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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 -
Scientific Reports Mar 2024Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function...
Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function variants in the melanocortin-4-receptor (MC4R) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (LEP) and MC4R. Therefore, we have Sanger sequenced the coding regions of LEP and MC4R in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls. In total, we have observed four and eight variants in LEP and MC4R, respectively. Previous studies showed different functional in vitro effects for the detected frameshift and non-synonymous variants: (1) LEP: reduced/loss of function (p.Val94Met), (2) MC4R: gain of function (p.Val103Ile, p.Ile251Leu), reduced or loss of function (p.Thr112Met, p.Ser127Leu, p.Leu211fsX) and without functional in vitro data (p.Val50Leut). In LEP, the variant p.Val94Met was detected in one patient with AN. For MC4R variants, one patient with AN carried the frameshift variant p.Leu211fsX. One patient with AN was heterozygous for two variants at the MC4R (p.Val103Ile and p.Ser127Leu). All other functionally relevant variants were detected in similar frequencies in patients with AN and lean individuals.
Topics: Female; Humans; Anorexia Nervosa; Leptin; Melanocortins; Mutation; Obesity; Receptor, Melanocortin, Type 4
PubMed: 38528040
DOI: 10.1038/s41598-024-57517-w -
Diabetology International Apr 2024We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center.
AIMS
We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center.
METHODS
We designed an amplicon-based NGS panel targeting 34 genes associated with known monogenic diabetes and performed resequencing in 56 patients with autoantibody-negative diabetes mellitus diagnosed at < 50 years who had not been highly obese. By bioinformatic analysis, we filtered significant variants based on allele frequency (< 0.005 in East Asians) and functional prediction. We estimated the pathogenicity of each variant upon considering the family history.
RESULTS
Overall, 16 candidate causative variants were identified in 16 patients. Among them, two previously known heterozygous nonsynonymous single-nucleotide variants associated with monogenic diabetes were confirmed as causative variants: one each in the and genes. The former was found in two independent diabetes-affected families. Two novel putatively deleterious heterozygous variants were also assumed to be causative from the family history: one frameshift and one nonsynonymous single-nucleotide variant in the gene. Twelve variants remained as candidates associated with the development of diabetes.
CONCLUSION
Targeted NGS panel testing was useful to diagnose various forms of monogenic diabetes in combination with familial analysis, but additional ingenuity would be needed for practice.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13340-023-00669-3.
PubMed: 38524932
DOI: 10.1007/s13340-023-00669-3 -
Frontiers in Endocrinology 2024Maturity-onset diabetes of the young (MODY) is a grouping of monogenic disorders. It is characterized by dominantly inherited, non-insulin-dependent diabetes. MODY is...
Maturity-onset diabetes of the young (MODY) is a grouping of monogenic disorders. It is characterized by dominantly inherited, non-insulin-dependent diabetes. MODY is relatively rare, encompassing up to 3.5% in those diagnosed under 30 years of age. Specific types are most commonly treated with sulfonylurea, particularly those identified as HNF4A-MODY and HNF1A-MODY. HNF1B-MODY is another type that is most frequently managed with insulin therapy but lacks a defined precision treatment. We present an 18-year-old, non-obese female patient diagnosed with HNF1B-MODY. She displays complete gene deletion, a renal cyst, and hypomagnesemia. Her treatment plan includes both long- and short-acting insulin, though she frequently encountered hypoglycemia and hyperglycemia. Semaglutide, a GLP-1RA, was administered weekly over 4 months. The patient's glucose level was continuously tracked using Dexcom's Continuous Glucose Monitoring system. The data suggested a notable improvement in her condition: time-in-range (TIR) increased from 70% to 88%, with some days achieving 100%, and the frequency of hypoglycemic episodes, indicated by time-below-range values, fell from 5% to 1%. The time-above-range values also dropped from 25% to 10%, and her HbA1c levels declined from 7% to 5.6%. During the semaglutide therapy, we were able to discontinue her insulin treatment. Additionally, her body mass index (BMI) was reduced from 24.1 to 20.1 kg/m. However, the semaglutide treatment was halted after 4 months due to side effects such as nausea, vomiting, and reduced appetite. Other contributing factors included exam stress and a COVID-19 infection, which forced a switch back to insulin. Her last recorded HbA1c level under exclusive insulin therapy rose to 7.1%, and her BMI increased to 24.9 kg/m. In conclusion, semaglutide could potentially replace insulin to improve glucose variability, TIR, and HbA1c in patients with HNF1B-MODY. However, more extensive studies are required to confirm its long-term safety and efficacy.
Topics: Humans; Female; Adolescent; Hypoglycemic Agents; Glycated Hemoglobin; Blood Glucose Self-Monitoring; Blood Glucose; Hypoglycemia; Insulin; Glucose; Hepatocyte Nuclear Factor 1-beta; Diabetes Mellitus, Type 2; Glucagon-Like Peptides
PubMed: 38524636
DOI: 10.3389/fendo.2024.1294264 -
Diabetes, Obesity & Metabolism Apr 2024Over the past few decades, there has been a global surge in the prevalence of obesity, rendering it a globally recognized epidemic. Contrary to simply being a medical...
Over the past few decades, there has been a global surge in the prevalence of obesity, rendering it a globally recognized epidemic. Contrary to simply being a medical condition, obesity is an intricate disease with a multifactorial aetiology. Understanding the precise cause of obesity remains a challenge; nevertheless, there seems to be a complex interplay among biological, psychosocial and behavioural factors. Studies on the genetic factors of obesity have revealed several pathways in the brain that play a crucial role in food intake regulation. The best characterized pathway, thus far, is the leptin-melanocortin pathway, from which disruptions are responsible for the majority of monogenic obesity disorders. The effectiveness of conservative lifestyle interventions in addressing monogenic obesity has been limited. Therefore, it is crucial to complement the management strategy with pharmacological and surgical options. Emphasis has been placed on developing drugs aimed at replacing the absent signals, with the goal of restoring the pathway. In both monogenic and polygenic forms of obesity, outcomes differ across various interventions, likely due to the multifaceted nature of the disease. This underscores the need to explore alternative therapeutic strategies that can mitigate this heterogeneity. Precision medicine can be regarded as a powerful tool that can address this concern, as it values the understanding of the underlying abnormality triggering the disease and provides a tailored treatment accordingly. This would assist in optimizing outcomes of the current therapeutic approaches and even aid in the development of novel treatments capable of more effectively managing the global obesity epidemic.
Topics: Humans; Obesity Management; Receptor, Melanocortin, Type 4; Precision Medicine; Obesity; Leptin; Melanocortins
PubMed: 38504134
DOI: 10.1111/dom.15555 -
Critical Reviews in Clinical Laboratory... Mar 2024Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases.... (Review)
Review
Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases. Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans. The spectrum of pathogenic and likely pathogenic variants includes loss of function variants that decrease receptor signaling on one extreme and gain of function that may result in biased signaling or constitutive activity, originally modeled on prototypical rhodopsin GPCR variants identified in retinitis pigmentosa, on the other. GPCR variants disrupt ligand binding, G protein coupling, accessory protein function, receptor desensitization and receptor recycling. Next generation sequencing has made it possible to identify variants of uncertain significance (VUS). We discuss variants in receptors known to result in disease and strategies for disambiguation of VUS such as sorting intolerant from tolerant and polymorphism phenotyping. Modeling of variants has contributed to drug development and precision medicine, including drugs that target the melanocortin receptor in obesity and interventions that reverse loss of gonadotropin-releasing hormone receptor from the cell surface in idiopathic hypogonadotropic hypogonadism. Activating and inactivating variants of the calcium sensing receptor () gene that are pathogenic in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia have enabled the development of calcimimetics and calcilytics. Next generation sequencing has continued to identify variants in GPCR genes, including orphan receptors, that contribute to human phenotypes and may have therapeutic potential. Variants of the gene, some encoding an arginine-rich region that promotes receptor phosphorylation and intracellular retention, have been linked to an idiopathic epilepsy syndrome. Agnostic strategies have identified variants of the pyroglutamylated RF amide peptide receptor gene in intellectual disability and G protein-coupled receptor 39 identified in psoriatic arthropathy. Coding variants of the G protein-coupled receptor L1 () orphan receptor gene have been identified in a rare familial progressive myoclonus epilepsy. The study of the role of GPCR variants in monogenic, Mendelian phenotypes has provided the basis of modeling the significance of more common variants of pharmacogenetic significance.
PubMed: 38497103
DOI: 10.1080/10408363.2023.2286606 -
Frontiers in Endocrinology 2024It has been proposed that not all children with short stature displaying an inadequate response to tests for growth hormone (GH) secretion truly suffer from GH...
Clinical and laboratory characteristics but not response to treatment can distinguish children with definite growth hormone deficiency from short stature unresponsive to stimulation tests.
INTRODUCTION
It has been proposed that not all children with short stature displaying an inadequate response to tests for growth hormone (GH) secretion truly suffer from GH deficiency (GHD). Only children with a monogenic cause of GHD or an identifiable combined hormonal deficiency or anatomical anomaly in the hypothalamic-pituitary axis should be considered definite GHD (dGHD). The remaining patients can be defined as a separate group of patients, "short stature unresponsive to stimulation tests" (SUS). The aim of this proof-of-concept study, was to assess whether SUS patients treated with rhGH exhibit any differences compared to GHD patients undergoing the same treatment.
METHODS
Retrospective analysis on 153 consecutive patients with short stature and pathological response to two GH stimulation tests. Patients with dGHD were defined as those with a clear genetic or anatomical hypothalamic-pituitary anomaly, as well as those with combined pituitary hormone deficiencies and those with a known insult to the hypothalamic-pituitary axis (i.e. total brain irradiation) (n=38, 25%); those without any of the previous anomalies were defined as SUS (n=115, 75%).
RESULTS
At diagnosis, dGHD and SUS populations did not differ significantly in sex (F 32% vs 28%, p=0.68), age (11.9 vs 12.1, p=0.45), height SDS at diagnosis (-2.2 vs. -2.0, p=0.35) and prevalence of short stature (height <-2 SDS) (56% vs 51%, p=0.45). IGF-1 SDS were significantly lower in dGHD (-2.0 vs -1.3, p<0.01). After 1 year of treatment, the prevalence of short stature was significantly reduced in both groups (31% in dGHD vs. 21% in SUS, p<0.01) without any significant differences between groups (p=0.19), while the increase in IGF-1 SDS for bone age was greater in the dGHD category (+1.9 vs. +1.5, p<0.01), with no further difference in IGF-1 SDS between groups. At the last available follow-up, 59 patients had reached the near adult height (NAH) and underwent retesting for GHD. No differences in NAH were found (-0.3 vs. -0.4 SDS, 0% vs. 4% of short stature). The prevalence of pathological retesting was higher in dGHD (60% vs. 10%, p<0.01) as well as of overweight and obesity (67% vs. 26%).
CONCLUSION
Stimulation tests and the equivalent benefit from rhGH therapy, cannot distinguish between dGHD and SUS populations. In addition, lower IGF-1 concentrations at baseline and their higher increase during treatment in dGHD patients, and the lack of pathological retesting upon reaching NAH in SUS patients, are facts that suggest that deficient GH secretion may not be the cause of short stature in the SUS studied population.
Topics: Child; Adult; Humans; Insulin-Like Growth Factor I; Retrospective Studies; Dwarfism, Pituitary; Human Growth Hormone; Growth Hormone
PubMed: 38495788
DOI: 10.3389/fendo.2024.1288497 -
The Journal of Clinical Endocrinology... Mar 2024Bi-allelic pathogenic leptin gene variants cause severe early onset obesity usually associated with low or undetectable circulating leptin levels. Recently, variants...
PURPOSE
Bi-allelic pathogenic leptin gene variants cause severe early onset obesity usually associated with low or undetectable circulating leptin levels. Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties.
METHODS
We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular and functional characteristics of the underlying leptin variants and investigated the correlation of disease subtype with severity of the clinical phenotype.
RESULTS
A total of 28 distinct homozygous leptin variants were identified in 148 patients. The identified variants can be divided into three different subtypes of congenital leptin deficiency: classical hormone deficiency (21 variants in 128 patients), biologically inactive hormone (3 variants in 12 patients) and antagonistic hormone (3 variants in 7 patients). Only 1 variant (n=1 patient) remained unclassified. Patients with biological inactive leptin have a higher percentage of 95th BMI percentile (%BMIp95) compared to patients with classical hormone deficiency. While patients with both classical hormone deficiency and biological inactive hormone can be treated with the same starting dose of metreleptin, patients with antagonistic hormone need a variant-tailored treatment approach to overcome the antagonistic properties of the variant leptin.
MAIN CONCLUSIONS
Categorization of leptin variants based on molecular and functional characteristics helps to determine the most adequate approach to treatment of patients with congenital leptin deficiency.
PubMed: 38470203
DOI: 10.1210/clinem/dgae149 -
Frontiers in Endocrinology 2024Early-onset obesity is a rising health concern influenced by heredity. However, many monogenic obesity variants (MOVs) remain to be discovered due to differences in...
Early-onset obesity is a rising health concern influenced by heredity. However, many monogenic obesity variants (MOVs) remain to be discovered due to differences in ethnicity and culture. Additionally, patients with known MOVs have shown limited weight loss after bariatric surgery, suggesting it can be used as a screening tool for new candidates. In this study, we performed whole-exome sequencing (WES) combined with postoperative data to detect candidate MOVs in a cohort of 62 early-onset obesity and 9 late-onset obesity patients. Our findings demonstrated that patients with early-onset obesity preferred a higher BMI and waist circumference (WC). We confirmed the efficacy of the method by identifying a mutation in known monogenic obesity gene, , which resulted in less weight loss after surgery. 5 genes were selected for further verification, and a frameshift variant in gene: NM_001270486.1, c.1614dup, (p. Gly539Argfs*3) was identified as a novel candidate MOV. This mutation influenced the improvement of metabolism after bariatric surgery. In conclusion, our data confirm the efficacy of WES combined with postoperative data in detecting novel candidate MOVs and c.1614dup (CAMKK2) might be a promising MOV, which needs further confirmation. This study enriches the human monogenic obesity mutation database and provides a scientific basis for clinically accurate diagnosis and treatment.
Topics: Humans; Exome Sequencing; Obesity; Mutation; Frameshift Mutation; Weight Loss; Calcium-Calmodulin-Dependent Protein Kinase Kinase
PubMed: 38469147
DOI: 10.3389/fendo.2024.1334342 -
Diabetes, Obesity & Metabolism Apr 2024Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by...
Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.
Topics: Humans; Leptin; Hypothalamic Diseases; Obesity; Hypothalamus; Craniopharyngioma; Hyperphagia; Pituitary Neoplasms; Melanocortins; Energy Metabolism
PubMed: 38450938
DOI: 10.1111/dom.15530