Rôle de l'épigénétique dans le diabète et la croissance

The understanding of genomic imprinting has made us realize that maternal and paternal contributions to the embryo are different. Disturbances during the imprinting process may lead to different pathologies due to an imbalance of gene expression either maternally or paternally derived. Known epigenetic diseases such as neonatal diabetes, growth retardation or overgrowth syndromes as well as cancer are better understood. It has become clear that environmental factors can be at the origin of such epigenetic changes. Careful analysis and diagnosis of epigenetic diseases are important for patient treatment and outcome

Pancreas development in health and disease

Diabetes is the most frequent endocrine disease in the pediatric population. The prevalence of both, type 1 and type 2 diabetes is increasing worldwide every year. The prevalence under age 15 years is predicted to rise in Europe by 70% between 2005 and 2020. Diabetes type 2, most often associated with obesity, is increasing rapidly as well and represents today between 8 and 43% of new-onset diabetes cases in children depending on geographic location. While in type 1 diabetes insulin-producing beta cells are destroyed, insulin resistance, followed by beta cell failure, characterizes diabetes type 2. Type 2 diabetes is associated with several environmental factors, the most important being obesity. Both, type 1 and type 2 diabetes are of polygenic origin. Over 40 distinct genomic locations have been associated with diabetes type 1. Recently, monogenic forms of diabetes, caused by a single gene defect in the beta cell machinery, are more often diagnosed due to new molecular insights into beta cell function and the possibility of genetic analyses, indispensable for diagnosis. Of all diabetic patients, 2% to 5% are thought to have a monogenic origin, affecting approximately 9,000 to 15,000 persons in Switzerland alone and four to ten millions worldwide. The fraction of underdiagnosed cases of monogenic diabetes is even higher in children and could represent up to 10% children with diabetes. Today the majority of these cases are missed, and there is an urgent need for better diagnostic tools. Understanding the complexity of transcriptional regulation in pancreas development constitutes the basis for the comprehension of beta cell physiology and several monogenic forms of diabetes. Mouse models provide insight into the underlying mechanisms of the development of diabetes. These transcription factors may also be promising candidates in future therapeutic approaches with the ultimate goal to cure diabetes. The identification of the genes involved is of outmost importance for the patient, since it will determine the choice of treatment and will allow for a more precise estimate of the risk for long-term complications. As several forms of monogenic diabetes can be treated with oral drugs, and multiple daily insulin injections are no longer needed, the accurate diagnosis may significantly improve metabolic control and the patient's quality of life

Programming of the pancreas

The pancreas, as most of the digestive tract, derives from the endoderm. Differentiation of these early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events. These are controlled by different classes of transcription factors including the homeodomain, the basic helix-loop-helix (bHLH) and the winged helix proteins. Recently, considerable progress has been made delineating this cascade. The present review focuses on the role of the different transcription factors during pancreas development, with a particular emphasis on the newly identified bHLH transcription factor neurogenin3

Many faces of monogenic diabetes

Monogenic diabetes represents a heterogeneous group of disorders resulting from defects in single genes. Defects are categorized primarily into two groups: disruption of β-cell function or a reduction in the number of β-cells. A complex network of transcription factors control pancreas formation, and a dysfunction of regulators high in the hierarchy leads to pancreatic agenesis. Dysfunction among factors further downstream might cause organ hypoplasia, absence of islets of Langerhans or a reduction in the number of β-cells. Many transcription factors have pleiotropic effects, explaining the association of diabetes with other congenital malformations, including cerebellar agenesis and pituitary agenesis. Monogenic diabetes variants are classified conventionally according to age of onset, with neonatal diabetes occurring before the age of 6 months and maturity onset diabetes of the young (MODY) manifesting before the age of 25 years. Recently, certain familial genetic defects were shown to manifest as neonatal diabetes, MODY or even adult onset diabetes. Patients with neonatal diabetes require a thorough genetic work-up in any case, and because extensive phenotypic overlap exists between monogenic, type 2, and type 1 diabetes, genetic analysis will also help improve diagnosis in these cases. Next generation sequencing will facilitate rapid screening, leading to the discovery of digenic and oligogenic diabetes variants, and helping to improve our understanding of the genetics underlying other types of diabetes. An accurate diagnosis remains important, because it might lead to a change in the treatment of affected subjects and influence long-term complications

Early Onset Diabetes in Two Children due to Progeria, a Monogenic Disease of DNA Repair

Progeria Syndrome is a rare disorder in childhood which causes accelerated systemic aging. Due to the accelerated aging process, disorders which normally occur only in old age will appear in these children at a much younger age. We report two children with Progeria syndrome, in whom fulminant diabetes mellitus manifested at a very early age

Diabète de type 2 en pédiatrie : diagnostic et prise en charge

Our way of life has led to a massive increase in the prevalence of obesity in adults and children. Therefore diabetes type 2 has also become a pediatric disease. Therapy consists above all of implementing modifications of life style such as a healthy diet and regular physical activity in order to achieve a decrease in body weight. If these measurements prove to be insufficient, medical treatments are introduced, either using metformine or insulin. The screening and treatment of complications (retinopathy, nephropathy) and comorbidities (arterial hypertension, dyslipidemia) will help to decrease mortality on the long haul

Genetic Defects of the β-Cell That Cause Diabetes

Individuals with higher-than-normal blood sugar levels used to be diagnosed as having either type 1 or type 2 diabetes. We now know that a wide range of different factors can cause diabetes, including single gene defects, which account for at least 1% of all diabetes cases and up to 4% of cases in the pediatric population. However, misdiagnosis remains common due to the considerable clinical overlap between the different diabetes forms. Monogenic diabetes onset can occur shortly after birth, as observed in neonatal diabetes mellitus, or any time later in life. The present chapter outlines the genes currently known to be involved in monogenic diabetes. Some of these genes are involved in β-cell development, with mutations often leading to a decreased β-cell number, while others play important roles in β-cell function and maintenance. Monogenic forms of autoimmune diabetes and epigenetic causes will also be discussed. A genetic diagnosis may influence treatment choice and prognosis determination and may also lead to family counseling. Genetic screening using next-generation sequencing is becoming more practical as it becomes increasingly accessible and less expensive

Modeling intrauterine growth retardation in rodents: Impact on pancreas development and glucose homeostasis

Fetal adverse environment, such as insufficient maternal nutrition, placental insufficiency and stress, alters organ development and leads to poor fetal growth, also called intrauterine growth retardation (IUGR). IUGR is associated with an increased risk of perinatal mortality and morbidity as well as late-onset metabolic diseases, such as obesity, diabetes and hypertension in adulthood. In the rodent model, IUGR can be induced by fetal caloric restriction, fetal protein restriction, by exposure to high levels of glucocorticoids or by restricted placental blood supply. Such experimental IUGR models show a decreased beta cell mass and lower pancreatic insulin content. Recent research has provided an insight into the mechanisms responsible for the loss of beta cells. Here we review models that give further details about the molecular determinants of fetal and postnatal pancreatic islet development that are required to understand the consequences of fetal insults