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Hormone Research in Paediatrics 2024Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and... (Review)
Review
BACKGROUND
Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI; however, there have been almost no new therapeutic modalities since the development of diazoxide.
SUMMARY
Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in "developed" countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use.
KEY MESSAGES
This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.
Topics: Humans; Infant, Newborn; Congenital Hyperinsulinism; Diazoxide; Infant; Female; Male; Practice Guidelines as Topic; Child
PubMed: 37454648
DOI: 10.1159/000531766 -
ERJ Open Research Nov 2023The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary... (Review)
Review
The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.
PubMed: 37965230
DOI: 10.1183/23120541.00350-2023 -
The Journal of Maternal-fetal &... Dec 2023To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH).
OBJECTIVES
To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH).
METHODS
This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included.
RESULTS
A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the gene were found in four patients with CHI.
CONCLUSIONS
The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.
Topics: Infant; Infant, Newborn; Humans; Diazoxide; Retrospective Studies; Congenital Hyperinsulinism; Sirolimus; Mutation
PubMed: 37860935
DOI: 10.1080/14767058.2023.2272014 -
Expert Opinion on Pharmacotherapy 2023The severity of positive symptoms in schizophrenia is associated with poor prognosis. About one-third of schizophrenia patients partially respond to treatment with... (Review)
Review
INTRODUCTION
The severity of positive symptoms in schizophrenia is associated with poor prognosis. About one-third of schizophrenia patients partially respond to treatment with available antipsychotics. The purpose of the present manuscript is to provide an updated overview of novel pharmacotherapy targeting positive symptoms in schizophrenia.
AREAS COVERED
A comprehensive research on the main database sources (PubMed, PsychINFO, Isi Web of Knowledge, MEDLINE, and EMBASE) was performed to obtain original articles published till 31 January 2023 about new pharmacological strategies for the treatment of positive symptoms in schizophrenia.
EXPERT OPINION
The most promising compounds include: lamotrigine, pro-cognitive-compounds (donepezil - in the short term, idazoxan and piracetam) and drugs acting partially or totally outside the Central Nervous System (CNS) (anti-inflammatory drugs: celecoxib, methotrexate; cardiovascular compounds: L-theanine, mononitrate isosorbide, propentofylline, sodium nitroprusside; metabolic regulators: diazoxide, allopurinol; others: bexarotene, raloxifene [in women]). The effectiveness of the latter compounds indicates that other biological systems, such as immunity or metabolism can be object of future research to identify pharmacological targets for positive symptoms of schizophrenia. Mirtazapine could be useful for treating negative symptoms without increasing the risk of a worsening of delusions/hallucinations. Nevertheless, the lack of replication of studies prevents to draw definitive conclusions and future studies are needed to confirm the findings presented in this overview.
Topics: Humans; Female; Schizophrenia; Antipsychotic Agents
PubMed: 37401388
DOI: 10.1080/14656566.2023.2231346 -
BioRxiv : the Preprint Server For... Aug 2023Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed,...
OBJECTIVE
Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed, and hypoglycemic conditions, yet metabolic regulation of α-cells remains poorly understood. Here, we identified a previously unexplored role for physiological levels of leucine, which is classically regarded as a β-cell fuel, in the intrinsic regulation of α-cell glucagon release.
METHODS
GcgCre:CAMPER and GcgCre:GCaMP6s mice were generated to perform dynamic, high-throughput functional measurements of α-cell cAMP and Ca within the intact islet. Islet perifusion assays were used for simultaneous, time-resolved measurements of glucagon and insulin release from mouse and human islets. The effects of leucine were compared with glucose and the mitochondrial fuels 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH, non-metabolized leucine analog that activates glutamate dehydrogenase), α-ketoisocaproate (KIC, leucine metabolite), and methyl-succinate (complex II fuel). CYN154806 (Sstr2 antagonist), diazoxide (K activator, which prevents Ca-dependent exocytosis from α, β, and δ-cells), and dispersed α-cells were used to inhibit islet paracrine signaling and identify α-cell intrinsic effects.
RESULTS
Mimicking the effect of glucose, leucine strongly suppressed amino acid-stimulated glucagon secretion. Mechanistically, leucine dose-dependently reduced α-cell cAMP at physiological concentrations, with an IC of 57, 440, and 1162 μM at 2, 6, and 10 mM glucose, without affecting α-cell Ca. Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonist or diazoxide, as well as dispersed α-cells, indicating an α-cell intrinsic effect. The effect of leucine was matched by KIC and the glutamate dehydrogenase activator BCH, but not methyl-succinate, indicating a dependence on mitochondrial anaplerosis. Glucose, which stimulates anaplerosis via pyruvate carboxylase, had the same suppressive effect on α-cell cAMP but with lower potency. Similarly to mouse islets, leucine suppressed glucagon secretion from human islets under hypoglycemic conditions.
CONCLUSIONS
These findings highlight an important role for physiological levels of leucine in the metabolic regulation of α-cell cAMP and glucagon secretion. Leucine functions primarily through an α-cell intrinsic effect that is dependent on glutamate dehydrogenase, in addition to the well-established α-cell regulation by β/δ-cell paracrine signaling. Our results suggest that mitochondrial anaplerosis-cataplerosis facilitates the glucagonostatic effect of both leucine and glucose, which cooperatively suppress α-cell tone by reducing cAMP.
PubMed: 37577685
DOI: 10.1101/2023.07.31.551113 -
Gene Aug 2023The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in...
The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding K channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.
Topics: Humans; Infant; Male; Congenital Hyperinsulinism; Diazoxide; Heterozygote; Insulin; Mutation; Sulfonylurea Receptors
PubMed: 37336273
DOI: 10.1016/j.gene.2023.147576 -
Indian Pediatrics Jun 2024Congenital hyperinsulinism (CHI) is a rare condition but is a common cause of severe and persistent hypoglycemia in early life. Prompt recognition of CHI is critical to... (Review)
Review
Congenital hyperinsulinism (CHI) is a rare condition but is a common cause of severe and persistent hypoglycemia in early life. Prompt recognition of CHI is critical to prevent the impact of neuroglycopenia and consequent lifelong neurodisability. It is important to be alert to the possibility of CHI in newborn babies with recurrent hypoglycemia associated with high glucose requirements. Pediatricians are advised to mitigate the risk of hypoglycemia by early treatment with high concentration dextrose and intravenous glucagon infusions. Specific medical therapies with diazoxide and/or somatostatin receptor analogues may be commenced after the finding of detectable insulin at hypoglycemia, a biochemical characteristic of CHI. Early exploration of genetic etiology is recommended, chiefly in the search for a focal form, amenable to limited pancreatic surgery. Genetic ascertainment is also useful to understand the basis of disease, variable responses to medical therapies and escalation of conservative treatment to subtotal pancreatectomy. CHI is a heterogeneous disorder with varying natural history. Many newborns and infants with CHI have severe and complex illness features; their long-term care is best achieved through review at specialist centers.
Topics: Humans; Congenital Hyperinsulinism; Infant, Newborn; Pediatricians; Infant; Hypoglycemia
PubMed: 38584412
DOI: No ID Found -
Diabetes Sep 2023Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can...
UNLABELLED
Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.
ARTICLE HIGHLIGHTS
Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.
Topics: Animals; Mice; Antibodies; Blood Glucose; Congenital Hyperinsulinism; Diazoxide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperinsulinism; Mutation; Sulfonylurea Receptors
PubMed: 37358194
DOI: 10.2337/db22-1039 -
Problemy Endokrinologii Feb 2024Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence... (Review)
Review
RELEVANCE
Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence of NET especially insulinoma.
AIM
Summarizing and analyzing current data on various approaches to the treatment of insulinoma. Our review includes a comprehensive assessment of the advantages and disadvantages of currently available insulinoma treatment methods in comparison with past experience, as well as a review of promising methods that are not currently widely used.
MATERIALS AND METHODS
Analysis of literature from such databases as scientific electronic library elibrary.ru, Pubmed, Google Scholar, MedLine, Scopus and Web of Science.
RESULTS
The most common treatment for insulinoma is surgery. For patients with high operative risk, alternative methods such as alcohol ablation, radiofrequency ablation, and tumor embolization may be used. Medications include the use of somatostatin analogues, diazoxide. The literature describes the potential benefit of the use of beta-blockers, phenytoin, glucagon, however, in clinical trials, these drugs have not demonstrated a significant effect. For the treatment of malignant and metastatically advanced insulinoma, targeted therapy (primarily Everolimus), chemotherapy, as well as embolization (including chemoembolization, radioembolization), radiofrequency ablation (RFA), microwave ablation and cryoablation, ultrasound ablation (HIFU), laser ablation, brachytherapy, irreversible electroporation are used.
CONCLUSION
The study of new drugs is an important task for scientists, among medications the most promising are new generations of somatostatin analogues, targeted drugs and chemotherapy drugs. The rare frequency of insulinoma makes it difficult to conduct randomized controlled trials and prospective studies. That is why physicians and scientists need to maintain close contacts with each other and take into account the experience of treating each patient with such disease, which will help develop effective treatment algorithms in the future.
Topics: Humans; Insulinoma; Prospective Studies; Neuroendocrine Tumors; Apudoma; Pancreatic Neoplasms; Somatostatin
PubMed: 38433541
DOI: 10.14341/probl13281 -
Physiological Reports Apr 2024High sodium intake is decisive in the incidence increase and prevalence of hypertension, which has an impact on skeletal muscle functionality. Diazoxide is an...
High sodium intake is decisive in the incidence increase and prevalence of hypertension, which has an impact on skeletal muscle functionality. Diazoxide is an antihypertensive agent that inhibits insulin secretion and is an opener of K channels (adosine triphosphate sensitive potasium channels). For this reason, it is hypothesized that moderate-intensity exercise and diazoxide improve skeletal muscle function by reducing the oxidants in hypertensive rats. Male Wistar rats were assigned into eight groups: control (CTRL), diazoxide (DZX), exercise (EX), exercise + diazoxide (EX + DZX), hypertension (HTN), hypertension + diazoxide (HTN + DZX), hypertension + exercise (HTN + EX), and hypertension + exercise + diazoxide (HTN + EX + DZX). To induce hypertension, the rats received 8% NaCl dissolved in water orally for 30 days; in the following 8 weeks, 4% NaCl was supplied to maintain the pathology. The treatment with physical exercise of moderate intensity lasted 8 weeks. The administration dose of diazoxide was 35 mg/kg intraperitoneally for 14 days. Tension recording was performed on the extensor digitorum longus and the soleus muscle. Muscle homogenates were used to measure oxidants using fluorescent probe and the activity of antioxidant systems. Diazoxide and moderate-intensity exercise reduced oxidants and increased antioxidant defenses.
Topics: Animals; Diazoxide; Male; Muscle, Skeletal; Rats, Wistar; Hypertension; Physical Conditioning, Animal; Rats; Antioxidants; Oxidative Stress; Oxidants
PubMed: 38653584
DOI: 10.14814/phy2.16026