Advances in Pharmacotherapy for Congenital Hyperinsulinism.

Persistent hyperinsulinemic hypoglycemia of infancy(PHHI) is the most common cause of persistent hypoglycemia in infancy. PHHi is a genetically heterogeneous disorder with two histological lesions ( diffuse and focal lesion) and several gene mutations that moderate insulin release in pancreatic β cells. The manifestation is persistent hypoglycemia in infancy, associated with inappropriate oversecretion of insulin and low plasma levels of ketone bodies and free fatty acids, which results in severe hypoglyeemie brain damage and secondary diabetes mellitus. Diazoxide, as the first-line therapy, can inhibit the secretion of insulin and may be effective in partial populations. To reduce the risk of brain damage, a near-total or focal pancreatectomy is necessary if the patient is non-responsive to conservative therapy, and the preoperative or intraoperative histological examination is essential to decide therapeutic approach and prognosis. Key words: Persistent hyperinsulinemic hypoglycemia of infancy; Etiology; Clinical manifestation; Management

To examine the hypoglycaemic effect on neurodevelopmental outcome in patients with transient and persistent congenital hyperinsulinism (CHI) born in the 21st century. A cohort of 117 patients (66 males, 51 females) with CHI aged 5 to 16years (mean age 8y 11mo, SD 2y 7mo) were selected from a Finnish nationwide registry to examine all the patients with similar methods. Neurodevelopment was first evaluated retrospectively. The 83 patients with no risk factors for neurological impairment other than hypoglycaemia were recruited and 44 participated (24 males, 20 females; mean age 9y 7mo, SD 3y 1mo) in neuropsychological assessment with the Wechsler Intelligence Scale for Children, Fourth Edition and the Finnish version of the Developmental Neuropsychological Assessment, Second Edition domains of attention, language, memory, sensorimotor, and visual functioning. In retrospective analysis, transient and persistent CHI groups had similar prevalences of mild (22% and 18% respectively) or severe (5% and 7% respectively) neurodevelopmental difficulties. In clinical assessment, the neurocognitive profile was within the average range in both groups, but children with persistent CHI showed significant but restricted deficits in attention, memory, visual, and sensorimotor functions compared with the general population. The transient CHI group did not differ from the standardization samples. Besides the more apparent broader neurological deficits, children with persistent CHI have an increased risk for milder specific neurocognitive problems, which should be considered in the follow-up. Children with persistent congenital hyperinsulinism showed deficits in attention, memory, visual, and sensorimotor functions. The deficits were potentially of hypoglycaemic origin. Children with transient hyperinsulinism did not differ from the general population.

The neonatal disorder persistent hyperinsulinemic hypoglycemia of infancy (PHHI) arises as the result of mutations in the subunits that form the ATP-sensitive potassium (KATP) channel in pancreatic beta cells, leading to insulin hypersecretion. Diazoxide (a specific KATP channel agonist in normal beta cells) and somatostatin (octreotide) are the mainstay of medical treatment for the condition. To investigate the mechanism of action of these agents in PHHI beta cells that lack KATP currents, we applied patch clamp techniques to insulin-secreting cells isolated from seven patients with PHHI. Five patients showed favorable responses to medical therapy, and two were refractory. Our data reveal, in drug-responsive patients, that a novel ion channel is modulated by diazoxide and somatostatin, leading to termination of the spontaneous electrical events that underlie insulin hypersecretion. The drug-resistant patients, both of whom carried a mutation in one of the genes that encode KATP channel subunits, also lacked this novel K+ channel. There were no effects of diazoxide and somatostatin on beta cell function in vitro. These findings elucidate for the first time the mechanisms of action of diazoxide and somatostatin in infants with PHHI in whom KATP channels are absent, and provide a rationale for development of new therapeutic opportunities by K+ channel manipulation in PHHI treatment.

Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

Anesthetic management of a 6 month-old infant for near total pancreatectomy with persistent hyperinsulinemic hypoglycemia

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.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) affects between 0.5% and 5% of pediatric patients. This condition is caused by a dysfunction of pancreatic β-cells, leading to tumors and hyperinsulinism, which result in persistent hypoglycemia. These episodes are often resistant to conventional treatment and require interventions to reduce insulin production and increase glucose levels, thereby restoring metabolic balance. We present three cases of PHHI. The first is a four-day-old Rarámuri patient with persistent hypoglycemia, diagnosed after a pancreatectomy and biopsy. The second case is a three-day-old Rarámuri patient with persistent hypoglycemia and a pancreatic lesion detected by scintigraphy, with PHHI confirmed after pancreatectomy. The third case is a three-day-old female patient with hypoactivity and persistent hypoglycemia, who was also diagnosed with PHHI after a pancreatectomy. While clinical presentation and biochemical findings raise high diagnostic suspicion, histopathological confirmation is essential. Early diagnosis is key to preventing long-term sequelae. PHHI should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia, such as prematurity, intrauterine growth restriction, low birth weight, maternal diabetes, tyrosinemia type 1, or Beckwith-Wiedemann syndrome. These cases highlight the complexity of PHHI and its unusual presentation in the Rarámuri ethnic group, underscoring the importance of culturally sensitive medical care.

Insulin secretion from pancreatic β-cells is tightly regulated to keep fasting blood glucose concentrations within the normal range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is a heterozygous condition in which insulin secretion becomes unregulated and its production persists despite low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. The most severe and permanent forms are due to congenital hyperinsulinism (CHI). Recent advances in genetics have linked CHI to mutations in 9 genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A and HNF1A). Histologically, CHI can be divided into 3 types; diffuse, focal and atypical. Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage. Therefore, it is essential to diagnose and treat HH promptly. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children. This review provides an overview of the genetic and molecular mechanisms leading to development of HH in children. The article summarizes the current diagnostic methods and management strategies for the different types of CHI.

Background/purpose Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the most common cause of persistent hypoglycemia in infancy with consequences such as seizures and brain damage. Treatment that prevents the occurrence of these sequele is essential. When medical therapy fails or complications are anticipated, early pancreatectomy is recommended to maintain euglycemia. The aim of this study was short-term evaluation of near-total pancreatectomy for PHHI after failure of medical treatment in patients in Mansoura, Egypt. Patients and methods During May 2002 to May 2010, 33 patients suffering from persistent hyperinsulinemic hypoglycemia were admitted to Mansoura university child hospital. Twenty patients responded to medical treatment and 13 patients (eight girls and five boys) were treated by near-total (90–95%) pancreatectomy after failure of medical treatment. Their ages at the time of surgery ranged from 20 days to 27 months. Only patients who were surgically managed were included in this study. All of them suffered from symptoms of PHHI: thermoregulatory problems in five cases, tremors in five cases, seizures in three, irritability in five, respiratory distress in eight, apnea in four, hypotonia in four, lethargy in five, and feeding difficulty in four cases. All cases were diagnosed following strict criteria that included bouts of hypoglycemia without acidosis coinciding with increased insulin level. Follow-up ranged from 3 months to 8 years. Results Primary success occurred in two cases (15%); four more cases (31%) developed temporary diabetes mellitus, and one case (8%) had a temporary pancreatic fistula. Eventually, total cure occurred in seven cases (54%); six cases (46%) developed a variety of complications; and persistent hypoglycemia was seen in two. Persistent diabetes mellitus was observed in three patients, developmental delay in one, and persistent neurological deficit in two patients; there was one case of mortality. Conclusion Near-total (90–95%) pancreatectomy is a suitable procedure for treatment of nesidioblastosis not responding to medical treatment and should be performed as early as possible. Keywords : Mansoura, near-total pancreatectomy, persistent hyperinsulinemic hypoglycemia

The regulation of insulin secretion by pancreatic beta cells is perturbed in several diseases, including adult-onset (type 2) diabetes and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The first mouse model for PHHI has a conditional deletion of the gene encoding the winged-helix transcription factor Foxa2 (Forkhead box a2, formerly Hepatocyte nuclear factor 3beta) in pancreatic beta cells. Using isolated islets, we found that Foxa2 deficiency resulted in excessive insulin release in response to amino acids and complete loss of glucose-stimulated insulin secretion. Most PHHI cases are associated with mutations in SUR1 (Sulfonylurea receptor 1) or KIR6.2 (Inward rectifier K(+) channel member 6.2), which encode the subunits of the ATP-sensitive K(+) channel, and RNA in situ hybridization of mutant mouse islets revealed that expression of both genes is Foxa2 dependent. We utilized expression profiling to identify additional targets of Foxa2. Strikingly, one of these genes, Hadhsc, encodes short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase, deficiency of which has been shown to cause PHHI in humans. Hadhsc is a direct target of Foxa2, as demonstrated by cotransfection as well as in vivo chromatin immunoprecipitation experiments using isolated islets. Thus, we have established Foxa2 as an essential activator of genes that function in multiple pathways governing insulin secretion.

Pancreatic tissue was obtained during therapeutic subtotal pancreatectomy from five infants with persistent hyperinsulinaemic hypoglycaemia of infancy (so-called nesidioblastosis). Collagenase digests of the specimens were cultured in RPMI 1640 medium on extracellular matrix-coated plates. Acute insulin secretion showed minimal sensitivity to changes in glucose concentration. Sensitivity to other nutrient secretagogues such as glyceraldehyde, leucine, alpha-ketoisocaproic acid and arginine was variable, showing either diminished or absent response. On the other hand, stimulators of Beta cell cAMP and modulators of the phosphoinositide-protein kinase C pathway were effective inducers of insulin release. The response to cAMP stimulators was independent of the glucose concentration. Although insulin output was high in the absence of glucose, this was not due to passive leak of hormone, since both removal of calcium and addition of somatostatin and epinephrine inhibited the secretion. Beta cells were more sensitive to somatostatin than epinephrine; however, both agents failed to completely suppress the release even at suprapharmacological concentrations. Although it cannot be excluded that the culture conditions affected Beta cell function, the present findings may suggest that cultured Beta cells in persistent hyperinsulinaemic hypoglycaemia of infancy behave like fetal Beta cells at early developmental stages.

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

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) results from defects of regulated insulin release from pancreatic beta cells and is often refractory to medical treatment. Histological changes in the pancreas associated with PHHI may be focal or diffuse, and the intraoperative confirmation and siting of focal lesions would require frozen section diagnosis. The recognition of focal involvement and its distinction from diffuse disease by frozen section depends on the identification and distribution pattern of islet cells with large hyperchromatic nuclei. This study was designed to test the feasibility of using this parameter in PHHI to delineate focal from diffuse diseases prior to the introduction of frozen sections to guide intraoperative management in our institution. A total of 66 coded and randomized paraffin sections (from 18 PHHI and 4 postmortem pancreases) were scored by three independent observers into the following categories: a focal lesion (A), no large endocrine nuclei (B), few large endocrine nuclei (C), and frequent large endocrine nuclei (D). Interobserver concordance was complete in 88%, but there were minor discrepancies in the remaining 12%. When a focal lesion was present in one section no large endocrine nuclei were seen in sections from the rest of the pancreas. In four patients with diffuse PHHI, no or only very scanty large endocrine nuclei were seen. From this finding, and the observation that in other examples of diffuse disease, large endocrine nuclei were sparse even in large paraffin sections, we have reservations about using small frozen sections for reliable diagnosis.

Background: Persistent neonatal hyperinsulinemic hypoglycemia (PNHH), frequently associated with nesidioblastosis, poses significant diagnostic and therapeutic challenges due to dysregulated insulin secretion. Congenital hyperinsulinism (CHI), the primary cause of PNHH, exhibits diverse genetic and phenotypic presentations, necessitating tailored management strategies. This review integrates insights from 20 studies, examining genetic, therapeutic, and psychosocial dimensions of CHI. Objectives: To evaluate genotype-phenotype correlations and their implications for therapeutic outcomes in CHI, compare long-term medical and surgical outcomes, and identify risk factors affecting growth, metabolism, and neurodevelopment. Additionally, the study explores effective strategies to address the psychosocial and dietary challenges associated with CHI. Methods: A systematic review of 20 studies, encompassing over 2,000 patients, was conducted. Diagnostic criteria included genetic analyses of mutations in KATP channel genes (ABCC8, KCNJ11), GLUD1, and HNF4A, along with imaging and histopathological assessments. Treatment efficacy, long-term outcomes, and the impact of caregiver burden were analyzed. Data were synthesized into thematic categories, supported by statistical and qualitative assessments. Results: Dominant KATP mutations exhibited high responsiveness to diazoxide (70%), whereas recessive mutations necessitated surgical interventions, particularly near-total pancreatectomy. Focal CHI resolved hypoglycemia effectively with lesionectomy, whereas diffuse CHI presented ongoing risks, including diabetes and neurodevelopmental impairments. Personalized dietary strategies, such as high-protein diets and gastrostomy feeding, were effective in stabilizing glucose levels. Psychological stress in caregivers emerged as a significant concern, emphasizing the need for supportive interventions. Emerging therapies like lanreotide showed promise in refractory CHI cases. Discussion: The findings align with prior research, confirming the role of genetic mutations in determining treatment responsiveness. Surgical interventions, though effective in resolving hypoglycemia, carry long-term metabolic risks. Recent advances in genetic diagnostics and personalized medical therapies highlight opportunities for optimizing outcomes. However, caregiver burden and psychosocial challenges remain underexplored areas that require structured support systems. Conclusion: Managing CHI necessitates a multidisciplinary approach, integrating genetic insights, advanced therapies, and psychosocial support. Continued research is essential to develop innovative solutions for refractory CHI cases and to improve long-term outcomes for patients and families.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is characterized by hyperinsulinism and profound hypoglycemia, with most children requiring pancreatic resection. The histological classification of PHHI is controversial. Most authors acknowledge the existence of focal areas of islet cell proliferation (adenomatosis) in 30%-50% of cases and a diffuse disorganisation of islet architecture, termed "nesidiodysplasia," in others. De Lonlay et al. reported that cases with adenomatosis are focal with normal remainder of pancreas and that focal and diffuse disease can be differentiated intraoperatively, on the basis of increased beta-cell nuclear size found only in the diffusely abnormal pancreas. We have examined pancreatic histology in a blinded controlled study of PHHI patients. Pancreatic tissue was obtained at autopsy from 60 normal subjects (age 17 weeks gestation to 76 years) and from surgical specimens of 31 PHHI patients. Sections from PHHI subjects (n = 294 blocks) and control sections were stained with hematoxylin and eosin, insulin, glucagon, somatostatin, NSE, cytokeratin 19, and vimentin. Three sections from each PHHI patient were randomly chosen for further analysis. Age-matched control (n = 34) and PHHI sections (n = 66) were examined, with the identity of subjects concealed. A diagnosis of normal histology, adenomatosis, or diffuse nesidiodysplasia was recorded for each section. The presence of large beta-cell nuclei (>19 microm), ductuloinsular complexes, and centroacinar cell proliferation was noted. Of a total of 65 subjects examined (34 control and 31 PHHI), 37 subjects were identified as normal on both sections examined. All the control cases were correctly identified as normal and none had large beta-cell nuclei or centroacinar cell proliferation. Of 31 PHHI patients, 28 were identified as abnormal, either on the basis of abnormal architecture and/or abnormally large beta-cell nuclei. Three patients were identified as normal in both sections. Fifteen of 31 patients had diffuse nesidiodysplasia only. Of 13 patients with areas of adenomatosis, 2 had resection of a nodule with adenomatosis present in most of the tissue removed at surgery. Nine patients had a diagnosis of adenomatosis in one section and a diagnosis of diffuse nesidiodysplasia in the other sections from nonadjacent pancreas. Only 2 of 31 PHHI cases had adenomatosis on one section examined and normal pancreas on the other section examined. Large beta-cell nuclei were variably found in PHHI sections. Only 5 of 15 patients with diffuse nesidiodysplasia had large nuclei in both sections examined. Centroacinar cell proliferation was identified in 12 PHHI subjects, 6 with adenomatosis and diffuse nesidiodysplasia and 6 with diffuse changes only. It was patchy in distribution within sections and present in only one section in 7 of the 12 subjects. In summary, we have shown that a blinded observer could differentiate control and PHHI pancreatic tissue. Only 2 of 31 patients (6%) had focal adenomatosis with normal nonadjacent pancreas, the majority (24 of 31) had diffuse nesidiodysplasia affecting the remainder of their pancreas, with 38% (9 of 24) also having areas of adenomatosis. Large beta-cell nuclei did not reliably identify those with diffuse disease in this study. There was evidence of significant ductal and centroacinar proliferation in 39% of PHHI cases, which was not observed in any of the controls. We have shown that PHHI subjects have a spectrum of pancreatic histological abnormalities, from no abnormality to diffuse subtle changes to florid adenomatosis. Patients could not be segregated into subtypes for different operative intervention despite the availability of full immunohistochemical staining.