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At least 19 recordsLinked to original sources
PubMed2000

Hyperinsulinism of infancy: towards an understanding of unregulated insulin release. European Network for Research into Hyperinsulinism in Infancy.

Insulin is synthesised, stored, and secreted from pancreatic beta cells. These are located within the islets of Langerhans, which are distributed throughout the pancreas. Less than 2% of the total pancreas is devoted to an endocrine function. When the mechanisms that control insulin release are compromised, potentially lethal diseases such as diabetes and neonatal hypoglycaemia are manifest. This article reviews the physiology of insulin release and illustrates how defects in these processes will result in the pathophysiology of hyperinsulinism of infancy.

Animals↗
PubMed2000

Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism.

OBJECTIVES: To identify infants with hyperinsulinism caused by defects of the beta-cell adenosine triphosphate-dependent potassium channel complex and to distinguish focal and diffuse forms of hyperinsulinism caused by these mutations. STUDY DESIGN: The acute insulin response to intravenous calcium stimulation (CaAIR) was determined in 9 patients <20 years with diffuse hyperinsulinism caused by defective beta-cell sulfonylurea receptor (SUR1(-/-)), 3 patients with focal congenital hyperinsulinism (6 weeks to 18 months), a 10-year-old with insulinoma, 5 with hyperinsulinism/hyperammonemia syndrome caused by defective glutamate dehydrogenase (6 months to 28 years), 4 SUR1(+/-) heterozygotes with no symptoms, and 9 normal adults. Three infants with congenital focal disease, 1 with diffuse hyperinsulinism, and the child with insulinoma underwent selective pancreatic intra-arterial calcium stimulation with hepatic venous sampling. RESULTS: Children with diffuse SUR1(-/-) disease and infants with congenital focal hyperinsulinism responded to CaAIR, whereas the normal control group, patients with hyperinsulinism/hyperammonemia syndrome, and SUR1(+/-) carriers did not. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling revealed selective, significant step-ups in insulin secretion that correlated anatomically with the location of solitary lesions confirmed surgically in 2 of 3 infants with congenital focal disease and in the child with insulinoma. Selective arterial calcium stimulation of the pancreas with hepatic venous sampling demonstrated markedly elevated baseline insulin levels throughout the pancreas of the infant with diffuse hyperinsulinism. CONCLUSIONS: The intravenous CaAIR is a safe and simple test for identifying infants with diffuse SUR1(-/-) hyperinsulinism or with focal congenital hyperinsulinism. Preoperative selective arterial calcium stimulation of the pancreas with hepatic venous sampling can localize focal lesions causing hyperinsulinism in children. The combination of these calcium stimulation tests may help distinguish focal lesions suitable for cure by local surgical resection.

ATP-Binding Cassette Transporters↗
PubMed2007

Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates.

Hyperinsulinism is the single most common mechanism of hypoglycemia in neonates. Dysregulated insulin secretion is responsible for the transient and prolonged forms of neonatal hypoglycemia, and congenital genetic disorders of insulin regulation represent the most common of the permanent disorders of hypoglycemia. Mutations in at least five genes have been associated with congenital hyperinsulinism: they encode glucokinase, glutamate dehydrogenase, the mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase, and the two components (sulfonylurea receptor 1 and potassium inward rectifying channel, subfamily J, member 11) of the ATP-sensitive potassium channels (K(ATP) channels). K(ATP) hyperinsulinism is the most common and severe form of congenital hyperinsulinism. Infants suffering from K(ATP) hyperinsulinism present shortly after birth with severe and persistent hypoglycemia, and the majority are unresponsive to medical therapy, thus requiring pancreatectomy. In up to 40-60% of the children with K(ATP) hyperinsulinism, the defect is limited to a focal lesion in the pancreas. In these children, local resection results in cure with avoidance of the complications inherent to a near-total pancreatectomy. Hyperinsulinism can also be part of other disorders such as Beckwith-Wiedemann syndrome and congenital disorders of glycosylation. The diagnosis and management of children with congenital hyperinsulinism requires a multidisciplinary approach to achieve the goal of therapy: prevention of permanent brain damage due to recurrent hypoglycemia.

Algorithms↗
PubMed1997

Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism.

The diagnosis of hypoglycemia caused by hyperinsulinism may be difficult because insulin levels are not uniformly elevated at the time of hypoglycemia. Insulin-like growth factor binding protein-1 (IGFBP-1) is a 28 kd protein whose secretion is acutely inhibited by insulin. We hypothesized that serum levels of IGFBP-1 would be a useful marker of hyperinsulinism. We measured IGFBP-1 levels during the course of standardized fasting studies in hospitalized children; 36 patients became hypoglycemic during the fasting studies, and samples obtained at the point of hypoglycemia were analyzed. On the basis of the currently used diagnostic criteria, 13 children had hyperinsulinism, 16 had ketotic hypoglycemia or no disorder, 3 had hypopituitarism or isolated growth hormone deficiency, 2 had glycogen storage disease type 1 and 2 had fatty acid oxidation disorders. In control subjects (children with ketotic hypoglycemia or no disorder), IGFBP-1 levels rose during fasting to a mean of 343.8 +/- 71.3 ng/ml in the sample drawn at the time of hypoglycemia. Mean IGFBP-1 levels at hypoglycemia for the entire group with hyperinsulinism were 52.4 +/- 11.5 ng/ml, significantly different from levels seen in control subjects (p < 0.0001). In children with moderately controlled hyperinsulinism (fasting tolerance > 4 hours), mean IGFBP-1 levels at the time of hypoglycemia were 71.5 +/- 16.9 ng/ml. IGFBP-1 levels in the children with poorly controlled hyperinsulinism (fasting tolerance < 4 hours) failed to rise during fasting, with a mean of 30.1 +/- 10.4 ng/ml in the final sample. IGFBP-1 levels were inversely correlated with serum insulin and C-peptide levels (r = -0.71 and -0.72, respectively; p < 0.0001). Patients with other endocrinologic or metabolic diseases that result in fasting hypoglycemia demonstrated a rise in IGFBP-1 levels similar to that seen in ketotic hypoglycemia. Low serum levels of IGFBP-1 at the time of hypoglycemia provide an additional marker of insulin action that might help to differentiate hyperinsulinism from other hypoglycemic disorders.

Adolescent↗
PubMed2005

Congenital hyperinsulinism and mosaic abnormalities of the ploidy.

BACKGROUND: Congenital hyperinsulinism and Beckwith-Wiedemann syndrome both lead to beta islet hyperplasia and neonatal hypoglycaemia. They may be related to complex genetic/epigenetic abnormalities of the imprinted 11p15 region. The possibility of common pathophysiological determinants has not been thoroughly investigated. OBJECTIVE: To report abnormalities of the ploidy in two unrelated patients with congenital hyperinsulinism. METHODS: Two patients with severe congenital hyperinsulinism, one overlapping with Beckwith-Wiedemann syndrome, had pancreatic histology, ex vivo potassium channel electrophysiological studies, and mutation detection of the encoding genes. The parental genetic contribution was explored using genome-wide polymorphism, fluorescent in situ hybridisation (FISH), and blood group typing studies. RESULTS: Histological findings diverged from those described in focal congenital hyperinsulinism or Beckwith-Wiedemann syndrome. No potassium channel dysfunction and no mutation of its encoding genes (SUR1, KIR6.2) were detected. In patient 1 with congenital hyperinsulinism and Beckwith-Wiedemann syndrome, paternal isodisomy for the whole haploid set was homogeneous in the pancreatic lesion, and mosaic in the leucocytes and skin fibroblasts (hemihypertrophic segment). Blood group typing confirmed the presence of two erythroid populations (bi-parental v paternal only contribution). Patient 2 had two pancreatic lesions, both revealing triploidy with paternal heterodisomy. Karyotype and FISH analyses done on the fibroblasts and leucocytes of both patients were unremarkable (diploidy). CONCLUSIONS: Diploid (biparental/paternal-only) mosaicism and diploid/triploid mosaicism were present in two distinct patients with congenital hyperinsulinism. These chromosomal abnormalities led to paternal disomy for the whole haploid set in pancreatic lesions (with isodisomy or heterodisomy), thereby extending the range and complexity of the mechanisms underlying congenital hyperinsulinism, associated or not with Beckwith-Wiedemann syndrome.

Chromosome Aberrations↗
PubMed1992

[Theoretical aspects of the relationship between diabetic macroangiopathy and hyperinsulinism].

Epidemiological and clinical data suggest a relationship between hyperinsulinism and macroangiopathy in non insulin-dependent diabetes. On the other hand, a relationship between the plasma free insulin level and macroangiopathy has not been documented in insulin-dependent diabetes. Other abnormalities in addition to hyperinsulinism and glucose intolerance are frequently associated in the presence of insulin resistance and have been grouped by Reaven under the term syndrome X: raised VLDL triglycerides, decreased HDL, and raised blood pressure. Iatrogenic hyperinsulinism appears to be an arterial risk factor, but by what mechanism may it also constitute an independent risk factor? The following theoretical aspects of a possible atherogenic role of hyperinsulinism are currently being investigated: a) insulin stimulates the proliferation and migration of smooth muscle cells either directly or via a rise in IGF1; b) insulin induces lipogenesis in the intima-media, but it has not been demonstrated that this in situ lipogenesis is atherogenic; c) insulin raises the VLDL production, decreases HDL and modifies the clearance of LDL; d) insulin increases blood pressure by stimulating both the renal reabsorption of sodium and the sympathetic nervous system; insulin resistance may also be expressed at the level of the Na-K-ATPase of vascular smooth muscle cells by decreasing the vasodilator effect of the hormone; e) lastly, insulin induces a defect of fibrinolysis mediated by an increase in the level of plasminogen activator inhibitors (PAI1). In conclusion, the combination of hyperglycemia and hyperinsulinism is probably damaging to the artery. Therapeutic intervention studies are necessary to confirm and define the role of hyperinsulinism in macroangiopathy and to answer the unresolved questions: direct or indirect role? effect of endogenous and/or exogenous hyperinsulinism?

Adult↗
PubMed2006

Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism.

OBJECTIVES: To characterize the clinical features and insulin regulation in infants with hypoglycemia due to prolonged neonatal hyperinsulinism. STUDY DESIGN: Data were collected on 26 infants with hypoglycemia due to neonatal hyperinsulinism that later resolved. Acute insulin response (AIR) tests to calcium, leucine, glucose, and tolbutamide were performed in 11 neonates. Results were compared to children with genetic hyperinsulinism due to mutations of the adenosine triphosphate-dependent potassium (K(ATP)) channel and glutamate dehydrogenase (GDH). RESULTS: Among the 26 neonates, there were significantly more males, small-for-gestational-age infants, and cesarean deliveries. Only 5 of the 26 had no identifiable risk factor. Hyperinsulinism was diagnosed at a median age of 13 days (range, 2 to 180 days) and resolved by a median age of 181 days (range, 18 to 403 days). Diazoxide was effective in 19 of the 21 neonates treated. In the 11 neonates tested, the AIRs to calcium, leucine, glucose, and tolbutamide resembled those in normal controls and differed from genetic hyperinsulinism due to K(ATP) channel and GDH mutations. CONCLUSIONS: We define a syndrome of prolonged neonatal hyperinsulinism that is responsive to diazoxide, persists for several months, and resolves spontaneously. AIR tests suggest that both the K(ATP) channel and GDH have normal function.

Antihypertensive Agents↗
PubMed1997

Hyperinsulinism in infants and children.

Hyperinsulinism is the most common cause of hypoglycemia in early infancy. Congenital hyperinsulinism, formerly termed nesidioblastosis, is usually caused by genetic defects in beta-cell regulation, including a severe recessive disorder of the sulfonylurea receptor, a milder dominant form of hyperinsulinism, and a syndrome of hyperinsulinism plus hyperammonemia. Transient neonatal hyperinsulinism may be associated with perinatal asphyxia or small-for-dates birthweight and maternal diabetes. To prevent permanent brain damage from hypoglycemia, the treatment of infants with hyperinsulinism must be prompt and aggressive. A combination of medical therapy with diazoxide or octreotide, a long-acting somatostatin analog, and surgical 95% subtotal pancreatectomy may be required.

Child↗
PubMed1981

Protean manifestations of neonatal hyperinsulinism.

Endogenous hyperinsulinism is the leading cause of persistent hypoglycemia in children under one year of age. Classically, the symptoms of neonatal hypoglycemia have been referable to central nervous system dysfunction, with seizures described in nearly all patients. Our experience with eight neonates emphasizes the protean manifestations of this disease. One patient presented with a maternal history of diuretic use, and developed asymptomatic hyperinsulinism documented by provocative testing. The hyperinsulinism cleared after two weeks of medical therapy. This transient hyperinsulinism may have been secondary to use of a thiazide-type diuretic. A second patient presented, as a neonate, with a large abdominal mass but no seizure activity. Exploratory laparotomy revealed an 11 x 5 x 3 cm pancreatic tumor, which required splenectomy, 60% gastrectomy and duodenectomy for removal. Histologic examination demonstrated an insulin-secreting hamartoma. A third patient died suddenly without prior symptoms, and was found to have striking nesidioblastosis on pathologic examination. One infant presented with absence of the abdominal musculature (prune belly syndrome) and features of the Beck-with-Wiedeman syndrome, as well as profound hypoglycemia. Only three patients had seizures, and an additional patient had jitteriness. Pathologic diagnoses were: nesidioblastosis (n = 2); islet cell hyperplasia (n = 1); adenoma (n = 1); hamartoma (n = 1); transient hyperinsulinism (n = 1). One patient's pancreas showed areas of nesidioblastosis, islet cell hyperplasia, and a discrete adenoma in the region of the common bile duct. Careful diagnostic testing is essential in these patients, inasmuch as hypoglycemia is poorly tolerated by neonates and infants. Using the diagnostic algorithm presented here, all patients' endogenous hyperinsulinism was documented quickly and efficiently. Recognition of the broad spectrum of symptoms with which these patients may present is essential if serious neurologic sequelae are to be avoided.

Chlorthalidone↗
PubMed1987

Involvement of endogenous opiates in glucose-stimulated hyperinsulinism of canine endotoxin shock. Inhibition by naloxone.

Hyperinsulinism has been associated with infection and endotoxin shock in rodents, dogs, and humans. In dogs with Escherichia coli-induced endotoxin shock, this hyperinsulinism was in response to glucose administration. To determine the role of endogenous opiates in endotoxin-induced glucose-stimulated hyperinsulinism, plasma beta-endorphin, Met-enkephalin, Leu-enkephalin, insulin, and glucose concentrations were measured for 6 h in fasted, anesthetized dogs given LD70 of E. coli endotoxin; endotoxin and glucose; endotoxin, glucose, and naloxone (an opiate antagonist); glucose and naloxone; or glucose alone. Plasma endogenous opiate immunoreactivity was elevated in dogs that received endotoxin, regardless of the presence of glucose or naloxone. The elevation of plasma Met-enkephalin and beta-endorphin preceded the onset of hyperinsulinism, but the elevation of plasma Leu-enkephalin did not. Plasma insulin was elevated 100-fold by 360 min in dogs given endotoxin and glucose. The magnitude of this hyperinsulinism was markedly reduced by naloxone, supporting the hypothesis that endogenous opiates are involved in the development of the glucose-stimulated hyperinsulinism associated with endotoxin shock. Interestingly, naloxone, given in conjunction with glucose, appeared to have a stimulatory effect on insulin secretion.

Animals↗
PubMed1976

Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia.

The metabolic adaptation to fasting in infants with hyperinsulinism was examined to see whether a characteristic abnormality could be found that would aid in the diagnosis of this disorder. Seven infants under 1 year of age with hyperinsulinism were studied; 7 control infants of similar age and 12 children with ketotic hypoglycemia served as contrast groups. At the time of hypoglycemia, four of the seven infants with hyperinsulinism did not have elevated levels of insulin. However, levels of beta-hydroxybutyrate were significantly lower in the infants with hyperinsulinism than in the control and ketotic hypoglycemic groups. Levels of free fatty acids were also lower in the infants with hyperinsulinism. Expected levels and normal limits for beta-hydroxybutyrate, insulin, and free fatty acids when plasma glucose is below 40 mg/100 ml were estimated by combining the control and ketotic hypoglycemic groups. Using these values as standards, the diagnosis of hyperinsulinism can be made by evaluation of the response to fasting hypoglycemia. The application of this approach is illustrated by three case examples.

Blood Glucose↗
PubMed1999

Congenital hyperinsulinism: molecular basis of a heterogeneous disease.

Congenital hyperinsulinism (CHI) is a disease phenotype characterized by increased, usually irregular, insulin secretion leading to hypoglycemia, coma, and severe brain damage, left untreated. Hyperinsulinism may be caused by a range of biochemical disturbances and molecular defects. In pancreatic beta cells, insulin secretion is stimulated by closure of the ATP-dependent potassium channel (K(ATP) channel). K(ATP) channel is a complex composed of at least two subunits: the sulfonylurea receptor SUR1 and Kir6.2, an inward rectifier K+ channel member. Mutations in both subunits have been identified in patients with the autosomal recessive form of hyperinsulinism, including 28 different mutations in the SUR1 gene and two mutations in the Kir6.2 gene. These mutations co-segregated with disease phenotype, also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI), and with attenuated K(ATP) channel function. Inadequately high insulin secretion in one family with an autosomal dominant mode of inheritance is caused by a mutation in the glucokinase gene, resulting in increased affinity of the enzyme for glucose. Five different mutations have been identified in the glutamate dehydrogenase gene, resulting in overactivity of this enzyme and causing a syndrome of hyperinsulinism and hyperammonemia. In 13 cases, hyperinsulinism was caused by one or more focal pancreatic lesions with specific loss of maternal alleles of the imprinted chromosome region 11p15. In five patients, this loss of heterozygosity unmasked a paternally inherited recessive SUR1 mutation. The new molecular approaches in PHHI give further insight into the mechanism of pancreatic beta cell insulin secretion. The heterogeneous group of patients with CHI may now be classified according to their basic defects in the four different genes, with potential implications for a more specific treatment.

Diabetes Mellitus, Type 2↗
PubMedDate not supplied

Serum and pancreatic immunoreactive insulin (IRI) and proinsulin-like component (PLC), serum IRI and PLC response to different stimuli in normal subjects and organic hyperinsulinism.

The serum levels of total immunoreactive insulin (IRI) and proinsulin-like component (PLC) in the fasting state and following the administration of insulin secretagogues in 5 patients with organic hyperinsulinism and age and sex matched normal subjects are reported. Diagnosis of organic hyperinsulinism could be established in all instances on the basis of the inappropriately high total serum IRI levels for the corresponding blood glucose values; such an abnormal relationship was not seen in normal subjects, and was further enhanced by insulin secretagogues. Unrestrained insulin secretion in organic hyperinsulinism was enhanced following the administration of glucose, tolbutamide, glucagon or amino acids; the last 2 stimuli are known to be ineffective in causing insulin secretion in the presence of hypoglycemia in normal subjects. Four patints had insulinomas and one probably had islet cell hyperplasia or abnormal function of islet cells. Chromatography of serum IRI to quantitate PLC is a useful adjunct to the diagnosis of organic hyperinsulinism as in the fasting state the proportion of PLC is always elevated, above the normal range of 5-22%. Following the administration of insulin secretagogues there was pronounced increase in total serum IRI in organic hyperinsulinism but the proportion of PLC generally decreased, suggesting thereby that mojor increase in IRI was due to release of stored granular IRI which is known to have a low proportion of PLC.

Adenoma, Islet Cell↗
PubMed1976

Hyperinsulinism in endotoxin shock dogs.

Extreme hyperinsulinism was observed in endotoxin-shock dogs made hyperglycemic by glucose infusion. Qualitatively (at least in terms of gel filtration characteristics), the insulin secreted under these conditions was normal. Hyperinsulinism was not observed in endotoxin-shock dogs not given glucose. Thus hyperinsulinism does not explain the hypoglycemia so frequently observed in endotoxin-treated dogs. Hyperinsulinsm could not be impaired degradation of insulin as disappearance of labeled insulin as well as cold insulin was comparable in control and endotoxin-treated animals. An adrenergic mechanism (either beta receptor stimulation or postadrenergic hyperresponsiveness of the beta cells) probably does not explain the hyperinsulinism observed in endotoxin-shock dogs given glucose as beta blockade failed to inhibit the hyperinsulinsm. Hyperinsulinism was not observed in endotoxin-shock dogs given tolbuamide. A tenfold rise in plasma IRG was observed in endotoxin-treated dogs whether glucose was infused or not. The persistently low IRI levels in endotoxin-treated dogs not given glucose suggest that hyperresponsiveness of the beta cell to glucagon was not present in these animals. Extreme hyperinsulinsm in response to induced hyperglycemia in endotoxin-shock dogs is unexplained. Hyperresponsiveness of the beta cell to glucose during endotoxin shock seems likely.

Alloxan↗
PubMed1999

Congenital hyperinsulinism and the surgeon: lessons learned over 35 years.

BACKGROUND/PURPOSE: Congenital hyperinsulinism induces severe and unremitting hypoglycemia in newborns and infants. If poorly controlled, seizures and irreversible brain damage may result. Subtotal (<95%) or near-total (95% to 98%) pancreatectomy have been performed for glycemic control in babies who do not respond to aggressive medical therapy. Because hypoglycemia often persists after subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To define the effect of more or less extensive pancreatectomy on the management and outcome of refractory congenital hyperinsulinism, the authors examined our single institutional experience. METHODS: The records of children treated between 1963 and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were reviewed. Outcome parameters included glycemic response to surgery, need for reresection, surgical morbidity, surgical and long-term mortality, and development of diabetes mellitus (DM). A complete response was defined as discharge to home on no glycemic medications, no continuous feedings, and without DM. Histological reports were reviewed and categorized as either diffuse or focal disease. RESULTS: Of 101 children treated for congenital hyperinsulinism during this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed a complete response, occurring in 50% of patients having > or = 95% pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16). The remaining three babies had local excision of a solitary focal lesion, and each showed a complete response. Histopathology showed diffuse islet abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A complete response was observed for 82% of focal but only 33% of diffuse lesions. Eight patients (15%) required reresection for persistent hypoglycemia, seven having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3) occurring before 1975. DM developed in seven children (14%), each having diffuse lesions, and was independent of resection type. CONCLUSION: Because euglycemia is more readily restored, and because the risks for surgical complications and DM do not appear increased, the authors recommend 95% pancreatectomy as the initial procedure of choice for newborns and infants with congenital hyperinsulinism.

Female↗
PubMed2006

Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism.

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.

ATP-Binding Cassette Transporters↗