, a relationship between ghrelin and epilepsy has been already shown in animal and human models, although the results are sometimes conflicting. Thus, this chapter would secondly describe the intriguing ghrelin role in relation to seizures activity and discuss open questions and future perspectives.

Il trattamento a lungo termine con GH del deficit di GH dell’adulto: sicurezza (safety)

RiassuntoLa terapia sostitutiva con ormone somatotropo (rhGH) del paziente adulto con deficit di GH (GHD) rappresenta ancora oggi una sfida per l’endocrinologo clinico e la sua realizzazione costante nella pratica quotidiana presenta ancora numerose difficoltà e incertezze. Essa va iniziata con dosi assai basse di GH ricombinante e monitorata sulla base dei livelli di IGF-I e sulla risposta clinica. La sensibilità al GH biosintetico presenta una spiccata variabilità inter-individuale e ciÒ spiega perché le dosi di mantenimento dell’ormone siano assai variabili. In accordo con le linee guida è consigliabile iniziare il trattamento con dosi basse di rhGH pari a 0,15–0,30 mg/die. La terapia deve essere intrapresa solo quando i concomitanti trattamenti sostitutivi di eventuali altri deficit endocrini siano già stati ottimizzati. Raggiunti i livelli normali di IGF-I, il trattamento andrà controllato a intervalli semestrali. Deve essere sottolineato che un dosaggio eccessivo di rhGH determina frequentemente effetti collaterali che ricordano i sintomi riscontrabili nei pazienti con ipersecrezione di GH (in particolare artralgie ed edemi declivi), mentre un trattamento sostitutivo adeguato assai raramente presenta effetti collaterali. La presenza di residui di neoplasia ipofisaria stabili nel tempo non costituisce una controindicazione al trattamento sostitutivo con rhGH, anche se, in queste condizioni, è raccomandato un controllo con esami appropriati di imaging della regione ipofisaria, a intervalli inizialmente semestrali e successivamente annuali. È infatti provato che il trattamento sostitutivo con rhGH non determina un aumento della massa tumorale ipofisaria, né induce un’insorgenza significativamente maggiore di neoplasie de novo rispetto alla popolazione generale. Le evidenze derivanti dagli studi rivelano che il rischio di sviluppare iperglicemia o diabete mellito nella popolazione di GHD trattati non è differente da quello della popolazione generale e maggior rischio potrebbe essere presente nei pazienti obesi. Sebbene non esistano prove certe che il trattamento con rhGH possa indurre o favorire la progressione del diabete o delle sue complicanze oculari (retinopatia diabetica), questo trattamento viene sconsigliato nei pazienti con diabete mellito scompensato e con retinopatia diabetica proliferante già in atto.