DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Hypoglycemia — screening already-approved drugs against its 14-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHypoglycemia maps to a 14-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
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Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Structures already discussed alongside hypoglycemia in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of AKR1C3 — Glyburide has a real, experimentally solved structure in complex with this target (PDB 4YVV, 2.3 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet gbmdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4YVV · 2.3 Å · ligand Glyburide (GBM). Experimental structure, not a prediction.
What the evidence adds up to
Three unrelated children with unexplained, recurrent, and severe fasting hypoglycemia and asymmetrical growth all carried the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2. In two cases the mutation was heterozygous and in one case it was mosaic. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. The authors concluded that systemic metabolic disease can result from constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin.
A re-evaluation of severe hypoglycemic events in the Treat-to-Target Trial, which compared insulin glargine and NPH insulin in patients with inadequately controlled type 2 diabetes, found that severe hypoglycemia was similarly uncommon with both insulins. For insulin glargine (n = 367), nine patients experienced 14 events; for NPH insulin (n = 389), nine patients experienced 13 events. All hypoglycemic events for glargine and nine for NPH were treated effectively at home. All severe hypoglycemic episodes were associated with sulfonylurea use. The review also found inconsistencies in the identification of severe hypoglycemia: seven of 14 severe events for glargine and three of 13 severe events for NPH had been coded as moderate. The authors noted difficulties in gathering and interpreting hypoglycemia data.
An analysis of inpatient hypoglycemia using an electronic health record-based prediction model identified 401 admissions with a hypoglycemic event (blood glucose below 50 mg/dL) among 1,875 admissions whose hypoglycemic risk was in the top fifth percentile. Five distinct phenotypes emerged: frail patients with a history of hypoglycemia receiving insulin on hospital day 1; a rapid downward trend in blood glucose in patients receiving an insulin infusion or with a history of hypoglycemia; administration of insulin in the presence of an active nothing by mouth order in frail patients; repeated low blood glucose in frail patients; and inadequate night-time blood glucose monitoring for patients on long-acting insulin. These five themes jointly described 53.0% of high-risk patients who experienced hypoglycemia.
What is still missing is a clear molecular target for the majority of hypoglycemia cases not explained by the AKT2 mutation, and the Treat-to-Target analysis shows that even in controlled trials, hypoglycemia event reporting is inconsistent. The inpatient phenotypes suggest that prevention strategies exist but are not systematically applied. No trial has tested a drug specifically to prevent or treat hypoglycemia in the general population of patients with diabetes, and no patient stratification beyond the AKT2 mutation has been validated for treatment.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 2011 · 181 citations · open access
An Activating Mutation of <i>AKT2</i> and Human Hypoglycemia
AbstractPathological fasting hypoglycemia in humans is usually explained by excessive circulating insulin or insulin-like molecules or by inborn errors of metabolism impairing liver glucose production. We studied three unrelated children with unexplained, recurrent, and severe fasting hypoglycemia and asymmetrical growth. All were found to carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2, in two cases as heterozygotes and in one case in mosaic form. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. Thus, systemic metabolic disease can result from constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin.
Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · 2004 · 36 citations
Severe and Resistant Hypoglycemia Associated with Concomitant Gatifloxacin and Glyburide Therapy
AbstractSevere and resistant hypoglycemia occurred in two patients with diabetes mellitus who were receiving concomitant gatifloxacin and glyburide. An 84-year-old woman treated with glyburide for type 2 diabetes mellitus experienced, for the first time, a severe episode of hypoglycemia after 2 days of gatifloxacin 400 mg/day for nonproductive cough. Her blood glucose level on hospital admission was 28 mg/dl. Gatifloxacin and glyburide were discontinued, and the patient was treated with intravenous dextrose infused over 36 hours. Glyburide was restarted before her discharge, with no recurrence of hypoglycemia. A 79-year-old man with type 2 diabetes mellitus treated with glyburide was prescribed gatifloxacin 400 mg/day for pneumonia. After 1 day of therapy, the patient was admitted to the emergency department in a coma. His blood glucose level was 18 mg/dl. Despite discontinuation of gatifloxacin and oral hypoglycemic therapy, hypoglycemia was reversed only after administration of multiple boluses of intravenous dextrose, followed by intravenous dextrose infused over 48 hours. On hospital day 7, gliclazide and levofloxacin were started; the patient experienced no recurrence of hypoglycemia and was discharged on day 10. Several cases of severe and resistant hypoglycemia associated with gatifloxacin therapy have been reported in the recent literature. Although the exact mechanism is not fully understood, it may be linked to a gatifloxacin-induced closing of the adenosine 5'-triphosphate-sensitive potassium channels in the pancreatic beta cells, leading to insulin secretion. The onset of hypoglycemia in relation to the start of gatifloxacin suggests that the drug precipitated this adverse event. Patients receiving oral hypoglycemic agents are at greater risk of experiencing gatifloxacin-induced hypoglycemia than patients not receiving these agents. Clinicians should be aware of this potentially life-threatening adverse event and monitor blood glucose levels in all patients receiving concomitant oral hypoglycemic agents and gatifloxacin.
Prolonged and Recurrent Tolazamide-induced Hypoglycemia: Report of a Case
AbstractA case of recurrent hypoglycemic coma precipitated by tolazamide (Tolinase) at therapeutic dosage is here reported. The patient, an elderly woman with diabetes and renal failure, experienced several episodes of profound hypoglycemic coma, the last one forty-eight hours after withdrawal of the sulfonylurea. With this report, cases of prolonged hypoglycemia have been described with all currently available hypoglycemic sulfonylureas.
Journal of Pediatric Endocrinology and Metabolism · 2008 · 11 citations
Familial Permanent Neonatal Diabetes with KCNJ11 Mutation and the Response to Glyburide Therapy - A Three-Year Follow-Up
AbstractWe describe 3 years follow-up of glyburide therapy in a child with permanent neonatal diabetes mellitus (PND) born to a 19 year-old mother with congenital diabetes mellitus. Genetic analysis identified a KCNJ11 mutation (R201H) in both the child and her mother. After 2 years of insulin therapy, the patient was switched to oral glyburide. After initial stabilization, glyburide therapy resulted in a marked decrease in glucose excursions in comparison to insulin. The patient had 3-10 episodes of hypoglycemia per week, including a total of eight episodes resulting in seizures, while on insulin. In contrast, no severe hypoglycemia was reported on glyburide. The patient's basal C-peptide was undetectable on insulin therapy (< 166 pmol/l) but was easily detectable on glyburide (189-761 pmol/l). The range of HbA1c improved significantly from 8-12% on insulin to 4.7-6% on glyburide. The frequency of glucose monitoring was gradually decreased from 4-8 times to 2-3 times a day on oral glyburide. This report confirms the superiority of sulfonylurea therapy in the treatment of PND with Kir6.2 mutations and shows sustained improved glycemic control over a 3-year follow-up period. Genetic exploration in other family members with diabetes might provide further insight into the nature of familial neonatal diabetes.
Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · 1997 · 10 citations
Prolonged Hypoglycemic Crisis Associated with Glyburide
AbstractAn elderly patient taking glyburide 5 mg/day for noninsulin-dependent diabetes mellitus was hospitalized because of severe hypoglycemia. Laboratory results indicated both renal and hepatic abnormalities were present at the time of admission. Despite infusion of 10% dextrose and supplemental boluses of 50% dextrose, the hypoglycemic crisis persisted for 3 days. After it resolved, the patient's diabetes was controlled by diet alone. The patient's age and the presence of hepatic and/or renal impairment must be taken in account in prescribing glyburide. Recognizing patients who may require dosage changes, and educating them on the signs and symptoms of hypoglycemia, may help prevent hospitalizations resulting from this complication associated with glyburide.
Reconsideration of Severe Hypoglycemic Events in the Treat-to-Target Trial
AbstractOBJECTIVE: This article reevaluates the hypoglycemic episodes reported as severe in the Treat-to-Target Trial comparing insulin glargine and NPH insulin use in patients with inadequately controlled type 2 diabetes. METHODS: Case report forms from the Treat-to-Target Trial were reviewed to identify additional severe hypoglycemic events and to further characterize those events already identified. Severe hypoglycemia was defined as symptoms consistent with hypoglycemia requiring assistance of another person and associated with either glucose levels < or =56 mg/dL or prompt recovery after oral carbohydrate intake, intravenous glucose administration, or glucagon injection. RESULTS: This analysis confirmed that severe hypoglycemia was similarly uncommon with both insulins (insulin glargine [n = 367], nine patients, 14 events; NPH insulin [n = 389], nine patients, 13 events); all hypoglycemic events for glargine and nine for NPH were treated effectively at home. All severe hypoglycemic episodes were associated with sulfonylurea use. A review of case report forms demonstrated inconsistencies in identification of severe hypoglycemia (seven of 14 severe events for glargine and three of 13 severe events for NPH were coded as moderate). CONCLUSIONS: The rate of severe hypoglycemia in this trial was low. Difficulties in gathering and interpreting hypoglycemia data highlight the need for more objective methods.
New England Journal of Medicine · 2009 · 6 citations
An Unusual Outbreak of Hypoglycemia — A Correction
AbstractTo the Editor: In our letter to the Editor (Feb. 12 issue),1 we reported on 150 nondiabetic patients with drug-induced hypoglycemia due to four brands of sexual-enhancement drugs that were contaminated with glyburide. Two recent articles by some of the authors of our letter have appeared elsewhere. One article described the neuroglycopenic and adrenergic symptoms of severe hypoglycemia in 15 of these patients,2 and the other described findings indicative of hypoglycemia on brain magnetic resonance imaging in 7 of these patients3; there were overlaps between these two groups of patients. The cases of hypoglycemia reported in both articles pertained . . .
American Journal of Health-System Pharmacy · 2019 · 3 citations
Common inpatient hypoglycemia phenotypes identified from an automated electronic health record–based prediction model
AbstractPURPOSE: Common inpatient hypoglycemia risk factor patterns (phenotypes) from an electronic health record (EHR)-based prediction model and preventive strategies were identified. METHODS: Patients admitted to 2 large academic medical centers who were in the top fifth percentile of a previously developed hypoglycemia risk score and developed hypoglycemia (blood glucose [BG] of <50mg/dL) were included in the study. Frequencies of all combinations of ≥4 risk factors contributing to the risk score among these patients were determined to identify common risk patterns. Clinical pharmacists developed clinical vignettes for each common pattern and formulated medication therapy management recommendations for hypoglycemia prevention. RESULTS: A total of 401 admissions with a hypoglycemic event were identified among 1,875 admissions whose hypoglycemic risk was in the top fifth percentile among all admissions that received antihyperglycemic drugs and evaluated. Five distinct phenotypes emerged: (1) frail patients with history of hypoglycemia receiving insulin on hospital day 1, (2) a rapid downward trend in BG values in patients receiving an insulin infusion or with a history of hypoglycemia, (3) administration of insulin in the presence of an active nothing by mouth order in frail patients, (4) repeated low BG level in frail patients, and (5) inadequate night-time BG monitoring for patients on long-acting insulin. The 5 themes jointly described 53.0% of high-risk patients who experienced hypoglycemia. CONCLUSION: Five distinct phenotypes that are prevalent in patients at greatest risk for inpatient hypoglycemia were identified.
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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