DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for GCGR-related hyperglucagonemia — 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 moduleGCGR-related hyperglucagonemia 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 gcgr-related hyperglucagonemia 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.
Molecular view
glucagon receptor (GCGR) — GCGR is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9N04 · 2.3 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A homozygous P86S mutation in the glucagon receptor was identified in a single patient with marked hyperglucagonemia, alpha cell hyperplasia, and islet cell tumour, but without glucagonoma syndrome. The mutant receptor, when expressed in human embryonic kidney 293 cells, bound 96% less radiolabelled glucagon than the wild-type receptor, and the median effective concentration for glucagon-induced cyclic adenosine monophosphate production was 24 nmol/L for the mutant versus 2.4 nmol/L for wild-type. The patient’s alpha cells also expressed glucagon-like peptide 1 and pancreatic polypeptide. This is the first reported homozygous missense mutation in the human glucagon receptor, and the authors concluded it likely causes the observed alpha cell hyperplasia and hyperglucagonemia.
In a separate study of 451 insulin-naïve type 2 diabetes patients, those in the highest quartile of glucagon-to-insulin ratio had higher glycated haemoglobin levels. HbA1c was positively correlated with both fasting and postprandial glucagon-to-insulin ratios. Subjects in the highest quartile of postprandial glucagon-to-insulin ratio were more likely to have uncontrolled hyperglycemia, with an odds ratio of 2.730 (95% confidence interval 1.236 to 6.028, p for trend < 0.01). The authors concluded that relative hyperglucagonemia could contribute to uncontrolled hyperglycemia in type 2 diabetes.
A 2021 abstract described a humanised GCGR mouse model (B-hGCGR) in which human GCGR protein and mRNA were detected in liver tissue. Random blood glucose, fasting blood glucose, and glucose tolerance in homozygous B-hGCGR mice were comparable to wild-type mice. Glucagon elicited a dose-specific increase in cAMP in membranes from humanised mice comparable to that in wild-type membranes. In pharmacodynamic experiments, an anti-GCGR antibody (Crotedumab) reduced random and fasting blood glucose and improved glucose tolerance in B-hGCGR mice, and blocked the functional response to glucagon more efficiently than targeting the wild-type murine receptor with antagonists. The authors stated that B-hGCGR mice are a promising model for preclinical in vivo assessment of anti-GCGR antibodies.
What remains missing is any clinical trial of a glucagon receptor antagonist or antibody in patients with GCGR-related hyperglucagonemia — the human data are limited to a single case report. No trial has tested whether blocking the receptor improves outcomes in this specific syndrome, and the mouse model data, while supportive, have not been translated into human studies. Funding for a properly designed trial, and a clear strategy for patient stratification given the rarity of the condition, are still absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Pancreas · 2009 · 146 citations · open access
Homozygous P86S Mutation of the Human Glucagon Receptor Is Associated With Hyperglucagonemia, α Cell Hyperplasia, and Islet Cell Tumor
AbstractOBJECTIVE: The goal of the study was to investigate the genetic and molecular basis of a novel syndrome of marked hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome. METHODS: The glucagon receptor (GCGR) gene and the glucagon gene were sequenced in a patient with hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome. Enhanced green fluorescent protein-conjugated wild type (WT) and mutant GCGR were used to characterize the functions of the mutant GCGR. RESULTS: The glucagon gene sequence was normal, but the GCGR sequencing uncovered a homozygous missense mutation, c.256C>T, p.P86S in the extracellular domain of GCGR. When expressed in human embryonic kidney 293 cells, GCGR P86S localized to the plasma membrane but bound 96% less radiolabeled glucagon than WT GCGR. The median effective concentration of glucagon-induced cyclic adenosine monophosphate production was 24 nmol/L for GCGR P86S but 2.4 nmol/L for WT GCGR. The patient's alpha cells also express glucagonlike peptide 1 and pancreatic polypeptide. CONCLUSIONS: We hereby report the first homozygous missense mutation in the human GCGR, which is associated with alpha cell hyperplasia and hyperglucagonemia. This mutation lowers the receptor's affinity to glucagon and decreases cyclic adenosine monophosphate production with physiological concentrations of glucagon. Thus, the P86S mutation in GCGR likely causes alpha cell hyperplasia and hyperglucagonemia.
The Korean Journal of Internal Medicine · 2017 · 29 citations · open access
Higher glucagon-to-insulin ratio is associated with elevated glycated hemoglobin levels in type 2 diabetes patients
AbstractBACKGROUND/AIMS: The importance of α-cell dysfunction in the pathogenesis of type 2 diabetes has re-emerged recently. However, data on whether relative glucagon excess is present in clinical settings are scarce. We aimed to investigate associations between glucagon-to-insulin ratio and various metabolic parameters. METHODS: A total of 451 patients with type 2 diabetes naïve to insulin treatment were recruited. Using glucagon-to-insulin ratio, we divided subjects into quartiles according to both fasting and postprandial glucagon-to-insulin ratios. RESULTS: The mean age of the subjects was 58 years, with a mean body mass index of 25 kg/m2 . The patients in the highest quartile of glucagon-to-insulin ratio had higher glycated hemoglobin (HbA1c) levels. HbA1c levels were positively correlated with both fasting and postprandial glucagon-to-insulin ratios. Subjects in the highest quartile of postprandial glucagon-to-insulin ratio were more likely to exhibit uncontrolled hyperglycemia, even after adjusting for confounding factors (odds ratio, 2.730; 95% confidence interval, 1.236 to 6.028; p for trend < 0.01). CONCLUSION: Hyperglucagonemia relative to insulin could contribute to uncontrolled hyperglycemia in type 2 diabetes patients.
Abstract 2951: Anti-GCGR <i>in vivo</i> efficacy evaluated in a novel humanized B-hGCGR mouse model
AbstractAbstract GCGR (glucagon receptor) is a G-protein-coupled seven-transmembrane protein, a typical representative of the class B GPCR family. Animals homozygous for a targeted mutation in this gene exhibit reduced blood glucose levels, increased plasma glucagon and amino acid levels associated with alpha-cell hyperplasia. Glucagon activates intracellular adenylate cyclase by specifically binding to GCGR on the surface of target cells in the liver. This results in an increase in intracellular cAMP levels, playing a role in promoting glycogenolysis and gluconeogenesis, and promoting blood glucose elevation. The crucial role in regulation of blood glucose levels and glucose homeostasis is posing GCGR as a potential drug target for type 2 diabetes and related diseases. Currently, much attention and many resources are directed towards research and development of antibody drugs targeting the glucagon receptor. Joining these efforts, Biocytogen has developed a GCGR humanized mouse model (B-hGCGR mouse). Human GCGR protein and mRNA were detected in liver tissue of homozygous B-hGCGR mice, but not in wild type mice. Physiological indexes have been analyzed. Results indicated that the random blood glucose, fasting blood glucose, and glucose tolerance were comparable to the wild type mice. In addition, we characterized the ability of glucagon to stimulate production of cAMP. We observed that glucagon elicits a dose specific increase of cAMP in membranes prepared from the humanized GCGR mice comparable to the cAMP levels observed in membranes prepared from wild type mice. In pharmacodynamic experiments using B-hGCGR mice we showed that an anti-GCGR antibody (Crotedumab) was able to effectively reduce random blood glucose and fasting blood glucose levels and improve the glucose tolerance, validating our humanized mouse model. This antibody also blocked the functional response to glucagon in B-hGCGR mice more efficiently than what can be observed in an approach targeting the wild type murine receptor using antagonists. These data demonstrate that B-hGCGR mice are a promising model for preclinical in vivo pharmacodynamic assessment of anti-GCGR antibodies. Citation Format: Rufeng Zhang, Chengzhang Shang, Yuting Hu, Veronika Chromikova, Qingcong Lin. Anti-GCGR in vivo efficacy evaluated in a novel humanized B-hGCGR mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2951.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
