Severe Hyperinsulinemic Hypoglycemia Research Articles

Congenital hyperinsulinism in a Nigerian infant: A case report and review of literature

Congenital hyperinsulinism, a rare genetic disorder characterized by excess insulin secretion even during hypoglycemic episodes, has two histological subtypes; diffuse and focal. Genotypes denote which of the two subtypes presents, and this is the first case being reported in Nigeria. The aims of this study were to report the first case of genetically confirmed compound heterozygote inheritance for two non-sense mutations in the ABCC8 gene in a Nigerian child and her family. A full-term average weight (7.5 lb) female baby presented with severe hyperinsulinemic hypoglycemia [HH] after birth and failed medical treatment with dextrose infusion. She had several hypoglycemic seizure episodes and spastic diplegic cerebral palsy, despite frequent feeding. Following physiotherapy, her spasticity was regressing and she was also able to say polysyllabic words. Genetic testing done 2 years after birth showed that her father was heterozygous for the ABCC8 non-sense mutation, P.W143*, and her mother was heterozygous for the P.Q416* ABCC8 mutation. This report shows the need for quick and early genetic testing for rare disorders and the possibility of collaboration with more specialized genetic laboratories. When diagnosed, diffuse or focal diazoxide unresponsive hypoglycemia may be treated by partial or complete pancreatectomy with the potential complication of diabetes mellitus later in life.

Combined laparoscopic Roux-en-Y gastric bypass reversal and gastric banding to treat severe hyperinsulinemic hypoglycemia: A case report and surgical video.

Non insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a recently described complication of Roux-en-Y gastric bypass (RYGB) characterised by pathologic features of nesidioblastosis and hyperinsulinemic hypoglycemias that can occur months to years after surgery. Increased incretin production appears to be one of the involved mechanisms. Currently, there is no Gold Standard treatment. We present the case of a 57-year-old woman with a history of silastic ring vertical gastroplasty (SRVG) converted into RYGB who suffered from severe daily episodes of neuroglycopenia due to NIPHS, with poor response to conservative and medical treatments. At first, as it is suggested in recent literature, we decided to evaluate whether reversal would efficiently reduce episodes of hypoglycemia by attempting gastrostomy tubing of the remaining stomach. Since gastrostomy proved to be efficient, we reversed the RYGB laparoscopically and added a gastric banding to keep control over the patient's weight. After an asymptomatic period of two months, mild hypoglycemias recurred, on average once every three weeks, easily managed by sugar ingestion. A preexisting gastroparesis was worsened by the intervention, possibly caused by vagus nerve injury secondary to the multiple gastric procedures. A year later, the patient returned to a regular lifestyle. Her weight gain was limited to 8 kg thanks to appropriate adjustments of the gastric band. Treatment of NIPHS includes appropriate diet, pharmacotherapy and surgical procedures; partial or total pancreatectomy, laparoscopic reversal of RYGB (with or without sleeve gastrectomy) and gastric banding have been proposed. This is the first described case of severe NIPHS after RYGB successfully treated with combined laparoscopic reversal of gastric bypass and gastric banding to avoid weight regain. We expect this novel approach will help to overcome hypoglycemic episodes from NIPHS, while maintaining weight control and preventing the resurgence of obesity-related comorbidities. Further studies with long term follow-up are necessary. • Non insulinoma pancreatogenous hypoglycemia syndrome is a recently described complication of Roux-en-Y gastric bypass • Currently, there is no Gold Standard treatment. • In this case, we successfully performed a combined laparoscopic reversal of gastric bypass and gastric banding

CRISPR/Cas9 ADCY7 Knockout Stimulates the Insulin Secretion Pathway Leading to Excessive Insulin Secretion.

AimDespite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI.PatientA 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative.MethodsA trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR.ResultsHyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7, ADCY7 gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m(-/- Adcy7 ) cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis Adcy7 loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes Ins1 and Ins2 (p ≤ 0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of Scl2a2 and Gck via upregulation of Pdx1, and Foxa2 leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway.ConclusionThis study identified a novel candidate gene, ADCY7, to cause CHI via activation of the GSIS pathway.

One-Anastomosis Jejunal Interposition with Gastric Remnant Resection (Branco-Zorron Switch) for Severe Recurrent Hyperinsulinemic Hypoglycemia after Gastric Bypass for Morbid Obesity.

The anatomical and physiological changes after Roux-en-Y gastric bypass for morbid obesity can lead to severe hyperinsulinemic hypoglycemia with neuroglycopenia in a small percentage of patients. The exact physiologic mechanism is not completely understood. Surgical reversal to the original anatomy and distal or total pancreatectomy are current therapeutic options to reverse the hypoglycemic effect, with substantial associated morbidity. Our group reports a pilot clinical series of a novel surgical technique using one-anastomosis jejunal interposition with gastric remnant resection (Branco-Zorron Switch). Patients with severe symptomatic hyperinsulinemic hypoglycemia refractory to conservative therapy were treated using the technique. The procedure started with resection of the remnant stomach close to pylorus. The alimentary limb was sectioned at 20cm from the gastrojejunal anastomosis, and the rest of the alimentary limb was resected until the Y-Roux anastomosis. A hand-sutured anastomosis was then performed with the proximal alimentary limb and the remnant antrum. Four patients were successfully submitted to the procedure with reversal of the symptomatology and normalization of insulin levels, postprandial glucose levels, and oral glucose tolerance test, with a mean follow-up of 24.3months. Mean operative time was 188min, and patients recovered without postoperative complications. Patients suffering from severe hyperinsulinemic hypoglycemia after gastric bypass may be efficiently treated by this innovative procedure, avoiding extreme surgical therapy such as pancreatectomy or restoring the gastric anatomy, while still maintaining sustained weight loss. Studies with larger series and longer follow-up are still needed to define the role of this therapy in managing this entity.

Dumping syndrome: Diagnostics and therapeutic options

Dumping syndrome is a common complication after surgery of the upper gastrointestinal tract with symptoms ranging from mild gastrointestinal discomfort and moderate vasomotor disturbances, to severe hyperinsulinemic hypoglycemia. Due to the increasing number of bariatric procedures being performed worldwide, bariatric surgery has become the most common cause for this disease entity. The aim of this review is to highlight the evidence for the physiological mechanisms contributing to dumping syndrome after the two most common bariatric surgery procedures, Roux-en-Y gastric bypass and sleeve gastrectomy, to discuss technical aspects of the procedures underlying the development of the syndrome, patient-related predictive factors and other differential diagnoses, together with diagnostic and therapeutic algorithms.

Molecular mechanisms of congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.

The Use of Gastrostomy Tube for the Long-Term Remission of Hyperinsulinemic Hypoglycemia After Roux-en-y Gastric Bypass: A Case Report

ABSTRACT Objective: Hyperinsulinemic hypoglycemia is an increasingly reported complication of Roux-en-Y gastric bypass surgery (RYGB), for which there is currently no acceptable treatment. We present a case of the reversal of severe hyperinsulinemic hypoglycemia through gastrostomy tube (GT) feeding to the remnant stomach and uniquely report the durable resolution of neuroglycopenic symptoms 3 years after GT placement. Methods: The case subject underwent standardized postprandial measurement of plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon concentrations after oral or GT administration of a standardized liquid meal. Results: Hypersecretion of insulin, GLP-1, and glucagon elicited by oral administration of the liquid meal were reversed with GT feeding. GIP was not secreted in excess of normal after the oral meal. Conclusion: This case of reversible hyperinsulinemic hypoglycemia through GT feeding illustrates the physiology of this disorder, pointing to an exaggerated GLP-1 response due to rapid nutrient transit to the distal bowel. The sustained resolution of the case subject's neuroglycopenic symptoms supports the use of GT as an effective and durable treatment for severe refractory hyperinsulinemic hypoglycemia after RYGB. Abbreviations: GIP glucose-dependent insulinotropic peptide GLP-1 glucagon-like peptide-1 GT gastrostomy tube RYGB Roux-en-Y gastric bypass

Sirolimus Therapy in Infants with Severe Hyperinsulinemic Hypoglycemia

Hyperinsulinemic hypoglycemia is the most common cause of severe, persistent neonatal hypoglycemia. The treatment of hyperinsulinemic hypoglycemia that is unresponsive to diazoxide is subtotal pancreatectomy. We examined the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor sirolimus in four infants with severe hyperinsulinemic hypoglycemia that had been unresponsive to maximal doses of diazoxide (20 mg per kilogram of body weight per day) and octreotide (35 μg per kilogram per day). All the patients had a clear glycemic response to sirolimus, although one patient required a small dose of octreotide to maintain normoglycemia. There were no major adverse events during 1 year of follow-up.

Sirolimus Is Effective in Infants with Severe Hyperinsulinemic Hypoglycemia

Severe infantile hypoglycemia from hyperinsulinemia, most often from genetic dysregulation of pancreatic beta cells, is a major therapeutic challenge.

Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism

SummaryBackground: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia.Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation.Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease.Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI.Learning points HH is a cause of severe hypoglycaemia in the newborn period.Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease. 18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions.Gallium-68 tetra-aza-cyclododecane-N N′N″N-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions.The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear.Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.

Hydroxychloroquine Associated Hyperinsulinemic Hypoglycemia

Introduction Hypoglycemia in the patient without diabetes mellitus is uncommon. 1 An initial evaluation of hypoglycemia begins with confirming Whipple’s triad which includes: the presence of sympathoadrenal and neuroglycopenic symptoms, documented low plasma glucose concentration, and resolution of symptoms when plasma glucose is raised. 2 Hypoglycemia secondary to hydroxychloroquine previously has been documented in humans. 3,4 We describe a case of severe hyperinsulinemic hypoglycemia in a patient initiated on hydroxychloroquine therapy.

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.

Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase

BackgroundLoss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoA dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial β-oxidation of fatty acids. Mutations in GLUD1 encoding glutamate dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a protein-protein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with HADH mutations.MethodsAn oral leucine tolerance test was conducted in controls and nine patients with HADH mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions.ResultsPatients demonstrated severe HH (glucose range 1.7–3.2 mmol/l; insulin range 4.8-63.8 mU/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity and half maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples.ConclusionsWe conclude that GDH and HADH have a direct protein-protein interaction, which is lost in patients with HADH mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with GLUD1 mutations).

Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia

Background: Loss of function mutations in the genes encoding the pancreatic β-cell ATP-sensitive potassium (KATP) channel are identified in approximately 80% of patients with diazoxide unresponsive hyperinsulinemic hypoglycemia (HH). For a small number of patients HH can occur as part of a multisystem disease such as Beckwith–Wiedemann syndrome (BWS). In approximately 20% of patients, BWS results from chromosome 11 paternal uniparental disomy (UPD), which causes dysregulation of imprinted growth regulation genes at 11p15.5. There is a considerable range in the clinical features and phenotypic severity associated with BWS which is likely to be due to somatic mosaicism. The cause of HH in these patients is not known. Research Design and Methods: We undertook microsatellite analysis of 12 markers spanning chromosome 11p in two patients with severe HH and diffuse disease requiring a pancreatectomy. In both patients mutations in the KATP channel genes had not been identified. Results: We identified segmental paternal UPD in DNA extracted from pancreatic tissue in both patients. UPD was not observed in DNA extracted from the patient’s leukocytes or buccal samples. In both cases the UPD encompassed the differentially methylated region at chromosome 11p15.5. Despite this neither patient had any further features of BWS. Conclusion: Paternal UPD of the chromosome 11p15.5 differentially methylated region limited to the pancreatic tissue may represent a novel cause of isolated diazoxide unresponsive HH. Loss of heterozygosity studies should therefore be considered in all patients with severe HH who have undergone pancreatic surgery when KATP channel mutation(s) have not been identified.

Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass

Glucagon-like peptide-1 (GLP-1) receptors are highly overexpressed in benign insulinomas, permitting in vivo tumour visualisation with GLP-1 receptor scanning. The present study sought to evaluate the GLP-1 receptor status in vitro in other pancreatic disorders leading to hyperinsulinaemic hypoglycaemia, specifically after gastric bypass surgery. Fresh frozen pancreatic tissue samples (n=7) from six gastric bypass surgery patients suffering from hyperinsulinaemic hypoglycaemia were evaluated for GLP-1 receptor content using in vitro receptor autoradiography, and compared with normal pancreas and with pancreatic insulinoma tissues. GLP-1 receptor analysis of the pancreatic tissues, which histopathologically were compatible with nesidioblastosis and originated from post-bypass hypoglycaemic patients, revealed a mean density value of GLP-1 receptors in the islets of 1,483 ± 183 dpm/mg tissue. Pharmacological characterisation indicated the presence of specific GLP-1 receptors. The density of islet GLP-1 receptor in post-gastric bypass patients did not differ from that of normal pancreas (1,563 ± 104 dpm/mg tissue, n = 10). Receptor density in pancreatic acini was low in post-bypass and control conditions. In contrast, benign insulinomas showed a high density of GLP-1 receptors, with a mean value of 8,302 ± 1,073 dpm/mg tissue (n = 6). In contrast to insulinoma, hyperinsulinaemic hypoglycaemia after gastric bypass surgery is not accompanied by overexpression of GLP-1 receptor in individual islets. Thus, patients with post-gastric bypass hyperinsulinaemic hypoglycaemia are not candidates for GLP-1 receptor imaging in vivo using radiolabelled exendin. These GLP-1 receptor data support the notion that the islet pathobiology of post-gastric bypass hypoglycaemia is distinctly different from that of benign insulinomas.

3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency and Hyperinsulinemic Hypoglycemia: Characterization of a Novel Mutation and Severe Dietary Protein Sensitivity

HADH encodes for the enzyme 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) and catalyses the penultimate reaction in the beta-oxidation of fatty acids. All previously reported patients with mutations in HADH gene and hyperinsulinemic hypoglycemia (HH) showed raised plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate. The aims of the study were: 1) to report a novel HADH gene mutation not associated with abnormal acylcarnitine or urinary organic acid profile; and 2) to report the novel observation of severe protein-sensitive HH in three patients with HADH gene mutations. The index case presented at 4 months of age with hypoglycemic seizures. Her HH responded to diazoxide, but she continued to have episodes of hypoglycemia even on diazoxide, especially when consuming high-protein foods. Investigations confirmed HH (blood glucose level of 1.8 mmol/liter with simultaneous serum insulin level of 58 mU/liter) with normal acylcarnitines and urine organic acids. Sequencing of the HADH gene identified a homozygous missense mutation (c.562A>G; p.Met188Val). Hydroxyacyl-coenzyme A dehydrogenase activity was significantly decreased compared with controls (index patient, mean +/- sem, 26.8 +/- 4.8 mU/mg protein; controls, 48.0 +/- 8.1 mU/mg protein; P = 0.029) in skin fibroblasts. This patient was severely protein sensitive. Two other children with HH due to HADH gene mutations also demonstrated marked protein sensitivity. Mutations in the HADH gene are associated with protein-induced HH, and patients with HH due to HADH gene mutations may have normal acylcarnitines and urine organic acids.

Mesenchymal Hamartoma of the Liver Associated with Features of Beckwith-Wiedemann Syndrome and High Serum Alpha-Fetoprotein Levels

A 5-month-old girl with clinical features of Beckwith-Wiedemann syndrome (BWS), including a repaired omphalocele, an earlobe crease, enlarged adrenal glands, renal size discrepancy, and hyperinsulinemic hyperglycemia, presented with a 1.9-cm liver nodule. Markedly increased serum alpha-fetoprotein (AFP) levels (1,060,000 mg/L), highly suspicious for hepatoblastoma, were detected, and resection of the liver mass was performed. Histologic sections showed features characteristic of a mesenchymal hamartoma of the liver (MHL). No features of embryonal or fetal hepatocellular proliferation or heterologous stromal components were noted. By immunohistochemistry, the hepatocytes expressed AFP, but no nuclear accumulation of beta-catenin was present. Electron microscopy revealed normal, mature hepatocytes. Here we address the diagnostic challenge of the uncommon association of MHL and BWS in the setting of markedly elevated serum AFP levels. In addition, we analyze the unusual pancreatic lesion (focal endocrine adenomatosis) leading to severe hyperinsulinemic hypoglycemia in a patient with possible BWS. We emphasize that MHLs may present with markedly increased serum AFP levels, mimicking hepatoblastomas, and may also be part of the expanding spectrum of findings of BWS.

The Diagnosis of Ectopic Focal Hyperinsulinism of Infancy with [18F]-Dopa Positron Emission Tomography

Congenital hyperinsulinism (CHI) is a cause of severe hypoglycemia in the neonatal and infancy period. Histologically, there are two subtypes with diffuse and focal disease. The preoperative differentiation of these two forms is very important because the surgical management is radically different. The focal form of the disease can be cured if the focal lesion can be localized accurately and completely resected with surgery. We report the case of a child who underwent three pancreatectomies with a choledochoduodenostomy and a cholecystectomy but continued to have severe hyperinsulinemic hypoglycemia. Radiological investigations including imaging with (18)fluoro-L-Dopa positron emission tomography scan showed a clear focus of increased (18)F-fluoro-L-Dopa uptake in the vicinity of the former head of the pancreas. On the magnetic resonance imaging scan, this focal uptake appeared to localize adjacent or next to duodenum (in the wall or cavity of the duodenum). This unique case highlights the importance of correctly localizing and completely resecting the focal lesion in patients with CHI. (18)Fluoro-L-Dopa positron emission tomography scan can identify ectopic focal lesions in patients with CHI.

Severe Congenital Hyperinsulinism Caused by a Mutation in the Kir6.2 Subunit of the Adenosine Triphosphate-Sensitive Potassium Channel Impairing Trafficking and Function

The ATP-sensitive potassium (K(ATP)) channel, assembled from the inwardly rectifying potassium channel Kir6.2 and the sulfonylurea receptor 1, regulates insulin secretion in beta-cells. A loss of function of K(ATP) channels causes depolarization of beta-cells and congenital hyperinsulinism (CHI), a disease presenting with severe hypoglycemia in the newborn period. Our objective was identification of a novel mutation in Kir6.2 in a patient with CHI and molecular and cell-biological analysis of the impact of this mutation. We combined immunohistochemistry, advanced life fluorescence imaging, and electrophysiology in HEK293T cells transiently transfected with mutant Kir6.2. The patient presented with macrosomia at birth and severe hyperinsulinemic hypoglycemia. Despite medical treatment, the newborn continued to suffer from severe hypoglycemic episodes, and at 4 months of age subtotal pancreatectomy was performed. We assessed patch-clamp recordings and confocal microscopy in HEK293T cells. We have identified a homozygous missense mutation, H259R, in the Kir6.2 subunit of a patient with severe CHI. Coexpression of Kir6.2(H259R) with sulfonylurea receptor 1 in HEK293T cells completely abolished K(ATP) currents in electrophysiological recordings. Double immunofluorescence staining revealed that mutant Kir6.2 was partly retained in the endoplasmic reticulum (ER) causing decreased surface expression as observed with total internal reflection fluorescence. Mutation of an ER-retention signal partially rescued the trafficking defect without restoring whole-cell currents. The H259R mutation of the Kir6.2 subunit results in a channel that is partially retained in the ER and nonfunctional upon arrival at the plasma membrane.

The Effect of Prematurity and Intrauterine Growth Restriction on Glucose Metabolism in the Newborn

After completing this article, readers should be able to: 1. List the three components required for the transition to independent glucose homeostasis in the newborn. 2. Explain why preterm infants are at increased risk for neonatal hypoglycemia. 3. Compare the capacity for gluconeogenesis in the term and preterm infant and in the infant who has intrauterine growth restriction. 4. Describe the effects of enteral feedings on glucose homeostasis in the newborn. At birth, the transplacental supply of nutrients, especially glucose, to the newborn is interrupted abruptly. This sets into motion a complex cascade of metabolic and endocrine events that allow a healthy term newborn to adjust to his or her new environment. This cascade is triggered by a surge in the concentrations of glucagon and catecholamines and cessation of insulin secretion. Glucagon and catecholamines increase glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. The complex enzyme machinery responsible for these processes is mature in term healthy newborns. In contrast, the metabolic and endocrine processes allowing the transition to the extrauterine environment are not developed fully in preterm infants and those who have suffered intrauterine growth restriction (IUGR), placing these newborns at significant risk of hypoglycemia. This review focuses on the regulation of glucose metabolism during the fetal period and the metabolic and endocrine changes that occur at birth and in the postnatal period, with special reference to preterm infants and infants who have experienced IUGR. Carbohydrate is transported to the fetus as glucose, which is taken up from the maternal plasma by glucose transporters. GLUT1 and GLUT3 are the primary glucose transporters involved in the transplacental movement of glucose and are present on both the microvillus and basal membranes of the syncytial barrier. Glucose is transported to the fetus by facilitative diffusion according to concentration-dependent kinetics, with placental glucose transport capacity increasing with gestational age. The …