{"doi":"10.1111/dom.16312","title":"Genetic evidence for the effects of glucokinase activation on frailty‐related outcomes: A Mendelian randomisation study","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:sec>\n                    <jats:title>Aims</jats:title>\n                    <jats:p>We aimed to use the Mendelian randomisation (MR) design to investigate the potential causal effects of glucokinase (GK) activation on frailty‐related outcomes and to explore the potential mediating effects of metabolic and inflammatory biomarkers.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods</jats:title>\n                    <jats:p>\n                      Seventeen independent single‐nucleotide polymorphisms (SNPs) located within the\n                      <jats:italic>GCK</jats:italic>\n                      gene and significantly correlated with the glycated haemoglobin (HbA\n                      <jats:sub>1c</jats:sub>\n                      ) level were used as genetic proxies for the effect of GK activation. We employed two‐sample MR analysis to assess the relationship between genetically proxied GK activation and multifactorial frailty‐related outcomes (frailty index, grip strength, walking pace, appendicular lean mass [ALM] and telomere length) We also explored the potential mediating effects using two‐step MR.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Results</jats:title>\n                    <jats:p>\n                      Genetically proxied GK activation was significantly associated with a lower frailty index (beta: −0.161 per 1% decrease in HbA\n                      <jats:sub>1c</jats:sub>\n                      level due to GK activation, 95% confidence interval: −0.282 to −0.040, false discovery rate‐adjusted\n                      <jats:italic>p</jats:italic>\n                       = 0.011). Additionally, GK activation showed significant associations with increased grip strength, higher ALM, faster walking pace and longer telomere length. GK activation also demonstrated a significant indirect effect on total grip strength and telomere length by reducing C‐reactive protein levels (proportion of mediation: 6.79% to 8.21%).\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion</jats:title>\n                    <jats:p>Our study provides genetic evidence supporting the causal effects of GK activation on lowering the risk of frailty. These findings suggest that GK activators (GKAs) may aid in the management of frailty and sarcopaenia in people with diabetes; however, future randomized controlled trials are necessary to validate these results and establish their clinical applicability.</jats:p>\n                  </jats:sec>","journal":"Diabetes, Obesity and Metabolism","year":2025,"id":664943,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1027928,"name":"Mai Shi","orcid":"0000-0002-2798-3268","position":1,"is_corresponding":false},{"id":1736310,"name":"Elaine Chow","orcid":"0000-0002-4147-3387","position":2,"is_corresponding":false},{"id":144495,"name":"Aimin Yang","orcid":"0000-0003-2968-1762","position":3,"is_corresponding":false},{"id":901924,"name":"Yin Ting Cheung","orcid":"0000-0001-9874-8938","position":4,"is_corresponding":false},{"id":1736309,"name":"Rong Hua","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Genetic evidence for the effects of glucokinase activation on frailty‐related outcomes: A Mendelian randomisation study","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:sec>\n                    <jats:title>Aims</jats:title>\n                    <jats:p>We aimed to use the Mendelian randomisation (MR) design to investigate the potential causal effects of glucokinase (GK) activation on frailty‐related outcomes and to explore the potential mediating effects of metabolic and inflammatory biomarkers.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods</jats:title>\n                    <jats:p>\n                      Seventeen independent single‐nucleotide polymorphisms (SNPs) located within the\n                      <jats:italic>GCK</jats:italic>\n                      gene and significantly correlated with the glycated haemoglobin (HbA\n                      <jats:sub>1c</jats:sub>\n                      ) level were used as genetic proxies for the effect of GK activation. We employed two‐sample MR analysis to assess the relationship between genetically proxied GK activation and multifactorial frailty‐related outcomes (frailty index, grip strength, walking pace, appendicular lean mass [ALM] and telomere length) We also explored the potential mediating effects using two‐step MR.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Results</jats:title>\n                    <jats:p>\n                      Genetically proxied GK activation was significantly associated with a lower frailty index (beta: −0.161 per 1% decrease in HbA\n                      <jats:sub>1c</jats:sub>\n                      level due to GK activation, 95% confidence interval: −0.282 to −0.040, false discovery rate‐adjusted\n                      <jats:italic>p</jats:italic>\n                       = 0.011). Additionally, GK activation showed significant associations with increased grip strength, higher ALM, faster walking pace and longer telomere length. GK activation also demonstrated a significant indirect effect on total grip strength and telomere length by reducing C‐reactive protein levels (proportion of mediation: 6.79% to 8.21%).\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion</jats:title>\n                    <jats:p>Our study provides genetic evidence supporting the causal effects of GK activation on lowering the risk of frailty. These findings suggest that GK activators (GKAs) may aid in the management of frailty and sarcopaenia in people with diabetes; however, future randomized controlled trials are necessary to validate these results and establish their clinical applicability.</jats:p>\n                  </jats:sec>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40035195","pmcid":"PMC12046474","openalex_id":"https://openalex.org/W4408162379","authors":[],"funders":[],"total_grants":0,"fwci":0.7371,"citation_percentile":0.6477371,"influential_citations":0,"citation_trend":[{"year":2025,"count":1}],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/dom.16312","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/dom.16312","host_type":"publisher"},{"url":"https://dom-pubs.pericles-prod.literatumonline.com/doi/pdf/10.1111/dom.16312","host_type":"publisher"},{"url":"https://doi.org/10.1111/dom.16312","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40035195","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12046474","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12046474","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12046474?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Frailty in Older Adults","Genetic Associations and Epidemiology","Chronic Disease Management Strategies","Humans","Mendelian Randomization Analysis","Frailty","Polymorphism, Single Nucleotide","Glucokinase","Male","Aged","Female","Hand Strength","Glycated Hemoglobin","Middle Aged","Diabetes Mellitus, Type 2"],"mesh_terms":["Frailty","Aged","Diabetes Mellitus, Type 2","Female","Glucokinase","Glycated Hemoglobin","Humans","Male","Middle Aged","Hand Strength","Polymorphism, Single Nucleotide","Mendelian Randomization Analysis"],"keywords":["Medicine","Mendelian inheritance","Mendelian randomization","Glucokinase","Bioinformatics","Gerontology","Genetics","Genetic variants","Diabetes mellitus","Gene","Endocrinology","Genotype","Elderly","Type 2 diabetes","Population Study","Antidiabetic Drug"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refsnp"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-13T04:41:44.053264Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}