Hyperinsulinism Research Articles

Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management

Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in children, which if unrecognized may lead to development delays and permanent neurologic damage. Prompt recognition and appropriate treatment of HI are essential to avoid these sequelae. Major advances have been made over the past two decades in understanding the molecular basis of hyperinsulinism and mutations in nine genes are currently known to cause HI. Inactivating KATP channel mutations cause the most common and severe type of HI, which occurs in both a focal and a diffuse form. Activating mutations of glutamate dehydrogenase (GDH) lead to hyperinsulinism/hyperammonemia syndrome, while activating mutations of glucokinase (GK), the “glucose sensor” of the beta cell, causes hyperinsulinism with a variable clinical phenotype. More recently identified genetic causes include mutations in the genes encoding short-chain 3-hydroxyacyl-CoA (SCHAD), uncoupling protein 2 (UCP2), hepatocyte nuclear factor 4-alpha (HNF-4α), hepatocyte nuclear factor 1-alpha (HNF-1α), and monocarboyxlate transporter 1 (MCT-1), which results in a very rare form of HI triggered by exercise. For a timely diagnosis, a critical sample and a glucagon stimulation test should be done when plasma glucose is < 50 mg/dL. A failure to respond to a trial of diazoxide, a KATP channel agonist, suggests a KATP defect, which frequently requires pancreatectomy. Surgery is palliative for children with diffuse KATPHI, but children with focal KATPHI are cured with a limited pancreatectomy. Therefore, distinguishing between diffuse and focal disease and localizing the focal lesion in the pancreas are crucial aspects of HI management. Since 2003, 18 F-DOPA PET scans have been used to differentiate diffuse and focal disease and localize focal lesions with higher sensitivity and specificity than more invasive interventional radiology techniques. Hyperinsulinism remains a challenging disorder, but recent advances in the understanding of its genetic basis and breakthroughs in management should lead to improved outcomes for these children.

Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism

PurposeThe purpose of the study was to determine the sensitivity of the 18fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography scan (18F-PET/CT) in the diagnosis of focal congenital hyperinsulinism (HI). MethodsA retrospective review of children with HI who underwent a preoperative 18F-PET/CT scan was performed. ResultsBetween 1/2008 and 2/2012 we performed 105 consecutive 18F-PET/CT scans on infants with HI. Fifty-three patients had focal HI. Of those fifty-three patients, eight had a preoperative 18F-PET/CT scan read as “diffuse disease”. The sensitivity of the study in the diagnosis of focal HI was 85%. The location of the eight missed focal lesions was: head (3), body (2), and tail (3). The 18F-PET/CT of the missed head lesions showed homogeneous tracer uptake (n =2) or heterogeneous uptake throughout the pancreas (n=1). The 18F-PET/CT of the 2 missed body lesions and 1 missed tail lesion showed heterogeneous uptake throughout the pancreas. The 18F-PET/CT of the other 2 missed tail lesions showed lesions adjacent to and obscured by the signal of the upper renal pole, identified retrospectively by closer observation. Fifty-two of the 105 patients had diffuse HI. Two of them had 18F-PET/CT studies read as “focal disease”. Therefore, the specificity of the study was 96%. Of the forty-seven 18F-PET/CT studies read as “focal disease”, forty-five had true focal HI. Therefore, the positive predictive value of the study in the diagnosis of focal HI was 96%. ConclusionThe sensitivity and specificity of 18 F-PET/CT can be affected by certain anatomic features of the pancreas, by the location of the lesion, and by the reader's experience.

Mechanisms of amino acid-stimulated insulin secretion in congenital hyperinsulinism

The role of amino acids in the regulation of insulin secretion in pancreatic beta-cells is highlighted in three forms of congenital hyperinsulinism (HI), namely gain-of-function mutations of glutamate dehydrogenase (GDH), loss-of-function mutations of ATP-dependent potassium channels, and a deficiency of short-chain 3-hydroxyacyl-CoA dehydrogenase. Studies on disease mouse models of HI suggest that amino acid oxidation and signaling effects are the major mechanisms of amino acid-stimulated insulin secretion. Amino acid oxidation via GDH produces ATP and triggers insulin secretion. The signaling effect of amino acids amplifies insulin release after beta-cell depolarization and elevation of cytosolic calcium.

Genotype and Phenotype Correlations in 417 Children With Congenital Hyperinsulinism

Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes. Our objective was to correlate genotype with phenotype in 417 children with HI. 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. 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. 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.

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: Few clinical features suggestive of Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Congenital Hyperinsulinism Associated With Beckwith Wiedemann Syndrome

J. D. is a 9-month-old Caucasian male with hyperinsulinism (HI). J. D. reportedly had hypoglycemia at birth (exact data unavailable). He was discharged day of life (DOL) 3, when blood glucose (BG) levels “stabilized.” On DOL 4, he had a seizure, was taken to the emergency room, and had a dangerously low BG level of 6 mg/dL (70–110). His medical evaluation was consistent with HI, but he failed medication therapy. He was discharged home on continuous feeds, but over the next several months had persistent hypoglycemia with BGs less than 50 mg/dL. Therefore, he was readmitted to his local hospital. Without additional treatment options, he was transferred to a hyperinsulinism center for further evaluation. J. D. was the product of a pregnancy complicated by maternal lupus. He was full term and weighed 4.6 kg (large for gestational age). HI was confirmed when laboratory values revealed a detectable insulin level, suppressed serum beta-hydroxybutyrate, and an inappropriate glycemic response to glucagon at the time of hypoglycemia. HI genetic testing was negative. An 18 F-DOPA PET scan of the pancreas suggested a possible focal lesion in the pancreatic head causing HI. During exploratory surgery, there was no evidence of focal or diffuse HI. The pathology of J. D.'s pancreatic biopsies indicated diffuse islet cell hyperplasia. J. D. had hemihypertrophy, raising the suspicion of Beckwith Wiedemann syndrome (BWS). Mosaic BWS was diagnosed, with a mutation on chromosome 11 (11p15.5p11.11). A gastrostomy tube was placed for continuous enteral administration of dextrose. J. D. maintained BGs greater than 70 mg/dL for 12 hours on a glucose infusion rate of 5 mg/kg per minute. He was discharged home on this regimen. BWS is frequently associated with HI. The clinical course and response to treatment have been variable, and medical therapy may not be successful. Further research is needed to analyze this association and treatment modalities. The genetic mutations in both HI and BWS are on chromosome 11, raising the question of a genetic link. Alternatively, because BWS is an overgrowth syndrome, perhaps the HI is simply an effect of islet cell hyperplasia.

An ABCC8 gene mutation leading to the onset of KATP-congenital hyperinsulinism in a Chinese boy and his pedigree analysis

ABCC8,KCNJ11,and GLUD1 gene mutations were investigated in a male patient with congenital hyperinsulinism and his parents were also investigated.A 1484 G＞A mutation was found in the 10th exon of ABCC8 gene in the patient,which leads to amino acid substitution at the 495 residue of the sulphonylurea receptor SUR1 protein.The patient's father also carried the same heterozygous inactive mutation,while the genotype of the mother was normal,indicating that the gene mutation of the patient was paternally inherited.According to that mutation,it is deduced that the patient may suffer from the focal type of congenital hyperinsulinism. Key words: Congenital hyperinsulinism; ABCC8 gene; KATP channel

Pancreatic head resection and Roux-en-Y pancreaticojejunostomy for the treatment of the focal form of congenital hyperinsulinism

Purpose To determine the outcome of patients who underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy to the remaining normal pancreatic body and tail for the treatment of a focal lesion in the pancreatic head causing congenital hyperinsulinism (HI). Methods One hundred thirty-eight patients underwent pancreatic resection for focal HI between 1998 and 2010. Twenty-three patients in the group underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy. Results There were 13 females and 10 males. Median age and weight at surgery were 8 weeks and 5.8 kg, respectively. Twenty-one patients had a near-total pancreatic head resection, and 2 patients had a pylorus-preserving Whipple procedure. The pancreaticojejunostomy anastomosis was performed with interrupted fine monofilament sutures such that the transected end of the pancreatic body was tucked within the end of the Roux-en-Y jejunal limb. Median hospital stay was 22 days. All patients were cured of HI. Conclusion We conclude that pancreatic head resection with Roux-en-Y pancreaticojejunostomy is a safe and effective procedure for the treatment of the HI patient with a large focal lesion in the pancreatic head that is not amenable to local resection alone.

Selective breeding of mice for different susceptibilities to high fat diet-induced glucose intolerance: Development of two novel mouse lines, Selectively bred Diet-induced Glucose intolerance-Prone and -Resistant.

Aims/Introduction: The development of type 2 diabetes is primarily due to lifestyle and environmental factors, as well as genetics, as shown by familial clustering. To establish mouse lines for evaluating heritable factors determining susceptibility to diet-induced diabetes, we performed selective breeding for differences in high fat diet (HFD)-induced glucose intolerance. Selective breeding was performed using hybrid mice of C57BL/6J, C3H/HeJ and AKR/N backgrounds. After 5-week HFD feeding, mice showing high and low 2-h blood glucose levels in an oral glucose tolerance test (OGTT) were selected and bred over 14 generations to produce lines prone and resistant to diet-induced glucose intolerance (designated Selectively bred Diet-induced Glucose intolerance-Prone [SDG-P] and -Resistant [SDG-R]). At 5 weeks of age (pre HFD feeding), SDG-P mice showed higher blood glucose levels both in the OGTT and insulin tolerance test as compared to SDG-R mice. After receiving HFD, the glucose intolerance of SDG-P mice became more evident without hyper insulin secretion. In addition, SDG-P mice had greater body weight gain and lower HDL-cholesterol levels as compared to SDG-R mice. In comparison with C57BL/6J, a well-known strain prone to HFD-induced glucose intolerance, SDG-P mice showed significantly higher glucose levels in OGTT after the 5-week HFD feeding. Susceptibility to HFD-induced glucose intolerance was transmitted over generations and was intensified by selective breeding. The newly established mouse lines, SDG-P and SDG-R, may be useful in investigating the pathophysiology of type 2 diabetes through elucidating the crucial factors for determining the susceptibility to HFD-induced glucose intolerance. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00175.x, 2011).

Successful treatment of congenital hyperinsulinism with long-acting release octreotide

Congenital hyperinsulinism (HI) is a common cause of hypoglycemia in infancy. The medical treatment of diazoxide-unresponsive HI is based on a somatostatin analogue. This study aims at replacing three daily s.c. octreotide (Sandostatin, Novartis) injections by a single and monthly i.m. injection of long-acting release (LAR) octreotide (Sandostatin LP, Novartis) in HI patients. LAR octreotide was injected every 4 weeks during 6 months and s.c. octreotide injections were stopped after the third injection of LAR octreotide. After this 6-month study, LAR octreotide was continued, with an average follow-up of 17 months. Ten HI pediatric patients unresponsive to diazoxide and currently treated with s.c. octreotide were included in the trial. Glycemias and other parameters (HbA1c, IGF1, height, weight, quality of life (QoL), and satisfaction) were monitored at each monthly visit. For all ten patients, glycemias were maintained in the usual range, HbAlc (mean 5.5%; 95% CI: 4.6-6.2) and IGF1 (mean 89.7 ng/ml; 95% CI: 26-153) were unchanged. Patients gained height significantly (mean 2.7 cm; 95% CI: 1.9-3.4) and no side effect was noted during the study and the later follow-up. Plasma octreotide levels were stable under LAR octreotide. Parents' questionnaires of general satisfaction were highly positive whereas children's QoL evaluation remained unchanged. In these diazoxide-unresponsive HI patients, LAR octreotide was efficient, well tolerated and contributed to a clear simplification of the medical care.

Congenital hyperinsulinism: current trends in diagnosis and therapy

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.

Congenital Hyperinsulinism: Overview and Clinical Update

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy. This review gives an overview and update of pathogenesis, genetics, diagnosis and management of CHI. This diesease is a genetically heterogeneous disorder with both familial and sporadic variants and is biochemically characterized by an unregulated secretion of insulin from pancreatic beta cells in relation to the blood glucose concentration. To date, there are eight different genes described which lead to CHI. However, in 50% of patients the genetic mechanism is still unknown. The clinical presentation is heterogeneous with regard to age of onset, severity and manner of symptoms. This is explained by different pathogenetic mechanism resulting in inappropriate insulin secretion. An early and rapid diagnosis including initiation of an effective treatment is essential for preventing hypoglycaemic brain damage and neurological sequelae in affected children. Over the last years, substantial progress in diagnostic with 18F-L-dopa positron emission tomography for differentiating diffuse from focal disease and new laparoscopic surgery techniques has been made. In patients with diffuse form of CHI medical treatment with diazoxide, which is ineffective in patients with defects of the KATP channel, is the first line treatment. When medical treatment failed a near-total pancreatectomy has to be considered as a last resort. In patients with focal CHI a limited pancreatectomy can lead to complete cure of the disease. Patients should be managed by centres with a highly experienced team in diagnostic work-up and treatment of CHI.

A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism

Hyperinsulinism (HI) is the most common cause of transient and permanent forms of hypoglycemia in infancy. Establishing the correct diagnosis and initiating appropriate therapy without delay is of utmost importance. Once the diagnosis is made and if medical therapy with diazoxide fails, one should assume that the infant has a K(ATP) channel defect and may require surgery. In this case, the infant should be referred to a center that specializes in HI with 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography scan. This report describes a center specializing in HI with a team of experts consisting of endocrinologists, nurse practitioners, geneticists, radiologists, pathologists, and a surgeon. It describes the center's paradigm for managing severe HI on the basis of more than 250 cases of HI in the past 10 years, including the diagnosis of HI, medical options, genetics of HI, imaging in HI, the surgical approach to HI, and outcomes.

Congenital Hyperinsulinism and Glucose Hypersensitivity in Homozygous and Heterozygous Carriers of Kir6.2 (KCNJ11) Mutation V290M Mutation

OBJECTIVEThe ATP-sensitive K+ channel (KATP) controls insulin secretion from the islet. Gain- or loss-of-function mutations in channel subunits underlie human neonatal diabetes and congenital hyperinsulinism (HI), respectively. In this study, we sought to identify the mechanistic basis of KATP-induced HI in two probands and to characterize the clinical course.RESEARCH DESIGN AND METHODSWe analyzed HI in two probands and characterized the course of clinical treatment in each, as well as properties of mutant KATP channels expressed in COSm6 cells using Rb efflux and patch-clamp methods.RESULTSWe identified mutation V290M in the pore-forming Kir6.2 subunit in each proband. In vitro expression in COSm6 cells supports the mutation resulting in an inactivating phenotype, which leads to significantly reduced activity in intact cells when expressed homomerically, and to a lesser extent when expressed heteromerically with wild-type subunits. In one heterozygous proband, a fluoro-DOPA scan revealed a causal focal lesion, indicating uniparental disomy with loss of heterozygosity. In a second family, the proband, homozygous for the mutation, was diagnosed with severe diazoxide–unresponsive hypersinsulinism at 2 weeks of age. The patient continues to be treated successfully with octreotide and amlodipine. The parents and a male sibling are heterozygous carriers without overt clinical HI. Interestingly, both the mother and the sibling exhibit evidence of abnormally enhanced glucose tolerance.CONCLUSIONSV290M results in inactivating KATP channels that underlie HI. Homozygous individuals may be managed medically, without pancreatectomy. Heterozygous carriers also show evidence of enhanced glucose sensitivity, consistent with incomplete loss of KATP channel activity.

Diabetes and cancer

Diabetes and cancer, two heterogeneous multffactorial severe chronic diseases, are closely related. Epidemiological studies clearly indicate that diabetics have an increased risk and mortality of several cancers, including cancers of the pancreas, liver, breast, colorectum and urinary tract. Insulin is a growth factor with preeminent metabolic and mitogenic effects and functions at both receptor and post-receptor level during cancer development. As a result, hyperinsulinemia is the most likely cause of cancers among diabetic patients. However, anti-diabetic drugs, obesity, hyperglycemia, and increased oxidative stress may also contribute to the increased cancer risk among diabetics. Key words: Diabetes mellitus; Neoplasms; Hyperinsulinism; Insulin-like growth factor Ⅰ

The hyperinsulinism/hyperammonemia syndrome

The hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common form of congenital hyperinsulinism (HI). Children affected by this syndrome have both fasting and protein sensitive hypoglycemia combined with persistently elevated ammonia levels. Gain of function mutations in the mitochondrial enzyme glutamate dehydrogenase (GDH) are responsible for the HI/HA syndrome. GDH is expressed in liver, kidney, brain, and pancreatic beta-cells. Patients with the HI/HA syndrome have an increased frequency of generalized seizures, especially absence-type seizures, in the absence of hypoglycemia. The hypoglycemia of the HI/HA syndrome is well controlled with diazoxide, a KATP channel agonist. GDH has also been implicated in another form of HI, short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency associated HI. The HI/HA syndrome provides a rare example of an inborn error of intermediary metabolism in which the effect of the mutation on enzyme activity is a gain of function.

Hyperinsulinisme de l'enfant et de l'adolescent: quand la détermination de la concentration en insuline n'est pas toujours suffisante (version française)

Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders. Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on beta-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma beta-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy. The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.

Hiperinsulinismo na infância: quando apenas uma dosagem de insulina não é suficiente

INTRODUCAO: A hipoglicemia em bebes e criancas pode causar convulsoes, atraso de desenvolvimento e dano cerebral permanente. O hiperinsulinismo (HI) e a causa mais comum de hipoglicemia, seja transitoria ou permanente. A HI e caracterizada pela secrecao inadequada de insulina, o que resulta em hipoglicemia persistente, de leve a grave. As diferentes formas de HI representam um grupo de doencas clinica, genetica e morfologicamente heterogeneo. CONTEUDO: Hiperinsulinismo congenito esta associado as mutacoes de SUR-1 e Kir6.2, glucoquinase, glutamato desidrogenase, 3-hidroxiacil-CoA desidrogenase de cadeia curta e expressao ectopica de SLC16A1 na membrana plasmatica das celulas beta. O HI pode estar associado ao estresse perinatal, como asfixia do nascimento, toxemia materna, prematuridade ou retardo do crescimento intra-uterino, resultando em hipoglicemia neonatal prolongada. Mimetismo de HI neonatal inclui pan-hipopituitarismo, hipoglicemia induzida por farmaco, insulinoma, anticorpos antiinsulina e estimuladores do receptor de insulina, sindrome de Beckwith-Wiedemann e disturbios congenitos de glicosilacao. Exames laboratoriais para HI podem incluir quantificacao de glicose, insulina, β-hidroxibutirato, acidos graxos, amonia e perfil de acilcarnitinas plasmaticos, alem de acidos orgânicos urinarios. Os exames geneticos estao disponiveis em laboratorios comerciais para os genes sabidamente associados a hiperinsulinemia. Testes de resposta insulinica aguda (RIA) sao uteis na caracterizacao fenotipica. Exames de imagem e histologicos tambem estao disponiveis para diagnosticar e classificar o HI. O objetivo do tratamento de criancas com HI e prevenir os danos cerebrais da hipoglicemia, mantendo niveis de glicose plasmatica acima de 70mg/dl por terapia farmacologica ou cirurgica. CONCLUSAO:A terapeutica do HI requer abordagem multidisciplinar que inclui endocrinologistas pediatricos, radiologistas, cirurgioes e patologistas, os quais sao treinados para diagnosticar, identificar e tratar o hiperinsulinismo.

Frequency, Severity, and Treatment Interventions in Patient With Hyperinsulinism and Feeding Dysfunction

Hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in young infants. Many require surgical treatment to control hypoglycemia. It has been suggested that feeding disorders are common in this group of patients.

Hyperinsulinism in Infancy and Childhood: When an Insulin Level Is Not Always Enough

Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders. Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on beta-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma beta-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy. The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.