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Minerva Pediatrics Dec 2021Type 2 diabetes (T2D) in adolescents has become an increasing health concern throughout the world and its prevention and screening should be implemented in pediatric... (Review)
Review
INTRODUCTION
Type 2 diabetes (T2D) in adolescents has become an increasing health concern throughout the world and its prevention and screening should be implemented in pediatric care. As clinical features at presentation, in some cases can be similar to type 1 diabetes and family history can be in favor of a monogenic form of diabetes, it is pivotal for physicians to be aware of youth-onset T2D specificities to ensure an accurate diagnosis.
EVIDENCE ACQUISITION
We conducted the first search in Medline, Embase, Web of Science, using different keywords and their compositions. The keywords used, also called "mesh" (MEdical Subject Headings) on PubMed, are the following: "type 2 diabetes" AND ("child*" OR "pediatr*" OR "adolesce*") AND ("epidem*" OR "diagnos*" OR "treat*" OR "complication" OR "comorbidit*"). International review, systematic reviews and meta-analyses, randomized control trials and case reports published between May 2018 and February 2021 were considered, to identify publications that deal with the topic. No restrictions were applied regarding the published paper's language.
EVIDENCE SYNTHESIS
The global increase of overweight and obesity can complicate the diagnostic process and makes it essential to apply a systematic approach to each new diagnosis. Microvascular complications may be present at the time of diagnosis and chronic complications are frequent and need to be screened regularly. Regular screening of comorbidities should also be performed. Childhood T2D should be followed up by pediatric diabetes units to avoid diagnostic errors and delay in care.
CONCLUSIONS
A multidisciplinary approach, by an experienced team, is pivotal to provide treatment options targeting the unique needs of pediatric patients. Treatment programs must include the whole family and address all the aspects of the care (lifestyle, pharmacological therapy, psychological aspects, complications and comorbidities). An organized process of transition to adult care is essential.
Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 2; Humans; Life Style; Overweight; Pediatrics; Physicians
PubMed: 34286947
DOI: 10.23736/S2724-5276.21.06530-7 -
Children (Basel, Switzerland) Jan 2024Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last... (Review)
Review
Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last decades. Nowadays, the genetic contribution to obesity is well-established. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the genetics of obesity and current pharmacological treatment, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between December 2022 and December 2023. We used the terms "obesity", "genetics", "monogenic", "syndromic", "drugs", "autosomal dominant", "autosomal recessive", "leptin-melanocortin pathway", and "children" in different combinations. Recognizing the genetic background in obesity can enhance the effectiveness of treatment. During the last years, intense research in the field of obesity treatment has increased the number of available drugs. This review analyzes the main categories of syndromic and monogenic obesity discussing current data on genetic-based pharmacological treatment of genetic obesity and highlighting the necessity that cases of genetic obesity should follow specific, pharmacological treatment based on their genetic background.
PubMed: 38397265
DOI: 10.3390/children11020153 -
Genes Jan 2024Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute... (Review)
Review
Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in , , , and triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.
Topics: Humans; Lipoprotein Lipase; Acute Disease; Pancreatitis; Hypertriglyceridemia; Triglycerides
PubMed: 38397180
DOI: 10.3390/genes15020190 -
Nederlands Tijdschrift Voor Geneeskunde Jan 2021Obesity is a complex endocrine disease, mainly caused by environmental, behavioral and biological factors. Maintaining weight loss is extremely difficult due to the...
Obesity is a complex endocrine disease, mainly caused by environmental, behavioral and biological factors. Maintaining weight loss is extremely difficult due to the neuro-endocrine dysregulations that stimulate the body to return to the previous, increased, weight. Identifying underlying weight-gaining factors is needed, including medication-related, psychological and endocrine factors, as well as monogenic obesity. The cornerstone of treatment is optimization of lifestyle and all other contributing factors. Achieving at least 5% weight loss already has important health benefits. If combined lifestyle intervention (CLI) alone is not successful, pharmacotherapy or bariatric surgery can be added for patients with increased weight-related health risks. Recently, novel pharmacotherapy became available, among which, liraglutide 3 mg and the combination therapy naltrexone/bupropion, which leads to an additional 5-6% mean weight loss compared to CLI alone. For rare forms of obesity there are specific drugs that target defects in the regulation of hunger and satiety. Promising new pharmacotherapy for obesity is under development.
Topics: Anti-Obesity Agents; Bariatric Surgery; Bupropion; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Humans; Hunger; Life Style; Liraglutide; Naltrexone; Obesity; Satiation; Treatment Outcome; Weight Loss
PubMed: 33560612
DOI: No ID Found -
Nucleic Acids Research Sep 2019Sickle cell disease (SCD) is a monogenic disorder that affects millions worldwide. Allogeneic hematopoietic stem cell transplantation is the only available cure. Here,...
Sickle cell disease (SCD) is a monogenic disorder that affects millions worldwide. Allogeneic hematopoietic stem cell transplantation is the only available cure. Here, we demonstrate the use of CRISPR/Cas9 and a short single-stranded oligonucleotide template to correct the sickle mutation in the β-globin gene in hematopoietic stem and progenitor cells (HSPCs) from peripheral blood or bone marrow of patients with SCD, with 24.5 ± 7.6% efficiency without selection. Erythrocytes derived from gene-edited cells showed a marked reduction of sickle cells, with the level of normal hemoglobin (HbA) increased to 25.3 ± 13.9%. Gene-corrected SCD HSPCs retained the ability to engraft when transplanted into non-obese diabetic (NOD)-SCID-gamma (NSG) mice with detectable levels of gene correction 16-19 weeks post-transplantation. We show that, by using a high-fidelity SpyCas9 that maintained the same level of on-target gene modification, the off-target effects including chromosomal rearrangements were significantly reduced. Taken together, our results demonstrate efficient gene correction of the sickle mutation in both peripheral blood and bone marrow-derived SCD HSPCs, a significant reduction in sickling of red blood cells, engraftment of gene-edited SCD HSPCs in vivo and the importance of reducing off-target effects; all are essential for moving genome editing based SCD treatment into clinical practice.
Topics: Anemia, Sickle Cell; Animals; CRISPR-Cas Systems; Cell Line, Tumor; Cells, Cultured; Erythrocytes; Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; K562 Cells; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Treatment Outcome; beta-Globins
PubMed: 31147717
DOI: 10.1093/nar/gkz475 -
Molecules and Cells Apr 2022A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular... (Review)
Review
A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.
Topics: Animals; Cilia; Humans; Hyperphagia; Hypothalamus; Leptin; Mice; Obesity
PubMed: 35387896
DOI: 10.14348/molcells.2022.2046 -
Endocrinology May 2019Much effort has been directed at studying the orexigenic actions of administered ghrelin and the potential effects of the endogenous ghrelin system on food intake, food... (Review)
Review
Much effort has been directed at studying the orexigenic actions of administered ghrelin and the potential effects of the endogenous ghrelin system on food intake, food reward, body weight, adiposity, and energy expenditure. Although endogenous ghrelin's actions on some of these processes remain ambiguous, its glucoregulatory actions have emerged as well-recognized features during extreme metabolic conditions. The blood glucose-raising actions of ghrelin are beneficial during starvation-like conditions, defending against life-threatening falls in blood glucose, but they are seemingly detrimental in obese states and in certain monogenic forms of diabetes, contributing to hyperglycemia. Also of interest, blood glucose negatively regulates ghrelin secretion. This article reviews the literature suggesting the existence of a blood glucose-ghrelin axis and highlights the factors that mediate the glucoregulatory actions of ghrelin, especially during metabolic extremes such as starvation and diabetes.
Topics: Adiposity; Animals; Blood Glucose; Body Weight; Eating; Energy Metabolism; Ghrelin; Humans; Hyperglycemia; Obesity
PubMed: 30874792
DOI: 10.1210/en.2019-00074 -
Appetite Nov 2022Hyperphagia is a key symptom in patients with monogenic obesity, but the assessment is challenging.
BACKGROUND
Hyperphagia is a key symptom in patients with monogenic obesity, but the assessment is challenging.
OBJECTIVES
We aimed to investigate the applicability of Dykens' Hyperphagia Questionnaire in patients with monogenic and syndromic obesity to assess the quality and severity of hyperphagia, and to compare our results with those reported in the literature.
METHODS
Patients with biallelic leptin receptor variants (LEPR, n = 8), heterozygous melanocortin-4 receptor variants (MC4R, n = 7) and 16p11.2 deletions, leading to a deletion of the Src homology 2B adaptor protein gene (n = 5) were included in the study. Hyperphagia was assessed by the parent-based, 13-item hyperphagia questionnaire from Dykens et al. (2007). A literature research was performed to identify published hyperphagia scores assessed by Dykens' Hyperphagia Questionnaire.
RESULTS
The total hyperphagia scores were similar in patients with biallelic LEPR and monoallelic MC4R variants (32.0 ± 9.3 vs. 31.4 ± 5.4), but significantly lower in patients with 16p11.2 deletions (21.4 ± 5.5, p < 0.05). Compared to patients with syndromic obesity (27.6 ± 9.0) from the literature, patients with LEPR and MC4R variants had higher total hyperphagia scores. Total hyperphagia scores in patients with 16p11.2 deletions were lower than for patients with other syndromic obesity forms (21.4 ± 5.5 vs. 24.6 ± 8.1), but similar to those for individuals with obesity without a genetic cause (22.9 ± 7.2).
CONCLUSIONS
Dykens' Hyperphagia Questionnaire seems to be a useful tool to assess hyperphagic behaviour in patients with monogenic and syndromic obesity.
Topics: Autistic Disorder; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 16; Humans; Hyperphagia; Intellectual Disability; Obesity
PubMed: 35809703
DOI: 10.1016/j.appet.2022.106161 -
Indian Journal of Pediatrics Jun 2018The aim of this article is to provide an in depth review of the rare genetic and syndromic forms of childhood obesity. The authors demonstrate the complexity and... (Review)
Review
The aim of this article is to provide an in depth review of the rare genetic and syndromic forms of childhood obesity. The authors demonstrate the complexity and inter-relationships of the leptin-melanocortin signaling pathway and its central nervous system and systemic effects. Authors highlight the clinical distinctive features of genetic/syndromic causes for childhood obesity, in particular, relative shorter height to their genetic potential, developmental challenges and in some instances, ophthalmological and retina changes. They outline specific genetic testing and treatment options available for these conditions.
Topics: Child; Genetic Testing; Humans; Leptin; Melanocortins; Pediatric Obesity; Signal Transduction; Syndrome
PubMed: 29177811
DOI: 10.1007/s12098-017-2502-2 -
Journal of Clinical Medicine Feb 2024Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can... (Review)
Review
Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.
PubMed: 38546831
DOI: 10.3390/jcm13051347