RARE DISEASE
Diazoxide-resistant diffuse hyperinsulinism
Diazoxide-resistant diffuse hyperinsulinism
Diazoxide-resistant diffuse hyperinsulinism
Synonyms: Hyperinsulinemic hypoglycemia, diazoxide-resistant diffuse form
Synonyms: Hyperinsulinemic hypoglycemia, diazoxide-resistant diffuse form
Synonyms: Hyperinsulinemic hypoglycemia, diazoxide-resistant diffuse form
Drug discovery
24
papers
On emerging therapies
Overview
Diazoxide-resistant diffuse hyperinsulinism (DRDH) is a rare, genetically driven form of congenital hyperinsulinism characterized by uncontrolled insulin secretion despite normoglycemia, leading to recurrent hypoglycemia. It arises from diffuse pancreatic β-cell dysfunction, often due to biallelic ABCC8 or KCNJ11 mutations affecting KATP channels. DRDH is typically unresponsive to diazoxide, necessitating aggressive interventions to prevent neurocognitive sequelae [1][6][12][16].
Burden
High hospitalization costs, with 5.9% of patients (e.g., pancreatectomy recipients) accounting for >60% of healthcare expenditures [14].
Long-term complications: Neurodevelopmental impairment (20-40% of cases), post-pancreatectomy diabetes (≥30%), and exocrine insufficiency [14][16][17].
Requires lifelong multidisciplinary care, including metabolic monitoring and neurologic follow-up [3][12][14].
Therapies
Second-line medical therapy: Octreotide (subcutaneous/infusion), glucagon (IV/continuous infusion), or lanreotide [3][8][17].
Surgical intervention: Near-total pancreatectomy (often required but risks diabetes and pancreatic insufficiency) [12][14].
Emerging options: mTOR inhibitors (e.g., sirolimus) remain experimental due to safety concerns [8][13].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
24 drug discovery papers about Diazoxide-resistant diffuse hyperinsulinism. Recent publications:
24 drug discovery papers about Diazoxide-resistant diffuse hyperinsulinism. Recent publications:
categories:
Small molecules
small molecules
2025-05-05 | Intra-operative indocyanine green (ICG) administration for surgical guidance in laparoscopic subtotal pancreatectomy for congenital hyperinsulinism: A case series
Indocyanine green (ICG)-guided surgery is gaining traction in pediatric surgery with its utilization reported in pancreatectomy for congenital hyperinsulinism (CHI). ICG can also be an adjunctive strategy to help surgeons new to complex laparoscopic surgeries. Both infants were Diazoxide-resistant diffuse CHI with ABCC8 mutations. Their surgeries were performed at 3 months of age. Patient 1: A laparoscopic subtotal pancreatectomy (85 % resection) was initially performed due to parental preference to preserve some pancreatic function. However, the patient experienced persistent hypoglycemia refractory to maximal medical management, necessitating a revision pancreatectomy. Serial low-dose intra-operative administration of ICG was used to identify vascular and biliary landmarks. However, the intra-pancreatic segment of the common bile duct (CBD) was not visualized despite multiple boluses of ICG, and thus pancreatic transection was performed at the level right of the superior mesenteric vein (SMV), accounting for a subtotal pancreatectomy (90 % resection). Patient 2: Serial low-dose intra-operative administration of ICG was used in identification and preservation of the splenic vessels during dissection and the identification of key vascular landmarks including SMV and portal vein (PV). A near-total pancreatectomy was initially attempted with serial ICG administrations to determine the level of pancreatic transection and to avoid an intra-pancreatic CBD injury. However, we were unable to identify the intra-pancreatic CBD which was buried deep within the bulky pancreatic head tissue. A subtotal pancreatectomy with pancreatic transection at the level right of the SMV (90 % resection) was performed. All surgeries were performed laparoscopically with no intra-operative complications. ICG-guidance can aid in real-time visualization of key vascular and extra-pancreatic biliary structures, potentially avoiding intra-operative injuries during laparoscopic subtotal pancreatectomy.
2025-03-27 | Effective Management of a Diffuse form of a Congenital Hyperinsulinism Due to a ABCC8 Mutation with a Combination of Diazoxide and Somatostatin Analogue (A Case Report)
Congenital hyperinsulinism (CHI) is a rare genetic disorder characterized by inappropriate and excessive insulin secretion, leading to severe, recurrent hypoglycemia in neonates, with significant neurological risks. We report a clinical case of a male neonate with a severe form of CHI, diagnosed through genetic analysis, who presented with diazoxide-resistant hypoglycemia and was successfully managed with the somatostatin analog, octreotide. Genetic testing revealed a homozygous mutation in the ABCC8 gene, confirming a diffuse form of CHI. Despite initial treatment with diazoxide, the neonate continued to experience severe hypoglycemic episodes. The addition of octreotide allowed for glycemic stabilization, reduced the need for continuous glucose infusion, and eventually led to the discontinuation of diazoxide. This case underscores the effectiveness of octreotide as a second-line treatment in managing diazoxide-resistant CHI and highlights the importance of early genetic diagnosis, personalized treatment strategies, and the potential of octreotide in avoiding the need for pancreatic surgery. Further research is needed to solidify the long-term safety and efficacy of octreotide in treating CHI and to optimize management protocols for this challenging condition.
2020-10-27 | Possible New Strategies for the Treatment of Congenital Hyperinsulinism
Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K+ (KATP) channels. Additionally, KATP channel-independent targets as Ca2+-activated K+ channels of intermediate conductance (KCa3.1) and L-type Ca2+ channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1-/-) mice. The cytosolic Ca2+ concentration ([Ca2+]c) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (ΔΨ) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique.The selective KATP channel opener NN414 (5 µM) diminished [Ca2+]c in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional KATP channels (SUR1-/-) the drug was without effect. VU0071063 (30 µM), another KATP channel opener considered to be selective, lowered [Ca2+]c in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1-/- mice, showing that [Ca2+]c is influenced by additional effects besides KATP channels. Contrasting to NN414, the drug depolarized ΔΨ in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of KCa3.1 channels, DCEBIO (100 µM), significantly decreased [Ca2+]c in SUR1-/- and human CHI islet cell clusters. To target L-type Ca2+ channels we tested two already approved drugs, dextromethorphan (DXM) and simvastatin. DXM (100 µM) efficiently diminished [Ca2+]c in stimulated human CHI islet cell clusters as well as in stimulated SUR1-/- islet cell clusters. Similar effects on [Ca2+]c were observed in experiments with simvastatin (7.2 µM).NN414 seems to provide a good alternative to the currently used KATP channel opener diazoxide. Targeting KCa3.1 channels by channel openers or L-type Ca2+ channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of KATP channels not sensitive to KATP channel openers.
2018-07-31 | Sirolimus-Induced Hepatitis in Two Patients with Hyperinsulinemic Hypoglycemia
Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects.Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment.A good response to sirolimus was observed.At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively].In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days.Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases.In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days.When the dose was increased, enzymes increased within three days.Sirolimus was discontinued in both cases.The rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis.To the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI.Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.
2015-07-30 | Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia
Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured.
proteins
2021-12-31 | Pasireotide treatment for severe congenital hyperinsulinism due to a homozygous ABCC8 mutation
ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI.
2017-12-14 | A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism
Congenital hyperinsulinism (CHI) is a rare disease characterized by recurrent severe hypoglycemia. In the diffuse form of CHI, pharmacotherapy is the preferred choice of treatment. Long-acting somatostatin analogues have been used in children as off-label medication. However, the efficacy, outcomes, and adverse effect profiles of long-acting somatostatin analogues have not been described in multicentered studies. The aim of this retrospective study is to summarize the experience with long-acting somatostatin analogues in a large group of children with CHI.Data were obtained retrospectively from 27 patients with CHI who received long-acting somatostatin analogues in 6 different centers in Europe. These included information on glycemic stability, auxology, and adverse effect profile in clinical follow-up assessments.Blood glucose control improved in most patients (89%). No life-threatening side effects occurred. Thirteen patients (48%) experienced side effects; in 3 patients (11%), the side effects were the main reason for discontinuation of the treatment. The most frequent side effect was elevated liver enzymes (n = 10, 37%).Long-acting somatostatin analogues are effective in glycemic control of patients with CHI. However, in 37% of all patients increased liver enzymes were observed. It is important to monitor liver function in all patients receiving long-acting somatostatin analogue therapy.
2017-10-27 | Population pharmacokinetics of exendin‐(9‐39) and clinical dose selection in patients with congenital hyperinsulinism
Aims Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin‐(9‐39), an inverse glucagon‐like peptide 1 (GLP‐1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose‐raising effect. We report the first population pharmacokinetic (PopPK) model of the exendin‐(9‐39) in patients with HI and propose the optimal dosing regimen for future clinical trials in neonates with HI. Methods A total of 182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using first order conditional estimation (FOCE) with interaction method in nonlinear mixed‐effects modelling (NONMEM). Exposure metrics (area under the curve [AUC] and maximum plasma concentration [ C max ]) at no observed adverse effect levels (NOAELs) in rats and dogs were determined in toxicology studies. Results Observed concentration–time profiles of exendin‐(9‐39) were described by a linear two‐compartmental PK model. Following allometric scaling of PK parameters, age and creatinine clearance did not significantly affect clearance. The calculated clearance and elimination half‐life for adult subjects with median weight of 69 kg were 11.8 l h −1 and 1.81 h, respectively. The maximum recommended starting dose determined from modelling and simulation based on the AUC 0‐last at the NOAEL and predicted AUC 0‐inf using the PopPK model was 27 mg kg −1 day −1 intravenously. Conclusions This is the first study to investigate the PopPK of exendin‐(9‐39) in humans. The final PopPK model was successfully used with preclinical toxicology findings to propose the optimal dosing regimen of exendin‐(9‐39) for clinical studies in neonates with HI, allowing for a more targeted dosing approach to achieve desired glycaemic response.
2017-07-10 | Efficacy and safety of octreotide for the treatment of congenital hyperinsulinism: a prospective, open-label clinical trial and an observational study in Japan using a nationwide registry
Octreotide, a long-acting somatostatin analog, has been used for treating hypoglycemia caused by congenital hyperinsulinism (CHI). However, octreotide has not been evaluated in clinical trials and has not been approved in any developed country. We aimed to test the efficacy and safety of octreotide for diazoxide-unresponsive CHI through a combination of a single-arm, open-label clinical trial (SCORCH study) and an observational study to collect data on the clinical course of patients treated off-label in Japan (SCORCH registry). In the SCORCH study, 5 patients were stabilized (blood glucose > 45 mg/dL) by hypertonic glucose infusion, and treated by continuous subcutaneous octreotide infusion at a dose of 5-25 μg/kg/day. Continuous blood glucose monitoring was performed between -24 and +48 hours. In 3 patients, a clinically meaningful rise in blood glucose was achieved and therapy was continued. The glucose infusion was gradually decreased and stopped after 5, 11, and 174 days, respectively. In one case, remission of CHI was reached after 606 days and octreotide was discontinued. The SCORCH registry included 19 diazoxide-unresponsive patients treated by subcutaneous octreotide, by continuous infusion or multiple daily injections. Of the 17 patients treated with hypertonic glucose infusion, the infusion rate was reduced after 4 weeks to less than 50% in 11 patients (64.7%) and stopped in 9 (52.9%). During the combined observation period of 695.4 patient-months in both studies, no severe adverse events related to octreotide were observed. In conclusion, subcutaneous octreotide injection was effective and well tolerated in the majority of patients with diazoxide-unresponsive CHI.
small molecules
2025-05-05 | Intra-operative indocyanine green (ICG) administration for surgical guidance in laparoscopic subtotal pancreatectomy for congenital hyperinsulinism: A case series
Indocyanine green (ICG)-guided surgery is gaining traction in pediatric surgery with its utilization reported in pancreatectomy for congenital hyperinsulinism (CHI). ICG can also be an adjunctive strategy to help surgeons new to complex laparoscopic surgeries. Both infants were Diazoxide-resistant diffuse CHI with ABCC8 mutations. Their surgeries were performed at 3 months of age. Patient 1: A laparoscopic subtotal pancreatectomy (85 % resection) was initially performed due to parental preference to preserve some pancreatic function. However, the patient experienced persistent hypoglycemia refractory to maximal medical management, necessitating a revision pancreatectomy. Serial low-dose intra-operative administration of ICG was used to identify vascular and biliary landmarks. However, the intra-pancreatic segment of the common bile duct (CBD) was not visualized despite multiple boluses of ICG, and thus pancreatic transection was performed at the level right of the superior mesenteric vein (SMV), accounting for a subtotal pancreatectomy (90 % resection). Patient 2: Serial low-dose intra-operative administration of ICG was used in identification and preservation of the splenic vessels during dissection and the identification of key vascular landmarks including SMV and portal vein (PV). A near-total pancreatectomy was initially attempted with serial ICG administrations to determine the level of pancreatic transection and to avoid an intra-pancreatic CBD injury. However, we were unable to identify the intra-pancreatic CBD which was buried deep within the bulky pancreatic head tissue. A subtotal pancreatectomy with pancreatic transection at the level right of the SMV (90 % resection) was performed. All surgeries were performed laparoscopically with no intra-operative complications. ICG-guidance can aid in real-time visualization of key vascular and extra-pancreatic biliary structures, potentially avoiding intra-operative injuries during laparoscopic subtotal pancreatectomy.
2025-03-27 | Effective Management of a Diffuse form of a Congenital Hyperinsulinism Due to a ABCC8 Mutation with a Combination of Diazoxide and Somatostatin Analogue (A Case Report)
Congenital hyperinsulinism (CHI) is a rare genetic disorder characterized by inappropriate and excessive insulin secretion, leading to severe, recurrent hypoglycemia in neonates, with significant neurological risks. We report a clinical case of a male neonate with a severe form of CHI, diagnosed through genetic analysis, who presented with diazoxide-resistant hypoglycemia and was successfully managed with the somatostatin analog, octreotide. Genetic testing revealed a homozygous mutation in the ABCC8 gene, confirming a diffuse form of CHI. Despite initial treatment with diazoxide, the neonate continued to experience severe hypoglycemic episodes. The addition of octreotide allowed for glycemic stabilization, reduced the need for continuous glucose infusion, and eventually led to the discontinuation of diazoxide. This case underscores the effectiveness of octreotide as a second-line treatment in managing diazoxide-resistant CHI and highlights the importance of early genetic diagnosis, personalized treatment strategies, and the potential of octreotide in avoiding the need for pancreatic surgery. Further research is needed to solidify the long-term safety and efficacy of octreotide in treating CHI and to optimize management protocols for this challenging condition.
2020-10-27 | Possible New Strategies for the Treatment of Congenital Hyperinsulinism
Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K+ (KATP) channels. Additionally, KATP channel-independent targets as Ca2+-activated K+ channels of intermediate conductance (KCa3.1) and L-type Ca2+ channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1-/-) mice. The cytosolic Ca2+ concentration ([Ca2+]c) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (ΔΨ) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique.The selective KATP channel opener NN414 (5 µM) diminished [Ca2+]c in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional KATP channels (SUR1-/-) the drug was without effect. VU0071063 (30 µM), another KATP channel opener considered to be selective, lowered [Ca2+]c in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1-/- mice, showing that [Ca2+]c is influenced by additional effects besides KATP channels. Contrasting to NN414, the drug depolarized ΔΨ in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of KCa3.1 channels, DCEBIO (100 µM), significantly decreased [Ca2+]c in SUR1-/- and human CHI islet cell clusters. To target L-type Ca2+ channels we tested two already approved drugs, dextromethorphan (DXM) and simvastatin. DXM (100 µM) efficiently diminished [Ca2+]c in stimulated human CHI islet cell clusters as well as in stimulated SUR1-/- islet cell clusters. Similar effects on [Ca2+]c were observed in experiments with simvastatin (7.2 µM).NN414 seems to provide a good alternative to the currently used KATP channel opener diazoxide. Targeting KCa3.1 channels by channel openers or L-type Ca2+ channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of KATP channels not sensitive to KATP channel openers.
2018-07-31 | Sirolimus-Induced Hepatitis in Two Patients with Hyperinsulinemic Hypoglycemia
Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects.Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment.A good response to sirolimus was observed.At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively].In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days.Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases.In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days.When the dose was increased, enzymes increased within three days.Sirolimus was discontinued in both cases.The rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis.To the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI.Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.
2015-07-30 | Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia
Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured.
proteins
2021-12-31 | Pasireotide treatment for severe congenital hyperinsulinism due to a homozygous ABCC8 mutation
ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI.
2017-12-14 | A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism
Congenital hyperinsulinism (CHI) is a rare disease characterized by recurrent severe hypoglycemia. In the diffuse form of CHI, pharmacotherapy is the preferred choice of treatment. Long-acting somatostatin analogues have been used in children as off-label medication. However, the efficacy, outcomes, and adverse effect profiles of long-acting somatostatin analogues have not been described in multicentered studies. The aim of this retrospective study is to summarize the experience with long-acting somatostatin analogues in a large group of children with CHI.Data were obtained retrospectively from 27 patients with CHI who received long-acting somatostatin analogues in 6 different centers in Europe. These included information on glycemic stability, auxology, and adverse effect profile in clinical follow-up assessments.Blood glucose control improved in most patients (89%). No life-threatening side effects occurred. Thirteen patients (48%) experienced side effects; in 3 patients (11%), the side effects were the main reason for discontinuation of the treatment. The most frequent side effect was elevated liver enzymes (n = 10, 37%).Long-acting somatostatin analogues are effective in glycemic control of patients with CHI. However, in 37% of all patients increased liver enzymes were observed. It is important to monitor liver function in all patients receiving long-acting somatostatin analogue therapy.
2017-10-27 | Population pharmacokinetics of exendin‐(9‐39) and clinical dose selection in patients with congenital hyperinsulinism
Aims Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin‐(9‐39), an inverse glucagon‐like peptide 1 (GLP‐1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose‐raising effect. We report the first population pharmacokinetic (PopPK) model of the exendin‐(9‐39) in patients with HI and propose the optimal dosing regimen for future clinical trials in neonates with HI. Methods A total of 182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using first order conditional estimation (FOCE) with interaction method in nonlinear mixed‐effects modelling (NONMEM). Exposure metrics (area under the curve [AUC] and maximum plasma concentration [ C max ]) at no observed adverse effect levels (NOAELs) in rats and dogs were determined in toxicology studies. Results Observed concentration–time profiles of exendin‐(9‐39) were described by a linear two‐compartmental PK model. Following allometric scaling of PK parameters, age and creatinine clearance did not significantly affect clearance. The calculated clearance and elimination half‐life for adult subjects with median weight of 69 kg were 11.8 l h −1 and 1.81 h, respectively. The maximum recommended starting dose determined from modelling and simulation based on the AUC 0‐last at the NOAEL and predicted AUC 0‐inf using the PopPK model was 27 mg kg −1 day −1 intravenously. Conclusions This is the first study to investigate the PopPK of exendin‐(9‐39) in humans. The final PopPK model was successfully used with preclinical toxicology findings to propose the optimal dosing regimen of exendin‐(9‐39) for clinical studies in neonates with HI, allowing for a more targeted dosing approach to achieve desired glycaemic response.
2017-07-10 | Efficacy and safety of octreotide for the treatment of congenital hyperinsulinism: a prospective, open-label clinical trial and an observational study in Japan using a nationwide registry
Octreotide, a long-acting somatostatin analog, has been used for treating hypoglycemia caused by congenital hyperinsulinism (CHI). However, octreotide has not been evaluated in clinical trials and has not been approved in any developed country. We aimed to test the efficacy and safety of octreotide for diazoxide-unresponsive CHI through a combination of a single-arm, open-label clinical trial (SCORCH study) and an observational study to collect data on the clinical course of patients treated off-label in Japan (SCORCH registry). In the SCORCH study, 5 patients were stabilized (blood glucose > 45 mg/dL) by hypertonic glucose infusion, and treated by continuous subcutaneous octreotide infusion at a dose of 5-25 μg/kg/day. Continuous blood glucose monitoring was performed between -24 and +48 hours. In 3 patients, a clinically meaningful rise in blood glucose was achieved and therapy was continued. The glucose infusion was gradually decreased and stopped after 5, 11, and 174 days, respectively. In one case, remission of CHI was reached after 606 days and octreotide was discontinued. The SCORCH registry included 19 diazoxide-unresponsive patients treated by subcutaneous octreotide, by continuous infusion or multiple daily injections. Of the 17 patients treated with hypertonic glucose infusion, the infusion rate was reduced after 4 weeks to less than 50% in 11 patients (64.7%) and stopped in 9 (52.9%). During the combined observation period of 695.4 patient-months in both studies, no severe adverse events related to octreotide were observed. In conclusion, subcutaneous octreotide injection was effective and well tolerated in the majority of patients with diazoxide-unresponsive CHI.
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