{"doi":"10.1210/en.2010-0289","title":"Glucagon-Like Peptide-1 Receptor Knockout Mice Are Protected from High-Fat Diet-Induced Insulin Resistance","abstract":"<jats:p>Glucagon-like peptide-1 augments nutrient-stimulated insulin secretion. Chow-fed mice lacking the glucagon-like peptide-1 receptor (Glp1r) exhibit enhanced insulin-stimulated muscle glucose uptake but impaired suppression of endogenous glucose appearance (endoRa). This proposes a novel role for the Glp1r to regulate the balance of glucose disposal in muscle and liver by modulating insulin action. Whether this is maintained in an insulin-resistant state is unknown. The present studies tested the hypothesis that disruption of Glp1r expression overcomes high-fat (HF) diet-induced muscle insulin resistance and exacerbates HF diet-induced hepatic insulin resistance. Mice with a functional disruption of the Glp1r (Glp1r−/−) were compared with wild-type littermates (Glp1r+/+) after12 wk on a regular chow diet or a HF diet. Arterial and venous catheters were implanted for sampling and infusions. Hyperinsulinemic-euglycemic clamps were performed on weight-matched male mice. [3-3H]glucose was used to determine glucose turnover, and 2[14C]deoxyglucose was used to measure the glucose metabolic index, an indicator of glucose uptake. Glp1r−/− mice exhibited increased glucose disappearance and muscle glucose metabolic index on either diet. This was associated with enhanced activation of muscle Akt and AMP-activated protein kinase and reduced muscle triglycerides in HF-fed Glp1r−/− mice. Chow-fed Glp1r−/− mice exhibited impaired suppression of endoRa and hepatic insulin signaling. In contrast, HF-fed Glp1r−/− mice exhibited improved suppression of endoRa and hepatic Akt activation. This was associated with decreased hepatic triglycerides and impaired activation of sterol regulatory element-binding protein-1. These results show that mice lacking the Glp1r are protected from HF diet-induced muscle and hepatic insulin resistance independent of effects on total fat mass.</jats:p>","journal":"Endocrinology","year":2010,"id":588491,"datarank":3.859548276252234,"base_score":4.553876891600541,"endowment":4.553876891600541,"self_citation_contribution":0.6830815337400812,"citation_network_contribution":3.176466742512153,"self_endowment_contribution":0.6830815337400812,"citer_contribution":3.176466742512153,"corpus_percentile":null,"corpus_rank":null,"citation_count":94,"citer_count":83,"citers_with_citation_signal":75,"citers_with_endowment":75,"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":502415,"name":"Deanna P. Bracy","orcid":null,"position":1,"is_corresponding":false},{"id":1505537,"name":"Freyja D. James","orcid":null,"position":2,"is_corresponding":false},{"id":1505538,"name":"Melissa A. Burmeister","orcid":null,"position":3,"is_corresponding":false},{"id":501630,"name":"David H. Wasserman","orcid":"0000-0002-3095-2665","position":4,"is_corresponding":false},{"id":237001,"name":"Daniel J. Drucker","orcid":"0000-0001-6688-8127","position":5,"is_corresponding":false},{"id":880967,"name":"Julio E. Ayala","orcid":"0000-0003-3224-2365","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Glucagon-Like Peptide-1 Receptor Knockout Mice Are Protected from High-Fat Diet-Induced Insulin Resistance","abstract":"<jats:p>Glucagon-like peptide-1 augments nutrient-stimulated insulin secretion. Chow-fed mice lacking the glucagon-like peptide-1 receptor (Glp1r) exhibit enhanced insulin-stimulated muscle glucose uptake but impaired suppression of endogenous glucose appearance (endoRa). This proposes a novel role for the Glp1r to regulate the balance of glucose disposal in muscle and liver by modulating insulin action. Whether this is maintained in an insulin-resistant state is unknown. The present studies tested the hypothesis that disruption of Glp1r expression overcomes high-fat (HF) diet-induced muscle insulin resistance and exacerbates HF diet-induced hepatic insulin resistance. Mice with a functional disruption of the Glp1r (Glp1r−/−) were compared with wild-type littermates (Glp1r+/+) after12 wk on a regular chow diet or a HF diet. Arterial and venous catheters were implanted for sampling and infusions. Hyperinsulinemic-euglycemic clamps were performed on weight-matched male mice. [3-3H]glucose was used to determine glucose turnover, and 2[14C]deoxyglucose was used to measure the glucose metabolic index, an indicator of glucose uptake. Glp1r−/− mice exhibited increased glucose disappearance and muscle glucose metabolic index on either diet. This was associated with enhanced activation of muscle Akt and AMP-activated protein kinase and reduced muscle triglycerides in HF-fed Glp1r−/− mice. Chow-fed Glp1r−/− mice exhibited impaired suppression of endoRa and hepatic insulin signaling. In contrast, HF-fed Glp1r−/− mice exhibited improved suppression of endoRa and hepatic Akt activation. This was associated with decreased hepatic triglycerides and impaired activation of sterol regulatory element-binding protein-1. These results show that mice lacking the Glp1r are protected from HF diet-induced muscle and hepatic insulin resistance independent of effects on total fat mass.</jats:p>","is_dataset_classified":null,"base_score":4.553876891600541,"endowment":4.553876891600541,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"20685876","pmcid":"PMC2946144","openalex_id":"https://openalex.org/W1978297557","authors":[],"funders":[{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK054902","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"U24 DK-59637","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK-54902","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"U24 DK059637","title":null}],"total_grants":4,"fwci":3.9591,"citation_percentile":0.94292359,"influential_citations":0,"citation_trend":[{"year":2012,"count":8},{"year":2013,"count":4},{"year":2014,"count":5},{"year":2015,"count":2},{"year":2016,"count":5},{"year":2017,"count":3},{"year":2018,"count":9},{"year":2019,"count":7},{"year":2021,"count":3},{"year":2022,"count":10},{"year":2023,"count":6},{"year":2024,"count":6},{"year":2025,"count":13},{"year":2026,"count":2}],"oa_status":"bronze","license":null,"oa_locations":[{"url":"https://academic.oup.com/endo/article-pdf/151/10/4678/9005901/endo4678.pdf","host_type":"journal"},{"url":"https://academic.oup.com/endo/article-pdf/151/10/4678/9005901/endo4678.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/endo/article-pdf/151/10/4678/9005901/endo4678.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1210/en.2010-0289","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/20685876","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.734.1047","host_type":""},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2946144","host_type":"repository"}],"fields_of_study":["Diabetes Treatment and Management","Pancreatic function and diabetes","Metabolism, Diabetes, and Cancer","Adiposity","Animals","Diet, Atherogenic","Dietary Fats","Female","Glucagon-Like Peptide-1 Receptor","Glucose","Insulin","Insulin Resistance","Liver","Male","Mice","Mice, Inbred C57BL","Mice, Knockout","Muscle, Skeletal","Receptors, Glucagon","Sex Characteristics"],"mesh_terms":["Glucagon-Like Peptide-1 Receptor","Animals","Diet, Atherogenic","Dietary Fats","Female","Glucose","Insulin","Insulin Resistance","Liver","Male","Mice, Inbred C57BL","Sex Characteristics","Receptors, Glucagon","Mice, Knockout","Muscle, Skeletal","Adiposity","Mice"],"keywords":["Internal medicine","Endocrinology","Insulin resistance","Insulin","Biology","Glucagon","Insulin receptor","Glucagon-like peptide-1","Glucose clamp technique","Protein kinase B","Glucose uptake","Carbohydrate metabolism","Type 2 diabetes","Pancreatic hormone","Diabetes mellitus","Medicine","Phosphorylation","Biochemistry"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-21T06:34:44.950445Z","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":[]}