RARE DISEASE
Congenital isolated hyperinsulinism
Congenital isolated hyperinsulinism
Congenital isolated hyperinsulinism
Synonyms: PHHI, Persistent hyperinsulinemic hypoglycemia of infancy
Synonyms: PHHI, Persistent hyperinsulinemic hypoglycemia of infancy
Synonyms: PHHI, Persistent hyperinsulinemic hypoglycemia of infancy
Drug discovery
19
drugs
With orphan designations
Overview
Congenital isolated hyperinsulinism (CHI) is a rare genetic disorder causing persistent hypoglycemia due to dysregulated insulin secretion from pancreatic β-cells. It is the most common cause of severe, recurrent hypoglycemia in neonates and infants, with up to 50% risk of permanent neurocognitive impairment if untreated. Genetic mutations (e.g., ABCC8, KCNJ11) disrupt insulin regulation, leading to excessive secretion independent of blood glucose levels [1][4][7].
Burden
Up to 25–50% risk of brain injury without prompt treatment [4][9].
High morbidity: Long-term neurodevelopmental delays, diabetes post-pancreatectomy, and pancreatic exocrine dysfunction in surgically treated cases [9][16].
Resource-intensive care: Requires frequent glucose monitoring, specialized centers, and multidisciplinary management [1][7].
Therapies
First-line: Diazoxide (KATP channel agonist) for diazoxide-responsive cases [4][16].
Second-line: Somatostatin analogs (octreotide, lanreotide) or glucagon for unresponsive cases; surgery (focal lesionectomy or subtotal pancreatectomy) for focal/diffuse forms [3][8][16].
Emergency: IV dextrose and glucagon to stabilize acute hypoglycemia [3][6].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
702 drug discovery papers about Congenital isolated hyperinsulinism, with 1 first-in-class and 20 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
702 drug discovery papers about Congenital isolated hyperinsulinism, with 1 first-in-class and 20 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-06 | Ghrelin and relamorelin counteract hypoglycemia in mice engrafted with congenital hyperinsulinism stem cell-derived islets.
KATP-channel-related hyperinsulinism (KATPHI) is a rare genetic disorder of the pancreatic beta cells, manifesting as life-threatening hypoglycemia in neonates due to excessive insulin secretion. Management of the severe diffuse form of KATPHI currently lacks treatment options, as the first-line therapy octreotide is often insufficiently effective, necessitating radical pancreatectomy in many patients. In this study, we differentiated stem cells carrying the KATPHI-causing mutation KCNJ11-/- to stem cell-derived islets (SC-islets) to develop new pharmaceutical therapies for KATPHI. We tested seven candidate molecules in vitro and the most effective ones in vivo in immunocompromised mice that were transplanted with the human KCNJ11-/- SC-islets. KCNJ11 -/- SC-islets inappropriately secreted 3.9 times more insulin in low glucose than KCNJ11+/+ controls. Transplanted KCNJ11-/- SC-islets caused persistent hyperinsulinemia and hypoglycemia to the recipient mice. We tested acyl-ghrelin identified in our in vitro experiments and its long-acting analogue relamorelin in these mice. Acyl-ghrelin and relamorelin alone increased fasting blood glucose. Combining relamorelin with octreotide increased blood glucose synergistically, ie, more than the sum of each drug alone, reverting hypoglycemia to normoglycemia while reducing the excessive insulin secretion. We show that ghrelin-receptor agonists have acute anti-hypoglycemic effects in a humanized mouse model of KATPHI, especially when combined with octreotide. Relamorelin has been tested in >650 diabetic adults with little side effects, leading us to propose relamorelin-octreotide combination for further development as a therapeutic candidate for severe KATPHI patients.
2026-07-23 | Indocyanine green fluorescence cholangiography enables safe laparoscopic near-total pancreatectomy for diffuse congenital hyperinsulinism.
Laparoscopic near-total pancreatectomy (NTP) for diffuse congenital hyperinsulinism (CHI) may reduce morbidity compared with open surgery. However, it is technically limited by uncertainty regarding the intrapancreatic common bile duct (CBD) course, risking bile duct injury or inadequate resection. We evaluated whether near-infrared indocyanine green fluorescence cholangiography (NIR ICG FC) improves intraoperative identification of the intrapancreatic CBD and supports laparoscopic NTP for medically-refractory diffuse CHI. We performed a retrospective single-centre review of consecutive infants undergoing laparoscopic NTP with NIR ICG FC for diffuse CHI (2021-2025). Intravenous ICG (0.5 mg/kg) was administered 10-15 h preoperatively. Outcomes included feasibility of CBD visualisation, extent of resection, biliary complications, postoperative recovery, persistence of hyperinsulinism and medium-term endocrine/exocrine function. Five infants underwent laparoscopic NTP at a median age of 3 months (range 2-6). The intrapancreatic CBD was visualised in all cases, enabling a consistent 95% resection without conversion to open surgery. There were no bile duct injuries. Enteral feeding commenced at a median of 3 postoperative days (range 2-4). One patient developed transient obstructive jaundice on postoperative day 13 that resolved with conservative management. At a median follow-up of 30 months (range 20-51), three infants had residual hyperinsulinism (managed by feeding strategies in two and medication in one), and one had exocrine insufficiency requiring enzyme supplementation; no child had diabetes at latest follow up. NIR ICG fluorescence cholangiography provides real time delineation of the intrapancreatic CBD and can support a safe minimally invasive approach to near-total pancreatectomy for diffuse CHI.
2026-07-23 | Indocyanine green fluorescence-guided intraoperative biliary mapping during pediatric laparoscopic duodenum-preserving pancreatic head resection: a standardized operative approach.
Laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) for focal congenital hyperinsulinism (CHI) poses a specific intraoperative challenge: reliable, continuous identification of the intrapancreatic common bile duct (CBD) in an anatomically diminutive, tactile-feedback-free operative field. We describe a standardized indocyanine green (ICG) fluorescence-guided biliary visualization workflow for pediatric LDPPHR and report its initial implementation experience. In this retrospective case series, we summarized the application of this standardized workflow in seven consecutive children with focal CHI who underwent ICG fluorescence-guided LDPPHR at Beijing Children's Hospital from February 2025 to March 2026. The workflow comprised seven sequential steps: exposure and preparation, first-dose ICG administration, initial biliary mapping, boundary-guided pancreatic head dissection, repeated fluorescence assessment and reinjection when required, post-resection perfusion assessment, and reconstruction with final intraoperative checking. The workflow was completed as planned in all seven cases, with full workflow adherence in 7/7 procedures. Continuous visualization of the intrapancreatic CBD under near-infrared (NIR) illumination was achieved in 7/7 procedures. Repeated white-light/NIR correlation was feasible throughout dissection in all cases. The fluorescence-guided workflow was implemented without intraoperative abandonment. No bile leak, clinically relevant postoperative pancreatic fistula (ISGPS 2016 criteria), or duodenal ischemia was observed. Median operative time was 310 min (range 229-570 min). This stepwise ICG biliary visualization workflow was technically feasible and was implemented without biliary adverse events in this initial retrospective case series. As a workflow description with feasibility observations rather than an efficacy study, this report suggests that repeated real-time delineation of the intrapancreatic CBD may facilitate duct-sparing dissection; whether it reduces bile duct injury requires validation in larger comparative studies.
2026-07-15 | Two threats in early life: congenital hyperinsulinemic hypoglycemia and thrombosis.
Congenital persistent hyperinsulinemic hypoglycemia (HH) is a rare disorder that can lead to severe and recurrent hypoglycemic episodes in neonates and infants. Management often requires intensive glucose infusion via central venous catheters (CVCs), which may increase the risk of thrombosis. While case reports suggest thrombosis can occur in HH, the incidence, risk factors, severity, and outcomes remain poorly understood. This study aimed to determine the incidence of thrombosis in children with persistent HH and to evaluate potential risk factors associated with thrombotic complications. A descriptive, retrospective cohort study of patients with persistent HH followed at a university pediatric endocrinology clinic between January 2000 and December 2025. Twenty patients with persistent HH were included. Data on demographics, clinical characteristics, laboratory results, treatment protocols, CVC use, timing and location of thrombosis were collected. Patients who developed thrombosis were compared with those who did not to identify risk factors. Among 20 patients, 55% were male, with a median age at diagnosis of 1 day. A total of 23 CVCs were placed in 15 patients, with a median dwell time of 38 days. Thrombosis occurred in nine patients (45%), including six catheter-related and three catheter-independent intracranial thrombosis. Median age at thrombosis detection was 74 days. Patients who developed thrombosis experienced significantly more hypoglycemic episodes and more days with hypoglycemia (p < 0.05). No association was found between genetic mutations (ABCC8, KCNJ11, etc.) and thrombosis development. All four patients treated with enoxaparin achieved complete resolution without complications. Thrombosis is a frequent and clinically significant complication in persistent HH. Recurrent and severe hypoglycemic episodes are major risk factors. Routine thrombosis screening, particularly in patients with CVCs, may allow early detection and treatment even in asymptomatic cases.
2026-06-10 | Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.
Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of αCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism.
2026-08-06 | Ghrelin and relamorelin counteract hypoglycemia in mice engrafted with congenital hyperinsulinism stem cell-derived islets.
KATP-channel-related hyperinsulinism (KATPHI) is a rare genetic disorder of the pancreatic beta cells, manifesting as life-threatening hypoglycemia in neonates due to excessive insulin secretion. Management of the severe diffuse form of KATPHI currently lacks treatment options, as the first-line therapy octreotide is often insufficiently effective, necessitating radical pancreatectomy in many patients. In this study, we differentiated stem cells carrying the KATPHI-causing mutation KCNJ11-/- to stem cell-derived islets (SC-islets) to develop new pharmaceutical therapies for KATPHI. We tested seven candidate molecules in vitro and the most effective ones in vivo in immunocompromised mice that were transplanted with the human KCNJ11-/- SC-islets. KCNJ11 -/- SC-islets inappropriately secreted 3.9 times more insulin in low glucose than KCNJ11+/+ controls. Transplanted KCNJ11-/- SC-islets caused persistent hyperinsulinemia and hypoglycemia to the recipient mice. We tested acyl-ghrelin identified in our in vitro experiments and its long-acting analogue relamorelin in these mice. Acyl-ghrelin and relamorelin alone increased fasting blood glucose. Combining relamorelin with octreotide increased blood glucose synergistically, ie, more than the sum of each drug alone, reverting hypoglycemia to normoglycemia while reducing the excessive insulin secretion. We show that ghrelin-receptor agonists have acute anti-hypoglycemic effects in a humanized mouse model of KATPHI, especially when combined with octreotide. Relamorelin has been tested in >650 diabetic adults with little side effects, leading us to propose relamorelin-octreotide combination for further development as a therapeutic candidate for severe KATPHI patients.
2026-07-23 | Indocyanine green fluorescence cholangiography enables safe laparoscopic near-total pancreatectomy for diffuse congenital hyperinsulinism.
Laparoscopic near-total pancreatectomy (NTP) for diffuse congenital hyperinsulinism (CHI) may reduce morbidity compared with open surgery. However, it is technically limited by uncertainty regarding the intrapancreatic common bile duct (CBD) course, risking bile duct injury or inadequate resection. We evaluated whether near-infrared indocyanine green fluorescence cholangiography (NIR ICG FC) improves intraoperative identification of the intrapancreatic CBD and supports laparoscopic NTP for medically-refractory diffuse CHI. We performed a retrospective single-centre review of consecutive infants undergoing laparoscopic NTP with NIR ICG FC for diffuse CHI (2021-2025). Intravenous ICG (0.5 mg/kg) was administered 10-15 h preoperatively. Outcomes included feasibility of CBD visualisation, extent of resection, biliary complications, postoperative recovery, persistence of hyperinsulinism and medium-term endocrine/exocrine function. Five infants underwent laparoscopic NTP at a median age of 3 months (range 2-6). The intrapancreatic CBD was visualised in all cases, enabling a consistent 95% resection without conversion to open surgery. There were no bile duct injuries. Enteral feeding commenced at a median of 3 postoperative days (range 2-4). One patient developed transient obstructive jaundice on postoperative day 13 that resolved with conservative management. At a median follow-up of 30 months (range 20-51), three infants had residual hyperinsulinism (managed by feeding strategies in two and medication in one), and one had exocrine insufficiency requiring enzyme supplementation; no child had diabetes at latest follow up. NIR ICG fluorescence cholangiography provides real time delineation of the intrapancreatic CBD and can support a safe minimally invasive approach to near-total pancreatectomy for diffuse CHI.
2026-07-23 | Indocyanine green fluorescence-guided intraoperative biliary mapping during pediatric laparoscopic duodenum-preserving pancreatic head resection: a standardized operative approach.
Laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) for focal congenital hyperinsulinism (CHI) poses a specific intraoperative challenge: reliable, continuous identification of the intrapancreatic common bile duct (CBD) in an anatomically diminutive, tactile-feedback-free operative field. We describe a standardized indocyanine green (ICG) fluorescence-guided biliary visualization workflow for pediatric LDPPHR and report its initial implementation experience. In this retrospective case series, we summarized the application of this standardized workflow in seven consecutive children with focal CHI who underwent ICG fluorescence-guided LDPPHR at Beijing Children's Hospital from February 2025 to March 2026. The workflow comprised seven sequential steps: exposure and preparation, first-dose ICG administration, initial biliary mapping, boundary-guided pancreatic head dissection, repeated fluorescence assessment and reinjection when required, post-resection perfusion assessment, and reconstruction with final intraoperative checking. The workflow was completed as planned in all seven cases, with full workflow adherence in 7/7 procedures. Continuous visualization of the intrapancreatic CBD under near-infrared (NIR) illumination was achieved in 7/7 procedures. Repeated white-light/NIR correlation was feasible throughout dissection in all cases. The fluorescence-guided workflow was implemented without intraoperative abandonment. No bile leak, clinically relevant postoperative pancreatic fistula (ISGPS 2016 criteria), or duodenal ischemia was observed. Median operative time was 310 min (range 229-570 min). This stepwise ICG biliary visualization workflow was technically feasible and was implemented without biliary adverse events in this initial retrospective case series. As a workflow description with feasibility observations rather than an efficacy study, this report suggests that repeated real-time delineation of the intrapancreatic CBD may facilitate duct-sparing dissection; whether it reduces bile duct injury requires validation in larger comparative studies.
2026-07-15 | Two threats in early life: congenital hyperinsulinemic hypoglycemia and thrombosis.
Congenital persistent hyperinsulinemic hypoglycemia (HH) is a rare disorder that can lead to severe and recurrent hypoglycemic episodes in neonates and infants. Management often requires intensive glucose infusion via central venous catheters (CVCs), which may increase the risk of thrombosis. While case reports suggest thrombosis can occur in HH, the incidence, risk factors, severity, and outcomes remain poorly understood. This study aimed to determine the incidence of thrombosis in children with persistent HH and to evaluate potential risk factors associated with thrombotic complications. A descriptive, retrospective cohort study of patients with persistent HH followed at a university pediatric endocrinology clinic between January 2000 and December 2025. Twenty patients with persistent HH were included. Data on demographics, clinical characteristics, laboratory results, treatment protocols, CVC use, timing and location of thrombosis were collected. Patients who developed thrombosis were compared with those who did not to identify risk factors. Among 20 patients, 55% were male, with a median age at diagnosis of 1 day. A total of 23 CVCs were placed in 15 patients, with a median dwell time of 38 days. Thrombosis occurred in nine patients (45%), including six catheter-related and three catheter-independent intracranial thrombosis. Median age at thrombosis detection was 74 days. Patients who developed thrombosis experienced significantly more hypoglycemic episodes and more days with hypoglycemia (p < 0.05). No association was found between genetic mutations (ABCC8, KCNJ11, etc.) and thrombosis development. All four patients treated with enoxaparin achieved complete resolution without complications. Thrombosis is a frequent and clinically significant complication in persistent HH. Recurrent and severe hypoglycemic episodes are major risk factors. Routine thrombosis screening, particularly in patients with CVCs, may allow early detection and treatment even in asymptomatic cases.
2026-06-10 | Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.
Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of αCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism.
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Drug Discovery Landscape
19 orphan drug designations for Congenital isolated hyperinsulinism.
19 orphan drug designations for Congenital isolated hyperinsulinism.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
solution stable glucagon analog | peptides | FDA | 2024-06-17 | — | AmideBio, Inc. |
Pegylated Glucagon Receptor Agonist | peptides | FDA | 2021-05-17 | — | Pegbio Co. Ltd. |
Zavolosotine | small molecules | EMA | 2020-12-09 | — | Crinetics Pharmaceuticals Europe GmbH |
solution stable glucagon analog | peptides | FDA | 2020-04-20 | — | AmideBio |
Exendin (9-39) | peptides | EMA | 2019-11-13 | — | Amylyx Pharmaceuticals EMEA B.V. |
Glucagon analogue linked to a human immunoglobulin Fc fragment | proteins | EMA | 2018-05-25 | — | JVM Europe B.V. |
glucagon analog conjugated with human immunoglobulin G4 fragment | proteins | FDA | 2018-02-01 | — | Hanmi Pharmaceutical Company, Ltd. |
glucagon (ready-to-use) | peptides | FDA | 2018-01-24 | — | Xeris Pharmaceuticals, Inc. |
dihydroxyphenylalanine F 18/Fluorodopa (F18) | small molecules | FDA | 2018-01-22 | — | Society of Nuclear Medicine and Molecular Imaging |
dasiglucagon | peptides | FDA | 2017-08-10 | — | Zealand Pharma A/S |
Synthetic glucagon analogue modified to contain 7 amino acid substitutions | peptides | EMA | 2017-06-20 | — | Zealand Pharma A/S |
avexitide | peptides | FDA | 2016-12-08 | — | Amylyx Pharmaceuticals, Inc. |
Recombinant human monoclonal antibody to insulin receptor | antibodies | EMA | 2016-07-14 | — | Rezolute (Bio) Ireland Limited |
fully human IgG2 monoclonal antibody that binds insulin receptors | antibodies | FDA | 2015-06-09 | — | Rezolute, Inc. |
Glucagon | peptides | EMA | 2014-10-15 | — | S-cubed Pharmaceutical Services ApS |
glucagon infusion | peptides | FDA | 2014-09-25 | — | Xeris Pharmaceuticals, Inc. |
glucagon | peptides | FDA | 2012-12-05 | — | Biodel, Inc. |
Glucagon | peptides | EMA | 2012-03-05 | — | Biodel UK Limited |
exendin-(9-39) | peptides | FDA | 2011-06-01 | — | The Children's Hospital of Philadelphia |
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