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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 -
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 -
Nature Reviews. Endocrinology Mar 2016Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of... (Review)
Review
Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin- resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Humans; Hyperinsulinism; Insulin Resistance
PubMed: 26678809
DOI: 10.1038/nrendo.2015.216 -
Diabetes & Metabolism Journal May 2021The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute... (Review)
Review
The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.
Topics: Diabetes Mellitus, Type 2; Humans; Hyperinsulinism; Inflammation; Insulin Resistance; Neoplasms; Obesity
PubMed: 33775061
DOI: 10.4093/dmj.2020.0250 -
Obesity Research & Clinical Practice 2016Hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass (RYGB) due to the changes in gut hormonal... (Review)
Review
Hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass (RYGB) due to the changes in gut hormonal milieu. Physicians should be aware of this complication to ensure timely and effective treatment of post-RYGB patients, who present to them with hypoglycemic symptoms. Possible causes of hypoglycemia in these patients include late dumping syndrome, nesidioblastosis and rarely insulinoma. Systematic evaluation including history, biochemical analysis, and diagnostic testing might help in distinguishing among these diagnoses. Continuous glucose monitoring is also a valuable tool, revealing the episodes in the natural environment and can also be used to monitor treatment success. Treatment should begin with strict low carbohydrate diet, followed by medication therapy. Therapy with diazoxide, acarbose, calcium channel blockers and octreotide have been proven to be beneficial, but the response apparently is highly variable. When other treatment options fail, surgical options can be considered.
Topics: Bariatric Surgery; Humans; Hyperinsulinism; Hypoglycemia; Obesity, Morbid
PubMed: 26522879
DOI: 10.1016/j.orcp.2015.07.003 -
The Journal of Clinical Investigation Oct 2019In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a... (Review)
Review
In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic β cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of β cell dysfunction correlates with the severity of MetS highlights the need to better understand β cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS, as well as recent findings addressing the complexity of β cell identity and heterogeneity within the islet during disease progression. The differential responses observed in β cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind β cell adaptation, identity, and dysfunction in MetS.
Topics: Adaptation, Physiological; Animals; Cell Dedifferentiation; Cell Transdifferentiation; Diabetes Mellitus, Type 2; Disease Progression; Humans; Hyperinsulinism; Insulin Resistance; Insulin-Secreting Cells; Metabolic Syndrome; Risk Factors
PubMed: 31424428
DOI: 10.1172/JCI129188 -
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 -
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 -
Current Opinion in Pediatrics Aug 2018Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children. Early and appropriate recognition and treatment of hypoglycemia... (Review)
Review
PURPOSE OF REVIEW
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children. Early and appropriate recognition and treatment of hypoglycemia is vital to minimize neurocognitive impairment.
RECENT FINDINGS
There are at least 11 known monogenic forms of hyperinsulinism and several associated syndromes. Molecular diagnosis allows for prediction of the effectiveness of diazoxide and the likelihood of focal hyperinsulinism. Inactivating mutations in the genes encoding the ATP-sensitive potassium channel (KATP hyperinsulinism) account for 60% of all identifiable mutations, including 85% of diazoxide-unresponsive cases. Syndromes or disorders associated with hyperinsulinism include Beckwith-Wiedemann syndrome, Kabuki syndrome, Turner syndrome, and congenital disorders of glycosylation. Although focal hyperinsulinism can be cured by resection of the lesion, therapeutic options for nonfocal hyperinsulinism remain limited and include diazoxide, octreotide, long-acting somatostatin analogs, and near-total pancreatectomy. Although sirolimus has been reported to improve glycemic control in infants with diazoxide-unresponsive hyperinsulinism, the extent of improvement has been limited, and significant adverse events have been reported.
SUMMARY
Identification of the cause of congenital hyperinsulinism helps guide management decisions. Use of therapies with limited benefit and significant potential risks should be avoided.
Topics: Child; Congenital Hyperinsulinism; Genetic Markers; Genetic Testing; Humans; Infant; Syndrome
PubMed: 29750770
DOI: 10.1097/MOP.0000000000000645 -
Current Opinion in Endocrinology,... Feb 2014Neonatal hypoglycemia is one of the most common biochemical abnormalities encountered in the newborn. However, controversy remains surrounding its definition and... (Review)
Review
PURPOSE OF REVIEW
Neonatal hypoglycemia is one of the most common biochemical abnormalities encountered in the newborn. However, controversy remains surrounding its definition and management especially in asymptomatic patients.
RECENT FINDINGS
New information has been published that describes the incidence and timing of low glucose concentrations in the groups most at risk for asymptomatic neonatal hypoglycemia. Furthermore, one large prospective study failed to find an association between repetitive low glucose concentrations and poor neurodevelopmental outcomes in preterm infants. But hypoglycemia due to hyperinsulinism, especially genetic causes, continued to be associated with brain injury. New advances were made in the diagnosis and management of hyperinsulinism, including acquired hyperinsulinism in small for gestational age infants and others. Continuous glucose monitoring remains an attractive strategy for future research in this area.
SUMMARY
The fundamental question of how best to manage asymptomatic newborns with low glucose concentrations remains unanswered. Balancing the risks of overtreating newborns with low glucose concentrations who are undergoing a normal transition following birth against the risks of undertreating those in whom low glucose concentrations are pathological, dangerous, and/or a harbinger of serious metabolic disease remains a challenge.
Topics: Biosensing Techniques; Blood Glucose; Developmental Disabilities; Diazoxide; Diuretics; Female; Glucose; Humans; Hydrochlorothiazide; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Premature; Male; Monitoring, Physiologic; Potassium Chloride; Vasodilator Agents
PubMed: 24275620
DOI: 10.1097/MED.0000000000000027