DeCure for Hyperinsulinemic hypoglycemia, familial, 8
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hyperinsulinemic hypoglycemia, familial, 8 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHyperinsulinemic hypoglycemia, familial, 8 maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for hyperinsulinemic hypoglycemia, familial, 8 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
Homozygous ABCC8 mutations cause severe diffuse hyperinsulinaemic hypoglycaemia that is usually unresponsive to diazoxide and often requires pancreatectomy. One case report describes a patient with a homozygous p.L171F ABCC8 mutation who presented with neonatal hyperinsulinaemic hypoglycaemia and later developed complete insulin-deficient diabetes that was responsive to sulphonylureas. The same report notes that family members carrying the identical mutation showed a broad range of clinical presentations, from asymptomatic to severe hypoglycaemia to diabetes, confirming phenotypic variation in ABCC8 mutations. The authors recommend long-term follow-up for patients with neonatal hyperinsulinaemic hypoglycaemia due to ABCC8 mutations, especially those managed medically, because of the risk of later diabetes.
A separate case of a 25-day-old girl from consanguineous parents presented with seizures and hypoketotic hyperinsulinaemic hypoglycaemia (glucose 1 mmol/L, insulin 19.32 mUI/L). Urinary organic acid chromatography showed increased 3-hydroxyglutaric acid and ethylmalonic acid, and plasma acylcarnitine profile showed increased 3-hydroxybutyrylcarnitine. Enzyme activity in cultured fibroblasts was 10.9 nmol/min/mg protein (reference 147.0 ± 29.4). Genetic testing revealed a homozygous deep intronic variant in HADH (c.636+471G>T). This is a short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency, of which fewer than 50 cases have been described and only 20 HADH variants listed in the public database. Unlike other fatty acid oxidation disorders, SCHAD deficiency presents with diazoxide-responsive hyperinsulinism, and patients are often sensitive to a protein diet with protein-induced hypoglycaemic episodes. The hyperinsulinism is thought to result from loss of the inhibitory protein–protein interaction between SCHAD and glutamate dehydrogenase, leading to overstimulation of the Krebs cycle and increased ATP-driven insulin secretion. In this patient, hyperinsulinism was controlled with diazoxide 10 mg/kg/day, and follow-up for 7 years showed normal mental outcome.
The 1997 review notes that familial persistent hyperinsulinaemic hypoglycaemia of infancy is rare in outbred communities (approximately 1 per 50,000) but reaches about 1 per 2,500 in inbred Arabic communities with autosomal recessive forms. Some patients respond to diazoxide or somatostatin, but others require partial pancreatectomy. No controlled trials or systematic comparisons of these treatments are reported in these abstracts. What remains missing is prospective data on long-term outcomes for medically managed patients, standardised protocols for transitioning from hypoglycaemia to diabetes care, and larger cohorts to stratify patients by genotype and treatment response.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 1997 · 222 citations · open access
Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy and Mutations in the Sulfonylurea Receptor
Abstract[1st paragraph] Persistent hyperinsulinemic hypoglycemia of infancy is caused by inappropriate and excessive secretion of insulin. Although the disease is rare in outbred communities (approximately 1 case per 50,000 persons), the incidence is approximately 1 per 2500 in inbred Arabic communities in which there is a familial (autosomal recessive) form of the disease. The disease most commonly presents with severe hypoglycemia a few hours after birth, although some cases present after several weeks or months. Some patients have a response to treatment with diazoxide or somatostatin, but others require partial pancreatectomy to control the hyperinsulinism.
Journal of Clinical Research in Pediatric Endocrinology · 2018 · 4 citations · open access
Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation
AbstractHomozygous ABCC8 mutations cause severe persistent diffuse hyperinsulinemic hypoglycaemia (HH) which is usually diazoxide unresponsive and requires surgical therapy. In medically managed patients with congenital hyperinsulinism (CHI), disease symptoms become milder overtime. Hyperinsulinemic hypoglycemia at neonatal period and later diabetes have been reported in heterozygous mutation of HNF4A and HNF1A as well as heterozygous ABCC8 mutations What this study adds? We describe the first homozygous ABCC8 mutation with HH at neonatal period and evolution to complete insulin deficient, sulphonylurea responsive diabetes mellitus. Findings from present work which show a broad range of clinical spectrum from asymptomatic, mild symptomatic hypoglycemia, severe hypoglycemia as well as insulin deficient diabetes mellitus in family members with identical mutation confirms the phenotypical variations in ABCC8 mutations Present case report emphasizes the need for long-term follow up of patients with HH at neonatal period due to ABCC8 mutations, particularly those managed with medical therapy for risk of developing diabetes in later life.
Clinical Chemistry · 2019 · 0 citations · open access
Hyperinsulinemic Hypoglycemia in a Neonate
AbstractA 25-day-old girl born from consanguineous parents presented with seizures. She was apyretic, and, except for axial hypotonia, her neurological examination was normal. A cerebral scan and cardiac and abdominal ultrasonography did not detect any abnormality. First-line biological investigations showed hypoketotic hyperinsulinemic hypoglycemia [glucose, 1 mmol/L (18 mg/dL); reference, 4–6 mmol/L (70–110 mg/dL); insulin, 19.32 mUI/L; reference, 2.00–12.00 mUI/L] and a constant hyperlactatemia (5.7 mmol/L; reference, 0.5–2.2 mmol/L). Cortisol (258 nmol/L; reference, 250–800 nmol/L), ammonia (34 μmol/L; reference, <35), bicarbonate (21 mmol/L; reference, 22–30 mmol/L), and free fatty acids (459 μmol/L; reference, 250–800 μmol/L) were within the normal intervals. The inappropriate insulin secretion, along with postprandial hypoglycemia in a patient of consanguineous parents, suggested congenital hyperinsulinemic hypoglycemia. Thus, complementary investigations were performed, including a plasma acylcarnitine profile and urine organic acid analysis using GC-MS. Postprandial hypoglycemia usually results from an alteration of insulin secretion by the pancreatic β cells. Several rare diseases may trigger insulin secretion by disrupting mitochondrial energy metabolism regulation underlying insulin release such as deficiencies in sulfonylurea receptor 1, inward-rectifier potassium channels, monocarboxylate transporter 1, mitochondrial uncoupling protein 2, glucokinase, glutamate dehydrogenase (GDH), or short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD). Extensive metabolic and molecular investigations are needed to establish the diagnosis of SCHAD deficiency. In our case, urinary organic acid chromatography highlighted an increased 3-hydroxyglutaric acid and ethylmalonic acid (creatine, 69 μmol/mmol; reference, <8) concentrations (Fig. 1), and a plasma acylcarnitine profile showed an increase of 3-hydroxybutyrylcarnitine (1.4 μmol/L; reference, <0.3). The sample was subjected to derivatization with N,O-bis(trimethylsilyl)trifluroacetamide and trimethylchlorosilane. Derivatized samples were injected into a Shimadzu QP-2010 Plus GC-MS operating in split mode. The metabolites were analyzed as trimethylsilyl compounds. Heptadecanoic acid was used as an internal standard. The profile peaks corresponding to ethylmalonic and 3-hydroxyglutaric acids are denoted. The association of hypoketotic hypoglycemia, hyperinsulinism, increased urinary 3-hydroxyglutaric acid, and increased 3 hydroxybutyrylcarnitine suggested a SCHAD deficiency (1). The abnormal increase of short-chain acid derivatives (3-hydroxybutyrylcarnitine, 3-hydroxyglutaric, and ethylmalonic acids) may have been related to β-oxidation dysfunction (2). Measurement of enzyme activity in cultured fibroblasts (10.9 nmol/min/mg protein; reference, 147.0 ± 29.4) allowed confirmation of the diagnosis. Genetic testing revealed a deep intronic pathogenic homozygous variant in HADH5, NM_00537.4: c.636 + 471G >T, which creates a cryptic splice donor site with the inclusion of an out-of-frame pseudoexon (3). SCHAD is a mitochondrial fatty acid β-oxidation enzyme that catalyzes the third step in the β-oxidation for medium and short-chain 3-hydroxy fatty acyl-CoA. The SCHAD enzyme is encoded by HADH located on chromosome 4q24–4q25. Fewer than 50 cases have been described, and only 20 variants in HADH have been listed in the public Human Gene Mutation Database. Unlike the other mitochondrial fatty acid oxidation disorders, SCHAD deficiency is revealed by diazoxide-responsive hyperinsulinism. Importantly, it has been reported that patients with SCHAD deficiency are often sensitive to a protein diet with protein-induced hypoglycemic episodes. Insulin secretion by the pancreatic β cells during the postprandial period is triggered by an increase of intracellular ATP. Intriguingly, the lack of SCHAD activity may lead to decreased acetyl-CoA production and subsequent ATP concentration depletion. Fatty acid oxidation disorders are known to cause fasting hypoglycemia rather than postprandial hypoglycemia. Thus, it is unlikely that the hyperinsulinism would be related to the decrease of fatty acid β-oxidation rate. In this condition, the hyperinsulinism has been shown to result from the disruption of the protein–protein link between SCHAD and GDH (4). Indeed, the SCHAD–GDH interaction inhibits GDH and thus decreases the production of α-ketoglutarate, a Krebs cycle intermediate. As shown in Fig. 2, GDH is activated upon the loss of its interaction with SCHAD and induces an overstimulation of the Krebs cycle with an increase of intracellular ATP, which in turn induces insulin secretion (4). By elucidating the mechanism of hyperinsulinism linked to SCHAD deficiency, the role of fatty acid oxidation in the regulation of insulin secretion and its interaction with amino acid metabolism have been unveiled. On the basis of these findings, a protein-restricted diet has been proposed to some patients. In our patient, the hyperinsulinism was controlled with diazoxide (10 mg/kg/day) and follow-up for 7 years showed a normal mental outcome. An early diagnosis and tightly monitored treatment are mandatory to prevent mental retardation. (A), Physiologically, there is an inhibitory protein–protein interaction of short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) and glutamate dehydrogenase (GDH). (B), In cases of SCHAD deficiency, the loss of this interaction induces an overstimulation of the Krebs cycle with an increase of intracellular ATP, which in turn induces closure of potassium channels, membrane depolarization, voltage-gated opening of calcium channels, and the exocytosis of insulin. hydroxyacyl-CoA dehydrogenase.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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