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Charles A Stanley - One of the best experts on this subject based on the ideXlab platform.
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diazoxide responsive forms of congenital Hyperinsulinism
2019Co-Authors: Daphne Yau, Charles A StanleyAbstract:Diazoxide responsiveness is typically the starting point for distinguishing congenital Hyperinsulinism phenotypes since those who do not respond will often require surgery. Operationally, diazoxide responsiveness is defined as being able to appropriately develop a hyperketonemic response to fasting (beta-hydroxybutyrate >2 mmol/L) prior to developing hypoglycemia (<2.8–3.3 mmol/L, <50–60 mg/dL), in addition to preventing any food-induced hypoglycemia. Of note, only 35% of diazoxide-responsive patients have an identifiable mutation in one of the currently known Hyperinsulinism genes. Perinatal stress-induced Hyperinsulinism is a transient but often prolonged form of Hyperinsulinism associated with risk factors such as birth asphyxia and intrauterine growth restriction. Screening for hypoglycemia is crucial when these risk factors are present, as is starting diuretic treatment before diazoxide to avoid fluid overload and pulmonary hypertension. Genetic forms of diazoxide-responsive Hyperinsulinism include a distinctive form caused by dominant activating mutations in glutamate dehydrogenase (GDH). Leucine-induced and fasting hypoglycemia, mild hyperammonemia, and neurologic abnormalities, most commonly atypical absence epilepsy, are key features. Recessive inactivating mutations in short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an inhibitor of GDH and a fatty acid oxidation enzyme, also cause leucine-sensitive hypoglycemia, but without hyperammonemia. Heterozygous mutations in the transcription factors, hepatocyte nuclear factors 4A and 1A, cause Hyperinsulinism and evolve into young adult-onset diabetes (HNF4A-MODY and HNF1A-MODY, respectively). Finally, mutations in the mitochondrial transport protein, uncoupling protein 2 (UCP2), and the plasma membrane protein, monocarboxylate transporter 1 (MCT1), cause rare forms of Hyperinsulinism with the unique features of post-glucose load and exercise-induced hypoglycemia, respectively.
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biomarkers of insulin for the diagnosis of hyperinsulinemic hypoglycemia in infants and children
The Journal of Pediatrics, 2016Co-Authors: Christine T Ferrara, Charles A Stanley, Susan Becker, Payal Patel, Andrea KellyAbstract:Objective To evaluate thresholds of various biomarkers for defining excess insulin activity to recognize congenital Hyperinsulinism. Study design This was a retrospective chart review of diagnostic fasting tests in children with ketotic hypoglycemia (n = 30) and genetically/pathology confirmed congenital Hyperinsulinism (n = 28). Sensitivity and specificity for congenital Hyperinsulinism were determined for plasma insulin, β-hydroxybutyrate, free fatty acids (FFA), C-peptide, insulin-like growth factor binding protein-1 (IGFBP-1), and the glycemic response to glucagon (through the glucagon stimulation test [GST]) at the time of hypoglycemia. Results Only 23 of the 28 subjects with congenital Hyperinsulinism had detectable insulin (median, 6.7 μIU/mL), and insulin was undetectable in all subjects with ketotic hypoglycemia. Compared with ketotic hypoglycemia, subjects with congenital Hyperinsulinism had higher GST values (57 vs 13 mg/dL; ΔGST ≥30 mg/dL in 24 of 27 subjects with congenital Hyperinsulinism vs 0 of 30 subjects with ketotic hypoglycemia) and C-peptide levels (1.55 vs 0.11 ng/mL), with lower levels of FFA (0.82 vs 2.51 mM) and IGFBP-1 (59.5 vs 634 ng/mL). At the time of hypoglycemia, the upper limits of β-hydroxybutyrate and FFA in subjects with congenital Hyperinsulinism were higher than reported previously (β-hydroxybutyrate Conclusion Because low or undetectable insulin level during hypoglycemia does not exclude the diagnosis of Hyperinsulinism, C-peptide and IGFBP-1 may inform the diagnosis of congenital Hyperinsulinism. In this group of children with well-defined congenital Hyperinsulinism, thresholds for “suppressed” β-hydroxybutyrate and FFA are higher than previously reported levels.
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Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations
2015Co-Authors: Mariko Suchi, Joseph Grimsby, Franz M. Matschinsky, Rebecca Taub, Charles A StanleyAbstract:OBJECTIVE—Heterozygous activating mutations of glucoki-nase have been reported to cause hypoglycemia attributable to Hyperinsulinism in a limited number of families. We report three children with de novo glucokinase Hyperinsulinism mutations who displayed a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics. RESEARCH DESIGN AND METHODS—Mutations were di-rectly sequenced, and mutants were expressed as glutathionyl S-transferase–glucokinase fusion proteins. Kinetic analysis of the enzymes included determinations of stability, activity index, the response to glucokinase activator drug, and the effect of glucokinase regulatory protein. RESULTS—Child 1 had an ins454A mutation, child 2 a W99L mutation, and child 3 an M197I mutation. Diazoxide treatment was effective in child 3 but ineffective in child 1 and only partiall
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hypertrophic cardiomyopathy in neonates with congenital Hyperinsulinism
Archives of Disease in Childhood, 2013Co-Authors: Tingting Huang, Charles A Stanley, Susan Becker, Andrea Kelly, Meryl S CohenAbstract:Introduction Hypertrophic cardiomyopathy (HCM) is a well-recognised complication in infants of diabetic mothers and is attributed to a compensatory increase in fetal insulin secretion. Infants with congenital Hyperinsulinism have excessive prenatal and postnatal insulin secretion due to defects in pathways of insulin secretion (most commonly the K ATP channel). HCM has been reported in a few neonates with Hyperinsulinism, but its extent and risk factors for its development have not been evaluated. Methods Retrospective chart review of infants, age Data Gestational age, birth weight, Hyperinsulinism form and treatments, echocardiogram results, cardiac/respiratory complications. Results 68 infants were included, 58 requiring pancreatectomy for diffuse (n=28) or focal (n=30) disease, 10 were diazoxide-sensitive. Twenty-five had echocardiograms performed. Ten had HCM, all of whom required pancreatectomy and eight of whom had confirmed ATP-sensitive potassium-Hyperinsulinism. Subjects with HCM had younger gestational age 36(32, 38) than their surgical counterparts without HCM 38 (31.6, 43), p=0.02. Discussion HCM appears common in infants with severe Hyperinsulinism. Routine echocardiogram and EKG of at-risk newborns should be considered. Fetal Hyperinsulinism is the likely mediating factor for HCM in HI infants.
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co inheritance of two abcc8 mutations causing an unresponsive congenital Hyperinsulinism clinical and functional characterization of two novel abcc8 mutations
Gene, 2013Co-Authors: Flavio Faletra, Show Ling Shyng, Qing Zhou, K E Snider, Carlo Dionisivici, Emmanouil Athanasakis, Irene Bruno, Paolo Gasparini, Alessandro Ventura, Charles A StanleyAbstract:Congenital Hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital Hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.
Show Ling Shyng - One of the best experts on this subject based on the ideXlab platform.
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carbamazepine as a novel small molecule corrector of trafficking impaired atp sensitive potassium channels identified in congenital Hyperinsulinism
Journal of Biological Chemistry, 2013Co-Authors: Pei Chun Chen, Erik M Olson, Qing Zhou, Yelena N Kryukova, Heidi M Sampson, David Y Thomas, Show Ling ShyngAbstract:ATP-sensitive potassium (KATP) channels consisting of sulfonylurea receptor 1 (SUR1) and the potassium channel Kir6.2 play a key role in insulin secretion by coupling metabolic signals to β-cell membrane potential. Mutations in SUR1 and Kir6.2 that impair channel trafficking to the cell surface lead to loss of channel function and congenital Hyperinsulinism. We report that carbamazepine, an anticonvulsant, corrects the trafficking defects of mutant KATP channels previously identified in congenital Hyperinsulinism. Strikingly, of the 19 SUR1 mutations examined, only those located in the first transmembrane domain of SUR1 responded to the drug. We show that unlike that reported for several other protein misfolding diseases, carbamazepine did not correct KATP channel trafficking defects by activating autophagy; rather, it directly improved the biogenesis efficiency of mutant channels along the secretory pathway. In addition to its effect on channel trafficking, carbamazepine also inhibited KATP channel activity. Upon subsequent removal of carbamazepine, however, the function of rescued channels was recovered. Importantly, combination of the KATP channel opener diazoxide and carbamazepine led to enhanced mutant channel function without carbamazepine washout. The corrector effect of carbamazepine on mutant KATP channels was also demonstrated in rat and human β-cells with an accompanying increase in channel activity. Our findings identify carbamazepine as a novel small molecule corrector that may be used to restore KATP channel expression and function in a subset of congenital Hyperinsulinism patients.
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co inheritance of two abcc8 mutations causing an unresponsive congenital Hyperinsulinism clinical and functional characterization of two novel abcc8 mutations
Gene, 2013Co-Authors: Flavio Faletra, Show Ling Shyng, Qing Zhou, K E Snider, Carlo Dionisivici, Emmanouil Athanasakis, Irene Bruno, Paolo Gasparini, Alessandro Ventura, Charles A StanleyAbstract:Congenital Hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital Hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.
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diazoxide unresponsive congenital Hyperinsulinism in children with dominant mutations of the β cell sulfonylurea receptor sur1
Diabetes, 2011Co-Authors: Courtney Macmullen, Show Ling Shyng, Susan Becker, Arupa Ganguly, Qing Zhou, K E Snider, Paul Tewson, Ali Rahim Aziz, Charles A StanleyAbstract:OBJECTIVE Congenital hyperinsulinemic hypoglycemia is a group of genetic disorders of insulin secretion most commonly associated with inactivating mutations of the β-cell ATP-sensitive K + channel (K ATP channel) genes ABCC8 (SUR1) and KCNJ11 (Kir6.2). Recessive mutations of these genes cause Hyperinsulinism that is unresponsive to treatment with diazoxide, a channel agonist. Dominant K ATP mutations have been associated with diazoxide-responsive disease. We hypothesized that some medically uncontrollable cases with only one K ATP mutation might have dominant, diazoxide-unresponsive disease. RESEARCH DESIGN AND METHODS Mutations of the K ATP genes were identified by sequencing genomic DNA. Effects of mutations on K ATP channel function in vitro were studied by expression in COSm6 cells. RESULTS In 15 families with diazoxide-unresponsive diffuse hyperinsulism, we found 17 patients with a monoallelic missense mutation of SUR1. Nine probands had de novo mutations, two had an affected sibling or parent, and four had an asymptomatic carrier parent. Of the 13 different mutations, 12 were novel. Expression of mutations revealed normal trafficking of channels but severely impaired responses to diazoxide or MgADP. Responses were significantly lower compared with nine SUR1 mutations associated with dominant, diazoxide-responsive Hyperinsulinism. CONCLUSIONS These results demonstrate that some dominant mutations of SUR1 can cause diazoxide-unresponsive Hyperinsulinism. In vitro expression studies may be helpful in distinguishing such mutations from dominant mutations of SUR1 associated with diazoxide-responsive disease.
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sulfonylurea receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure
Journal of Biological Chemistry, 2009Co-Authors: Emily B Pratt, Charles A Stanley, Fei Fei Yan, Show Ling ShyngAbstract:Abstract The β-cell ATP-sensitive potassium (KATP) channel composed of sulfonylurea receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability. Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital Hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes. Here we report that two Hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. Under normal conditions, both mutant channels showed poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital Hyperinsulinism patients. This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for KATP channels. The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels, respectively. Further analyses revealed a nucleotide-independent decrease in mutant channel intrinsic open probability, suggesting the mutations may reduce ATP sensitivity by causing functional uncoupling between SUR1 and Kir6.2. In insulin-secreting cells, rescue of both mutant channels to the cell surface led to hyperpolarized membrane potentials and reduced insulin secretion upon glucose stimulation. Our results show that sulfonylureas, as chemical chaperones, can dictate manifestation of the two opposite insulin secretion defects by altering the expression levels of the disease mutants.
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sulfonylurea receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure
Journal of Biological Chemistry, 2009Co-Authors: Emily B Pratt, Charles A Stanley, Fei Fei Yan, Show Ling ShyngAbstract:The beta-cell ATP-sensitive potassium (K(ATP)) channel composed of sulfonylurea receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability. Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital Hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes. Here we report that two Hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. Under normal conditions, both mutant channels showed poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital Hyperinsulinism patients. This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for K(ATP) channels. The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels, respectively. Further analyses revealed a nucleotide-independent decrease in mutant channel intrinsic open probability, suggesting the mutations may reduce ATP sensitivity by causing functional uncoupling between SUR1 and Kir6.2. In insulin-secreting cells, rescue of both mutant channels to the cell surface led to hyperpolarized membrane potentials and reduced insulin secretion upon glucose stimulation. Our results show that sulfonylureas, as chemical chaperones, can dictate manifestation of the two opposite insulin secretion defects by altering the expression levels of the disease mutants.
Paul S. Thornton - One of the best experts on this subject based on the ideXlab platform.
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Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism.
Hormone Research in Paediatrics, 2019Co-Authors: Paul S. Thornton, Lisa Truong, Courtney Reynolds, Tyler Hamby, Jonathan NedrelowAbstract:Introduction: Diazoxide is the first line and only Federal Drug Agency approved pharmacological agent for the treatment of Hyperinsulinism. Its use has increased over the years to include patients with various genetic forms of Hyperinsulinism, perinatal stress Hyperinsulinism and infants of diabetic mothers with more babies than ever being exposed to this therapy. Methods: We performed a retrospective analysis of 194 patients with Hyperinsulinism in our clinic and looked for those who had experienced serious adverse events (SAE) including pulmonary hypertension and neutropenia. We compared the rates of SAE in the different types of Hyperinsulinism. Results: Out of 194 patients with Hyperinsulinism, 165 (85.1%) were treated with diazoxide. There were 17 SAEs in 16 patients including 8 cases of pulmonary hypertension and 8 of neutropenia. These data show that overall the frequency of SAE associated with diazoxide use is 9.7%, but that those with perinatal stress Hyperinsulinism have a much higher rate than those with genetic forms of Hyperinsulinism (16.7 vs. 3.6%; p = 0.01). We also found diazoxide is associated with pulmonary hypertension (4.8% of patients treated). Although more patients with perinatal stress Hyperinsulinism (7.6%) were affected than genetic Hyperinsulinism (1.2%), the difference was not significant (p = 0.088). Conclusion: The rate of SAEs associated with (not necessarily caused by) diazoxide has been demonstrated. The rate of SAE in newborns with perinatal stress Hyperinsulinism is significantly higher than that of otherwise healthy babies with genetic forms of Hyperinsulinism, suggesting that caution should be used when prescribing diazoxide to this population. This information should help balance the risk benefit of treatment and provide guidance on screening for these complications in the population of treated patients.
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molecular and immunohistochemical analyses of the focal form of congenital Hyperinsulinism
Modern Pathology, 2006Co-Authors: Mariko Suchi, Paul S. Thornton, Eduardo Ruchelli, Scott N Adzick, Arupa Ganguly, Courtney Macmullen, Charles A StanleyAbstract:Congenital Hyperinsulinism is a rare pancreatic endocrine cell disorder that has been categorized histologically into diffuse and focal forms. In focal Hyperinsulinism, the pancreas contains a focus of endocrine cell adenomatous hyperplasia, and the patients have been reported to possess paternally inherited mutations of the ABCC8 and KCNJ11 genes, which encode subunits of an ATP-sensitive potassium channel (K(ATP)). In addition, the hyperplastic endocrine cells show loss of maternal 11p15, where imprinted genes such as p57(kip2) reside. In order to evaluate whether all cases of focal Hyperinsulinism are caused by this mechanism, 56 pancreatectomy specimens with focal Hyperinsulinism were tested for the loss of maternal allele by two methods: immunohistochemistry for p57(kip2) (n=56) and microsatellite marker analysis (n=27). Additionally, 49 patients were analyzed for K(ATP) mutations. Out of 56 focal lesions, 48 demonstrated clear loss of p57(kip2) expression by immunohistochemistry. The other eight lesions similarly showed no nuclear labeling, but the available tissue was not ideal for definitive interpretation. Five of these eight patients had paternal K(ATP) mutations, of which four demonstrated loss of maternal 11p15 within the lesion by microsatellite marker analysis. All of the other three without a paternal K(ATP) mutation showed loss of maternal 11p15. K(ATP) mutation analysis identified 32/49 cases with paternal mutations. There were seven patients with nonmaternal mutations whose paternal DNA material was not available, and one patient with a mutation that was not present in either parent's DNA. These eight patients showed either loss of p57(kip2) expression or loss of maternal 11p15 region by microsatellite marker analysis, as did the remaining nine patients with no identifiable K(ATP) coding region mutations. The combined results from the immunohistochemical and molecular methods indicate that maternal 11p15 loss together with paternal K(ATP) mutation is the predominant causative mechanism of focal Hyperinsulinism.
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preoperative evaluation of infants with focal or diffuse congenital Hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Charles A Stanley, Paul S. Thornton, Arupa Ganguly, Courtney Macmullen, Patricia Underwood, Pooja Bhatia, Linda Steinkrauss, Laura Wanner, Robin D Kaye, Eduardo RuchelliAbstract:Infants with congenital Hyperinsulinism often require pancreatectomy. Recessive mutations of the ATP-dependent plasma membrane potassium channel (KATP) genes, SUR1 and Kir6.2, cause diffuse Hyperinsulinism. KATP channel mutations can also cause focal disease through loss of heterozygosity for maternal 11p, resulting in expression of a paternal mutation. This study evaluated whether focal vs. diffuse Hyperinsulinism could be diagnosed by acute insulin response (AIR) tests and whether arterial calcium stimulation/venous sampling (ASVS) could localize focal lesions. Fifty infants with diazoxide-unresponsive Hyperinsulinism were studied. Focal lesions occurred in 70% of the cases. Positive AIR calcium occurred in 17 of 30 focal and 10 of 13 diffuse cases (P < 0.04). Positive AIR tolbutamide occurred in 27 of 30 focal vs. seven of 13 diffuse cases (P < 0.02); KATP channel mutations were identified in four of the latter. ASVS localized the lesion in 24 of 33 focal cases (73%) but correctly diagnosed diffuse dis...
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clinical and molecular characterization of a dominant form of congenital Hyperinsulinism caused by a mutation in the high affinity sulfonylurea receptor
Diabetes, 2003Co-Authors: Paul S. Thornton, Lydia Aguilarbryan, Eduardo Ruchelli, Arupa Ganguly, Courtney Macmullen, Linda Steinkrauss, Ana Crane, Charles A StanleyAbstract:Recessive mutations of sulfonylurea receptor 1 (SUR1) and potassium inward rectifier 6.2 (Kir6.2), the two adjacent genes on chromosome 11p that comprise the β-cell plasma membrane ATP-sensitive K+ (KATP) channels, are responsible for the most common form of congenital Hyperinsulinism in children. The present study was undertaken to identify the genetic defect in a family with dominantly inherited Hyperinsulinism affecting five individuals in three generations. Clinical tests were carried out in three of the patients using acute insulin responses (AIRs) to intravenous stimuli to localize the site of defect in insulin regulation. The affected individuals showed abnormal positive calcium AIR, normal negative leucine AIR, subnormal positive glucose AIR, and impaired tolbutamide AIR. This AIR pattern suggested a KATP channel defect because it resembled that seen in children with recessive Hyperinsulinism due to two common SUR1 mutations, g3992-9a and delPhe1388. Genetic linkage to the KATP locus was established using intragenic polymorphisms. Mutation analysis identified a novel trinucleotide deletion in SUR1 exon 34 that results in the loss of serine 1387. Studies of delSer1387 in COSm6 cells confirmed that the expressed mutant protein assembles with Kir6.2 and trafficks to the plasma membrane, but it had no 86Rb efflux ion transport activity. These results indicate that Hyperinsulinism in this family is caused by a SUR1 mutation that is expressed dominantly rather than recessively.
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acute insulin responses to leucine in children with the Hyperinsulinism hyperammonemia syndrome
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Andrea Kelly, Paul S. Thornton, Adda Grimberg, Robert J Ferry, Samantha Koomccoy, Charles A StanleyAbstract:Mutations of glutamate dehydrogenase cause the Hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by GTP. Normal allosteric activation of glutamate dehydrogenase by leucine is thus uninhibited, leading us to propose that children with Hyperinsulinism/hyperammonemia syndrome will have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases β-cell GTP, we also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in Hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, seven Hyperinsulinism/hyperammonemia syndrome patients (aged 9 months to 29 yr) had acute insulin responses to leucine performed using an iv bolus of l-leucine (15 mg/kg) administered over 1 min and plasma insulin measurements obtained at −10, −5, 0, 1, 3, and 5 min. The acute insulin response to leucine was defined as the mean increase in insulin from baseline at 1 and 3 min afte...
Andrea Kelly - One of the best experts on this subject based on the ideXlab platform.
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biomarkers of insulin for the diagnosis of hyperinsulinemic hypoglycemia in infants and children
The Journal of Pediatrics, 2016Co-Authors: Christine T Ferrara, Charles A Stanley, Susan Becker, Payal Patel, Andrea KellyAbstract:Objective To evaluate thresholds of various biomarkers for defining excess insulin activity to recognize congenital Hyperinsulinism. Study design This was a retrospective chart review of diagnostic fasting tests in children with ketotic hypoglycemia (n = 30) and genetically/pathology confirmed congenital Hyperinsulinism (n = 28). Sensitivity and specificity for congenital Hyperinsulinism were determined for plasma insulin, β-hydroxybutyrate, free fatty acids (FFA), C-peptide, insulin-like growth factor binding protein-1 (IGFBP-1), and the glycemic response to glucagon (through the glucagon stimulation test [GST]) at the time of hypoglycemia. Results Only 23 of the 28 subjects with congenital Hyperinsulinism had detectable insulin (median, 6.7 μIU/mL), and insulin was undetectable in all subjects with ketotic hypoglycemia. Compared with ketotic hypoglycemia, subjects with congenital Hyperinsulinism had higher GST values (57 vs 13 mg/dL; ΔGST ≥30 mg/dL in 24 of 27 subjects with congenital Hyperinsulinism vs 0 of 30 subjects with ketotic hypoglycemia) and C-peptide levels (1.55 vs 0.11 ng/mL), with lower levels of FFA (0.82 vs 2.51 mM) and IGFBP-1 (59.5 vs 634 ng/mL). At the time of hypoglycemia, the upper limits of β-hydroxybutyrate and FFA in subjects with congenital Hyperinsulinism were higher than reported previously (β-hydroxybutyrate Conclusion Because low or undetectable insulin level during hypoglycemia does not exclude the diagnosis of Hyperinsulinism, C-peptide and IGFBP-1 may inform the diagnosis of congenital Hyperinsulinism. In this group of children with well-defined congenital Hyperinsulinism, thresholds for “suppressed” β-hydroxybutyrate and FFA are higher than previously reported levels.
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hypertrophic cardiomyopathy in neonates with congenital Hyperinsulinism
Archives of Disease in Childhood, 2013Co-Authors: Tingting Huang, Charles A Stanley, Susan Becker, Andrea Kelly, Meryl S CohenAbstract:Introduction Hypertrophic cardiomyopathy (HCM) is a well-recognised complication in infants of diabetic mothers and is attributed to a compensatory increase in fetal insulin secretion. Infants with congenital Hyperinsulinism have excessive prenatal and postnatal insulin secretion due to defects in pathways of insulin secretion (most commonly the K ATP channel). HCM has been reported in a few neonates with Hyperinsulinism, but its extent and risk factors for its development have not been evaluated. Methods Retrospective chart review of infants, age Data Gestational age, birth weight, Hyperinsulinism form and treatments, echocardiogram results, cardiac/respiratory complications. Results 68 infants were included, 58 requiring pancreatectomy for diffuse (n=28) or focal (n=30) disease, 10 were diazoxide-sensitive. Twenty-five had echocardiograms performed. Ten had HCM, all of whom required pancreatectomy and eight of whom had confirmed ATP-sensitive potassium-Hyperinsulinism. Subjects with HCM had younger gestational age 36(32, 38) than their surgical counterparts without HCM 38 (31.6, 43), p=0.02. Discussion HCM appears common in infants with severe Hyperinsulinism. Routine echocardiogram and EKG of at-risk newborns should be considered. Fetal Hyperinsulinism is the likely mediating factor for HCM in HI infants.
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acute insulin responses to leucine in children with the Hyperinsulinism hyperammonemia syndrome
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Andrea Kelly, Paul S. Thornton, Adda Grimberg, Robert J Ferry, Samantha Koomccoy, Charles A StanleyAbstract:Mutations of glutamate dehydrogenase cause the Hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by GTP. Normal allosteric activation of glutamate dehydrogenase by leucine is thus uninhibited, leading us to propose that children with Hyperinsulinism/hyperammonemia syndrome will have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases β-cell GTP, we also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in Hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, seven Hyperinsulinism/hyperammonemia syndrome patients (aged 9 months to 29 yr) had acute insulin responses to leucine performed using an iv bolus of l-leucine (15 mg/kg) administered over 1 min and plasma insulin measurements obtained at −10, −5, 0, 1, 3, and 5 min. The acute insulin response to leucine was defined as the mean increase in insulin from baseline at 1 and 3 min afte...
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protein sensitive and fasting hypoglycemia in children with the Hyperinsulinism hyperammonemia syndrome
The Journal of Pediatrics, 2001Co-Authors: Betty Y L Hsu, Cheryl R Greenberg, Paul S. Thornton, Andrea Kelly, Louise A Dilling, Charles A StanleyAbstract:Abstract Objective: Because the Hyperinsulinism/hyperammonemia (HI/HA) syndrome is associated with gain of function mutations in the leucine-stimulated insulin secretion pathway, we examined whether protein feeding or fasting was responsible for hypoglycemia in affected patients. Study design: Patients with HI/HA (8 children and 6 adults) were studied. All had dominantly expressed mutations of glutamate dehydrogenase and plasma concentrations of ammonium that were 2 to 5 times normal. The responses to a 24-hour fasting test were determined in 7 patients. Responses to a 1.5 gm/kg oral protein tolerance test in 12 patients were compared with responses of 5 control subjects. Results: The median age at onset of hypoglycemia in the 14 patients was 9 months; diagnosis was delayed beyond age 2 years in 6 patients, and 4 were not given a diagnosis until adulthood. Fasting tests revealed unequivocal evidence of Hyperinsulinism in only 1 of 7 patients. Three did not develop hypoglycemia until 12 to 24 hours of fasting; however, all 7 demonstrated inappropriate glycemic responses to glucagon that were characteristic of Hyperinsulinism. In response to oral protein, all 12 patients with HI/HA showed a fall in blood glucose compared with none of 5 control subjects. Insulin responses to protein loading were similar in the patients with HI/HA and control subjects. Conclusion: The postprandial blood glucose response to a protein meal is more sensitive than prolonged fasting for detecting hypoglycemia in the HI/HA syndrome. (J Pediatr 2001;138:383-9)
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dysregulation of insulin secretion in children with congenital Hyperinsulinism due to sulfonylurea receptor mutations
Diabetes, 2001Co-Authors: Adda Grimberg, Kenneth S Polonsky, Lydia Aguilarbryan, Benjamin Glaser, M A Permutt, Robert J Ferry, Andrea Kelly, Samantha Koomccoy, Diane E J Stafford, P S ThorntonAbstract:Mutations in the high-affinity sulfonylurea receptor (SUR)-1 cause one of the severe recessively inherited diffuse forms of congenital Hyperinsulinism or, when associated with loss of heterozygosity, focal adenomatosis. We hypothesized that SUR1 mutations would render the β-cell insensitive to sulfonylureas and to glucose. Stimulated insulin responses were compared among eight patients with diffuse Hyperinsulinism (two mutations), six carrier parents, and ten normal adults. In the patients with diffuse Hyperinsulinism, the acute insulin response to intravenous tolbutamide was absent and did not overlap with the responses seen in either adult group. There was positive, albeit significantly blunted, acute insulin response to intravenous dextrose in the patients with diffuse Hyperinsulinism. Graded infusions of glucose, to raise and then lower plasma glucose concentrations over 4 h, caused similar rises in blood glucose but lower peak insulin levels in the hyperinsulinemic patients. Loss of acute insulin response to tolbutamide can identify children with diffuse SUR1 defects. The greater response to glucose than to tolbutamide indicates that ATP-sensitive potassium (KATP) channel-independent pathways are involved in glucose-mediated insulin release in patients with diffuse SUR1 defects. The diminished glucose responsiveness suggests that SUR1 mutations and lack of KATP channel activity may contribute to the late development of diabetes in patients with Hyperinsulinism independently of subtotal pancreatectomy.
Diva D. De León - One of the best experts on this subject based on the ideXlab platform.
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heterozygous recurrent hnf4a variant p arg85trp causes fanconi renotubular syndrome 4 with maturity onset diabetes of the young an autosomal dominant phenocopy of fanconi bickel syndrome with colobomas
American Journal of Medical Genetics Part A, 2021Co-Authors: Sarah E Sheppard, Diva D. De León, Brett Barrett, Colleen Muraresku, Heather Mcknight, Katherine Lord, Rebecca D GanetzkyAbstract:Heterozygous pathogenic variants in HNF4A cause Hyperinsulinism, maturity onset diabetes of the young type 1, and more rarely Fanconi renotubular syndrome. Specifically, the recurrent missense pathogenic variant c.253C>T (p.Arg85Trp) has been associated with a syndromic form of Hyperinsulinism with additional features of macrosomia, renal tubular nephropathy, hypophosphatemic rickets, and liver involvement. We present an affected mother, who had been previously diagnosed clinically with the autosomal recessive Fanconi Bickel Syndrome, and her affected son. The son's presentation expands the clinical phenotype to include multiple congenital anomalies, including penile chordee with hypospadias and coloboma. This specific pathogenic variant should be considered in the differential diagnosis of Fanconi Bickel Syndrome when genetics are negative or the family history is suggestive of autosomal dominant inheritance. The inclusion of Hyperinsulinism and maturity onset of the diabetes of the young changes the management of this syndrome and the recurrence risk is distinct. Additionally, this family also emphasizes the importance of genetic confirmation of clinical diagnoses, especially in adults who grew up in the premolecular era that are now coming to childbearing age. Finally, the expansion of the phenotype to include multiple congenital anomalies suggests that the full spectrum of HNF4A is likely unknown.
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Hyperinsulinism in an individual with an ep300 variant of rubinstein taybi syndrome
American Journal of Medical Genetics Part A, 2021Co-Authors: Diva D. De León, Sarah E Sheppard, Taylor K Wild, Tomoki T Nomakuchi, Karla F LeavensAbstract:Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant genetic syndrome characterized by distinct facial features, broad thumbs, growth restriction, microcephaly, intellectual disability, and developmental delay. Pathogenic variants in both CREBBP and EP300 have been associated with RSTS. Here we present a case of a female with Hyperinsulinism and features consistent with RSTS, found to have a pathogenic variant in EP300. While there have been a few rare case reports of Hyperinsulinism in RSTS, we suggest that Hyperinsulinism might be a more prominent feature in EP300 variant RSTS than previously recognized.
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activation of protein kinase a pka signaling mitigates congenital Hyperinsulinism associated hypoglycemia in the sur1 mouse model
PLOS ONE, 2020Co-Authors: Mangala M Soundarapandian, Diva D. De León, Jinghua Chai, Christine Juliana, Patrick Haslett, Kevin FitzgeraldAbstract:There is a significant unmet need for a safe and effective therapy for the treatment of children with congenital Hyperinsulinism. We hypothesized that amplification of the glucagon signaling pathway could ameliorate Hyperinsulinism associated hypoglycemia. In order to test this we evaluated the effects of loss of Prkar1a, a negative regulator of Protein Kinase A in the context of hyperinsulinemic conditions. With reduction of Prkar1a expression, we observed a significant upregulation of hepatic gluconeogenic genes. In wild type mice receiving a continuous infusion of insulin by mini-osmotic pump, we observed a 2-fold increase in the level of circulating ketones and a more than 40-fold increase in Kiss1 expression with reduction of Prkar1a. Loss of Prkar1a in the Sur1-/- mouse model of KATP Hyperinsulinism significantly attenuated fasting induced hypoglycemia, decreased the insulin/glucose ratio, and also increased the hepatic expression of Kiss1 by more than 10-fold. Together these data demonstrate that amplification of the hepatic glucagon signaling pathway is able to rescue hypoglycemia caused by Hyperinsulinism.
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meeting report updates in diagnosis and management of Hyperinsulinism and neonatal hypoglycemia highlights from the fourth international Hyperinsulinism symposium
Pediatric endocrinology reviews, 2020Co-Authors: Katherine Lord, Diva D. De LeónAbstract:Hypoglycemia remains a significant cause of morbidity in infants and children. Up to 50% of children with hypoglycemic disorders suffer from neurodevelopmental deficits, as a consequence of delays in the diagnosis and inadequate treatment. Recent advances in the field have resulted in new therapies and improved outcomes. To review these advances and have a dialogue regarding controversies in the field, the Fourth International Hyperinsulinism Symposium, sponsored by the Children's Hospital of Philadelphia was held in Philadelphia, Pennsylvania on September 5-6, 2019. The symposium faculty, leaders in the field of Hyperinsulinism and hypoglycemia, presented 25 plenary lectures on all aspects of these disorders. Additionally, a mini-symposium on neonatal hypoglycemia closed out the conference. Objectives of the symposium were to: 1. Describe the clinical manifestations, genetics and natural history of congenital Hyperinsulinism 2. Review recent advances in the medical and surgical management of Hyperinsulinism 3. Discuss current controversies and management options of neonatal hypoglycemia.
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Congenital Hyperinsulinism disorders: Genetic and clinical characteristics
American journal of medical genetics. Part C Seminars in medical genetics, 2019Co-Authors: Elizabeth Rosenfeld, Arupa Ganguly, Diva D. De LeónAbstract: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.