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Journal of Clinical Research in... Dec 2017Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L).... (Review)
Review
Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate secretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH. In HH due to the inhibitory effect of insulin on lipolysis and ketogenesis there is suppressed ketone body formation in the presence of hypoglycaemia thus leading to increased risk of hypoglycaemic brain injury. Therefore, a prompt diagnosis and immediate management of HH is essential to avoid hypoglycaemic brain injury and long-term neurological complications in children. Advances in molecular genetics, imaging techniques (18F-DOPA positron emission tomography/computed tomography scanning), medical therapy and surgical advances (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This review article provides an overview to the background, clinical presentation, diagnosis, molecular genetics and therapy in children with different forms of HH.
Topics: Congenital Hyperinsulinism; Humans
PubMed: 29280746
DOI: 10.4274/jcrpe.2017.S007 -
International Journal of Molecular... Feb 2020Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning... (Review)
Review
Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves' orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula).
Topics: Antineoplastic Agents, Hormonal; Diabetic Retinopathy; Graves Ophthalmopathy; Growth Hormone-Secreting Pituitary Adenoma; Humans; Intestinal Neoplasms; Macular Edema; Neuroendocrine Tumors; Pancreatic Neoplasms; Pituitary Neoplasms; Somatostatin; Stomach Neoplasms
PubMed: 32121432
DOI: 10.3390/ijms21051682 -
American Journal of Medical Genetics.... Dec 2019Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate... (Review)
Review
Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.
Topics: Child; Congenital Hyperinsulinism; Epigenesis, Genetic; Genetic Testing; Humans; Infant; Mutation; Philadelphia; Syndrome
PubMed: 31414570
DOI: 10.1002/ajmg.c.31737 -
Human Mutation May 2020The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell... (Review)
Review
The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.
Topics: Congenital Hyperinsulinism; Diabetes Mellitus; Gain of Function Mutation; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant, Newborn; Insulin-Secreting Cells; Loss of Function Mutation; Mutation; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors
PubMed: 32027066
DOI: 10.1002/humu.23995 -
Frontiers in Endocrinology 2021Hypoglycemia is the result of defects/impairment in glucose homeostasis. The main etiological causes are metabolic and/or endocrine and/or other congenital disorders.... (Review)
Review
Hypoglycemia is the result of defects/impairment in glucose homeostasis. The main etiological causes are metabolic and/or endocrine and/or other congenital disorders. Despite hypoglycemia is one of the most common emergencies in neonatal age and childhood, no consensus on the definition and diagnostic work-up exists yet. Aims of this review are to present the current age-related definitions of hypoglycemia in neonatal-pediatric age, to offer a concise and practical overview of its main causes and management and to discuss the current diagnostic-therapeutic approaches. Since a systematic and prompt approach to diagnosis and therapy is essential to prevent hypoglycemic brain injury and long-term neurological complications in children, a comprehensive diagnostic flowchart is also proposed.
Topics: Child; High-Throughput Nucleotide Sequencing; Humans; Hypoglycemia
PubMed: 34408725
DOI: 10.3389/fendo.2021.684011 -
Tidsskrift For Den Norske Laegeforening... Dec 2023This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common...
This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common cause of persistent neonatal hypoglycaemia. The condition is a rare monogenic disorder characterised by elevated insulin secretion and is a result of mutations in genes that regulate insulin secretion from pancreatic beta cells. The anabolic effect of insulin induces systemic glucose uptake and inhibits gluconeogenesis, glycogenolysis, ketogenesis and lipolysis. Low levels of glucose and ketone bodies in the blood are harmful to the central nervous system and can lead to brain damage or death. Early diagnosis and treatment of congenital hyperinsulinism are therefore crucial for a good prognosis.
Topics: Child; Infant, Newborn; Humans; Congenital Hyperinsulinism; Ketone Bodies; Insulin
PubMed: 38088279
DOI: 10.4045/tidsskr.23.0425 -
The Journal of Clinical Endocrinology... Feb 2013Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes.
CONTEXT
Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes.
OBJECTIVE
Our objective was to correlate genotype with phenotype in 417 children with HI.
METHODS
Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1.
RESULTS
Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxide-unresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity.
CONCLUSIONS
Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI.
Topics: Child; Child, Preschool; Congenital Hyperinsulinism; Female; Genetic Association Studies; Genotype; Germinal Center Kinases; Glutamate Dehydrogenase; Humans; Infant; Male; Mutation; Phenotype; Potassium Channels; Protein Serine-Threonine Kinases
PubMed: 23275527
DOI: 10.1210/jc.2012-2169 -
Hormone Research in Paediatrics 2022Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the... (Review)
Review
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the field has advanced significantly. It was the development of the insulin radioimmunoassay by Yalow and Berson a decade later that made it possible to demonstrate that this form of persistent hypoglycemia was caused by insulin, and a few years later, Drash described the successful treatment of children with hyperinsulinism with the antihypertensive diazoxide, which until today remains the only approved treatment for hyperinsulinism. In the mid 1970s, Baker and Stanley described that hyperinsulinism can be recognized by inappropriate responses of metabolic fuels and hormones during the course of a provocative fasting challenge. Later, advances in molecular genetics led to the discovery of the different genetic subtypes of hyperinsulinism. One of the most impactful discoveries in the field was the recognition of the focal form of hyperinsulinism and the development of 18F-DOPA PET for the localization of focal lesions before surgery which has resulted in the possibility of cure for children with focal disease. However, treatment options for children with nonfocal diazoxide-unresponsive hyperinsulinism have continued to be limited. New drug development programs for hyperinsulinism promise to change this in the next few years. Unfortunately, despite all these advances, children with hyperinsulinism around the world continue to experience neurological sequelae at high rates, highlighting the importance of early diagnosis and effective treatment.
Topics: Child; Humans; Infant; Infant, Newborn; Antihypertensive Agents; Congenital Hyperinsulinism; Diazoxide; Insulin
PubMed: 36446321
DOI: 10.1159/000526442 -
Reviews in Endocrine & Metabolic... Dec 2020Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative... (Review)
Review
Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.
Topics: Adolescent; Child; Child, Preschool; Congenital Hyperinsulinism; Humans; Infant
PubMed: 32185602
DOI: 10.1007/s11154-020-09548-7