Maltodextrin May Be a Promising Treatment Modality After Near-total Pancreatectomy in Infants Younger Than Six Months with Persistent Hyperinsulinism: A Case Report

Persistent hypoglycemia in infants with congenital hyperinsulinism (CHI) can be challenging in approximately half of these cases, even after undergoing a near-total pancreatectomy. While maltodextrin has been recommended in the nutritional management of CHI cases younger than six months, information regarding its efficacy in managing hypoglycemia are not yet clear. Here, we present a male infant with CHI who experienced persistent hypoglycemia even after undergoing a near-total pancreatectomy and despite multiple medical treatments. The infant's hypoglycemic episodes were successfully controlled by adding maltodextrin to his diet.

Cardiopulmonary Bypass for a Patient With Congenital Hyperinsulinemia.

Congenital hyperinsulinism is a clinical syndrome of pancreatic ß-cell dysfunction characterized by failure to suppress insulin secretion in the presence of hypoglycemia. Here, we describe the concerns, the techniques used to ameliorate these potential problems, and the outcomes for a child with this condition undergoing cardiopulmonary bypass for correction of an atrial septal defect.

Hyperinsulinism-Causing Mutations Cause Multiple Molecular Defects in SUR1 NBD1.

The sulfonylurea receptor 1 (SUR1) protein forms the regulatory subunit in ATP sensitive K+ (KATP) channels in the pancreas. SUR proteins are members of the ATP binding cassette (ABC) superfamily of proteins. Binding and hydrolysis of MgATP at the SUR nucleotide binding domains (NBDs) lead to channel opening. Pancreatic KATP channels play an important role in insulin secretion. SUR1 mutations that result in increased levels of channel opening ultimately inhibit insulin secretion and lead to neonatal diabetes. In contrast, SUR1 mutations that disrupt trafficking and/or decrease gating of KATP channels cause congenital hyperinsulinism, where oversecretion of insulin occurs even in the presence of low glucose levels. Here, we present data on the effects of specific congenital hyperinsulinism-causing mutations (G716V, R842G, and K890T) located in different regions of the first nucleotide binding domain (NBD1). Nuclear magnetic resonance (NMR) and fluorescence data indicate that the K890T mutation affects residues throughout NBD1, including residues that bind MgATP, NBD2, and coupling helices. The mutations also decrease the MgATP binding affinity of NBD1. Size exclusion and NMR data indicate that the G716V and R842G mutations cause aggregation of NBD1 in vitro, possibly because of destabilization of the domain. These data describe structural characterization of SUR1 NBD1 and shed light on the underlying molecular basis of mutations that cause congenital hyperinsulinism.

The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.

ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators.

Congenital hyperinsulinism and glucose hypersensitivity in homozygous and heterozygous carriers of Kir6.2 (KCNJ11) mutation V290M mutation: K(ATP) channel inactivation mechanism and clinical management.

OBJECTIVE: The ATP-sensitive K(+) channel (K(ATP)) 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 K(ATP)-induced HI in two probands and to characterize the clinical course. RESEARCH DESIGN AND METHODS: We analyzed HI in two probands and characterized the course of clinical treatment in each, as well as properties of mutant K(ATP) channels expressed in COSm6 cells using Rb efflux and patch-clamp methods. RESULTS: We 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. CONCLUSIONS: V290M results in inactivating K(ATP) 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 K(ATP) channel activity.

Hipoglicemia infantil / Hypoglycemia of infancy

Hypoglycemia of infancy is a common metabolic disorder that can have serious neurological consequences. Therefore, its early diagnosis and treatment are crucial prognostic factors. Hypoglycemia has a variety of causes and a good clinical history, physical examination and laboratory determination will orient the correct diagnosis. Occasionally a molecular study will be required.

Case report: pathological features of aberrant pancreatic development in congenital hyperinsulinism due to ABCC8 mutations.

We describe a patient with congenital hyperinsulinism with previously unreported pathological findings including normal to decreased number of insulin-positive cells with very few enlarged nuclei, aberrant distribution of glucagon-positive cells, and a non-insulin producing adenomatous focus of unusual morphology. Molecular analysis showed that the patient was a compound heterozygote for two mutations of the ABCC8 gene: a previously unreported nonsense mutation (R841X) and a missense mutation (D1471N) that has been previously described. This case suggests that abnormal function of ABCC8 may result in aberrant pancreatic development.

Functional imaging of the pancreas: the role of [18F]fluoro-L-DOPA PET in the diagnosis of hyperinsulinism of infancy.

Congenital hyperinsulinism (HI) of infancy, the most frequent cause of hypoglycaemia in young children, is a neuro-endocrine disease secondary to either focal adenomatous hyperplasia or a diffuse abnormal pancreatic insulin secretion. This inappropriate secretion of insulin induces severe hypoglycaemias that require aggressive treatment to prevent the high risk of irreversible brain damage. Focal and diffuse forms of HI share a similar clinical presentation, but their treatment is dramatically different. Selective surgical resection can cure focal HI whilst diffuse forms require near-total pancreatectomy if resistant to medical treatment. Until recently, preoperative differential diagnosis was based on pancreatic venous sampling, an invasive method, technically difficult to perform, which requires general anaesthesia. The pancreas is one of the most heavily innervated peripheral organs in the body, and its functional imaging with positron emission tomography (PET) is difficult to perform, in part because of the vast number of physiological roles and cell types that characterize this organ. However, HI, as all neuro-endocrine diseases, is notable for the ability to take up amine precursors and to convert them into biogenic amines. Therefore, we have evaluated the use of PET with [18F]fluoro-L-DOPA, a precursor of catecholamines, to image the pancreas and distinguish focal from diffuse HI.

Accuracy of [18F]fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism.

OBJECTIVES: Focal lesions in infants with congenital hyperinsulinism (HI) represent areas of adenomatosis that express a paternally derived ATP-sensitive potassium channel mutation due to embryonic loss of heterozygosity for the maternal 11p region. This study evaluated the accuracy of 18F-fluoro-l-dihydroxyphenylalanine ([18F]DOPA) positron emission tomography (PET) scans in diagnosing focal vs. diffuse disease and identifying the location of focal lesions. DESIGN: A total of 50 infants with HI unresponsive to medical therapy were studied. Patients were injected iv with [18F]DOPA, and PET scans were obtained for 50-60 min. Images were coregistered with abdominal computed tomography scans. PET scan interpretations were compared with histological diagnoses. RESULTS: The diagnosis of focal or diffuse HI was correct in 44 of the 50 cases (88%). [18F]DOPA PET identified focal areas of high uptake of radiopharmaceutical in 18 of 24 patients with focal disease. The locations of these lesions matched the areas of increased [18F]DOPA uptake on the PET scans in all of the cases. PET scan correctly located five lesions that could not be visualized at surgery. The positive predictive value of [18F]DOPA in diagnosing focal adenomatosis was 100%, and the negative predictive value was 81%. CONCLUSIONS: [18F]DOPA PET scans correctly diagnosed 75% of focal cases and were 100% accurate in identifying the location of the lesion. These results suggest that [18F]DOPA PET imaging provides a useful guide to surgical resection of focal adenomatosis and should be considered as a guide to surgery in all infants with congenital HI who have medically uncontrollable disease.

Congenital hyperinsulinism associated ABCC8 mutations that cause defective trafficking of ATP-sensitive K+ channels: identification and rescue.

Congenital hyperinsulinism (CHI) is a disease characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive K(+) (K(ATP)) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11, respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Previous studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide. The purpose of this study is to identify additional mutations that cause channel biogenesis/trafficking defects and those that are amenable to rescue by pharmacological chaperones. Fifteen previously uncharacterized CHI-associated missense SUR1 mutations were examined for their biogenesis/trafficking defects and responses to pharmacological chaperones, using a combination of immunological and functional assays. Twelve of the 15 mutations analyzed cause reduction in cell surface expression of K(ATP) channels by >50%. Sulfonylureas rescued a subset of the trafficking mutants. By contrast, diazoxide failed to rescue any of the mutants. Strikingly, the mutations rescued by sulfonylureas are all located in the first transmembrane domain of SUR1, designated as TMD0. All TMD0 mutants rescued to the cell surface by the sulfonylurea tolbutamide could be subsequently activated by metabolic inhibition on tolbutamide removal. Our study identifies a group of CHI-causing SUR1 mutations for which the resulting K(ATP) channel trafficking and expression defects may be corrected pharmacologically to restore channel function.

Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.

BACKGROUND: Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS: We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS: HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.

Congenital hyperinsulinism in an infant caused by a macroscopic insulin-producing lesion.

Congenital hyperinsulinism is the most common cause of persistent neonatal hypoglycemia. Severe congenital hyperinsulinism is most often due to inactivating mutations in either the ABCC8 or KCNJ11 genes, which encode the SUR1 and Kir6.2 proteins, respectively--the two components of the ATP-sensitive K+ (KATP) channel; neonatal hypoglycemia due to macroscopic insulin-producing pancreatic lesions or adenomas are extremely rare. KATP channel hyperinsulinism is classified as diffuse or focal, the latter being associated with paternally-derived mutations of ABCC8 or KCNJ11 and somatic loss of heterozygosity of the maternal alleles. KATP channelopathies usually produce microscopic intra-pancreatic lesions and are typically unresponsive to drug therapy, requiring > 95% pancreatectomy for diffuse disease and occasionally more limited pancreatic resection for focal disease; macroscopic pancreatic lesions and adenomas are focally excised. We describe a 1 month-old infant with severe congenital hyperinsulinism who had a macroscopic insulin-producing pancreatic lesion successfully treated with focal lesion enucleation.

Hypoglycemia in the neonate.

Hypoglycemic episodes occurring during the newborn period are often due to transient immaturity of glucoregulatory pathways. Normal feeding is generally the only measure required to treat such episodes. After the first few hours of life, however, hyperinsulinism (HI) is the most common cause of neonatal hypoglycemia. HI may persist for the first weeks/months of life and then remit spontaneously, particularly in low birth weight neonates and those exposed to perinatal stresses; hypoglycemia in such infants can nearly always be medically controlled using diazoxide. There are also several forms of congenital hyperinsulinism presenting with hypoglycemia in neonates that does not remit. Depending on the type of genetic mutation, hypoglycemia in these infants with congenital hyperinsulinism may be controlled medically or may require surgery. The extent of surgery required in infants with ATP-dependent potassium channel mutations unresponsive to diazoxide is dependent upon histological subtype: focal vs. diffuse disease. Disease-specific diagnoses and treatments are therefore essential for effective management of the various forms of neonatal hyperinsulinism.

Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism.

The mechanisms involved in the release of glucagon in response to hypoglycemia are unclear. Proposed mechanisms include the activation of the autonomic nervous system via glucose-sensing neurons in the central nervous system, via the regulation of glucagon secretion by intra-islet insulin and zinc concentrations, or via direct ionic control, all mechanisms that involve high-affinity sulfonylurea receptor/inwardly rectifying potassium channel-type ATP-sensitive K(+) channels. Patients with congenital hyperinsulinism provide a unique physiological model to understand glucagon regulation. In this study, we compare serum glucagon responses to hyperinsulinemic hypoglycemia versus nonhyperinsulinemic hypoglycemia. In the patient group (n = 20), the mean serum glucagon value during hyperinsulinemic hypoglycemia was 17.6 +/- 5.7 ng/l compared with 59.4 +/- 7.8 ng/l in the control group (n = 15) with nonhyperinsulinemic hypoglycemia (P < 0.01). There was no difference between the serum glucagon responses in children with diffuse, focal, and diazoxide-responsive forms of hyperinsulinism. The mean serum epinephrine and norepinephrine concentrations in the hyperinsulinemic group were 2,779 +/- 431 pmol/l and 2.9 +/- 0.7 nmol/l and appropriately rose despite the blunted glucagon response. In conclusion, the loss of ATP-sensitive K(+) channels and or elevated intraislet insulin cannot explain the blunted glucagon release in all patients with congenital hyperinsulinism. Other possible mechanisms such as the suppressive effect of prolonged hyperinsulinemia on alpha-cell secretion should be considered.

Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function.

CONTEXT: 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. OBJECTIVE: 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. DESIGN AND SETTING: We combined immunohistochemistry, advanced life fluorescence imaging, and electrophysiology in HEK293T cells transiently transfected with mutant Kir6.2. PATIENT AND INTERVENTION: 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. MAIN OUTCOME MEASURE: We assessed patch-clamp recordings and confocal microscopy in HEK293T cells. RESULTS: 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. CONCLUSION: 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.

Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.

Congenital hyperinsulinism (HI) is most commonly caused by recessive mutations of the pancreatic beta-cell ATP-sensitive potassium channel (K(ATP)), encoded by two genes on chromosome 11p, SUR1 and Kir6.2. The two mutations that have been best studied, SUR1 g3992-9a and SUR1 delF1388, are null mutations yielding nonfunctional channels and are characterized by nonresponsiveness to diazoxide, a channel agonist, and absence of acute insulin responses (AIRs) to tolbutamide, a channel antagonist, or leucine. To examine phenotypes of other K(ATP) mutations, we measured AIRs to calcium, leucine, glucose, and tolbutamide in infants with recessive SUR1 or Kir6.2 mutations expressed as diffuse HI (n = 8) or focal HI (n = 14). Of the 24 total mutations, at least seven showed evidence of residual K(ATP) channel function. This included positive AIR to both tolbutamide and leucine in diffuse HI cases or positive AIR to leucine in focal HI cases. One patient with partial K(ATP) function also responded to treatment with the channel agonist, diazoxide. Six of the seven patients with partial defects had amino acid substitutions or insertions; whereas, the other patient was compound heterozygous for two premature stop codons. These results indicate that some K(ATP) mutations can yield partially functioning channels, including cases of hyperinsulinism that are fully responsive to diazoxide therapy.

Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy.

Most cases of congenital hyperinsulinism (HI) manifest as either a diffuse or focal form. Diffuse HI is characterized by the presence of enlarged islet cell nuclei, defined as those occupying an area 3 times larger than the surrounding nuclei, throughout the pancreas, and usually requires near total pancreatectomy. Focal HI contains, within an otherwise normal pancreas with islet cell nuclei of normal size, a focus of adenomatous hyperplasia characterized by endocrine cell overgrowth occupying more than 40% of a given area. This form of HI is amenable to partial pancreatectomy. The current study assesses whether intraoperative frozen section evaluation can distinguish the 2 forms and guide the extent of pancreatectomy. By frozen section analysis, diffuse HI is diagnosed when enlarged islet cell nuclei are present in random intraoperative biopsies from the head, body, and tail of the pancreas. Focal HI is suggested when random biopsies contain no large islet cell nuclei, prompting a further search for a focal lesion. Fifty-two HI patients who underwent pancreatectomy from October 1, 1998 to September 30, 2002 were reviewed. On permanent sections, 18 were classified as diffuse HI, 30 had focal HI, and 4 could not be categorized as either. Among 18 diffuse HI patients, 17 were correctly diagnosed by frozen section; all underwent near total pancreatectomy. One case was interpreted as not belonging to typical diffuse or focal HI; however, the permanent sections showed diffuse HI. Twenty-six of 30 focal HI cases were correctly diagnosed by frozen section. The remaining 4 focal HI cases posed diagnostic difficulties on frozen sections because of one the following reasons: 1) presence of equivocally large islet cell nuclei or rare truly large islet cell nuclei in areas nonadjacent to the focal lesion, and 2) large and/or ill defined focus of adenomatous hyperplasia. Twenty-one of 30 focal HI patients eventually had 10% to 93% (mean, 41.8%) of their pancreas resected. In addition to cases typical for diffuse and focal HI, there were 4 other cases whose pancreata did not fit well with either category. These pancreata showed islet cell nuclear enlargement, as characteristically seen in diffuse HI, but only in confined areas of the pancreas. Examination of routinely processed tissue confirmed frozen section findings in all 4 cases. Intraoperative frozen section evaluation, therefore, can assume an essential role in identifying patients with focal HI to limit the extent of pancreatectomy. However, a small number of cases with unusual histology warrant caution when performing frozen section evaluation.