{"doi":"10.1101/2021.02.08.430304","title":"The protection of Gα <sub>z</sub> -null NOD mice from hyperglycemia is sexually dimorphic and only partially β-cell autonomous","abstract":"Abstract The mechanisms that underlie the β-cell pathophysiology of Type 1 Diabetes (T1D) are not fully understood. Our group has defined the unique heterotrimeric G protein alpha-subunit, Gα z , as a key negative regulator of β-cell signal transduction pathways. Non-obese diabetic (NOD) mice lacking Gα z throughout the body are protected from developing T1D-like hyperglycemia. To determine whether this phenotype is β-cell autonomous, we generated and validated a β-cell-specific Gα z knockout (βKO) on the NOD background and characterized the phenotype of female and male cohorts. Long-term hyperglycemia incidence was lower in Gα z βKO mice as compared to wild-type (WT) controls, but, unlike global Gα z knockout mice, this protection was incomplete. While young male and female Gα z βKO NOD mice had improved glucose tolerance, WT NOD males were significantly less glucose tolerant than females, and only female Gα z βKO mice retained improved glucose tolerance at 28-29 weeks of age. Conversely, β-cell-specific Gα z loss only influenced insulitis in 28-29-week old male NOD mice, a phenotype correlating directly with body burden of glucose during oral glucose challenge. Using surrogates for β-cell function and apoptosis, the partial penetrance of euglycemia in Gα z βKO NOD was best explained by an early failure to up-regulate β-cell proliferation. We conclude β-cell Gα z is an important regulator of the sexually-dimorphic T1D-like phenotype of NOD mice. Yet, other factors must be important in imparting full protection from the disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223169,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":819957,"name":"Darby C. Peter","orcid":"0000-0001-9639-1541","position":1,"is_corresponding":false},{"id":820271,"name":"Haley Wienkes","orcid":null,"position":2,"is_corresponding":false},{"id":506837,"name":"Michael D. Schaid","orcid":"0000-0002-3633-5748","position":3,"is_corresponding":false},{"id":824662,"name":"Austin Reuter","orcid":"0000-0003-4031-0356","position":4,"is_corresponding":false},{"id":825128,"name":"Kathryn A. Carbajal","orcid":null,"position":5,"is_corresponding":false},{"id":380536,"name":"Michelle E. Kimple","orcid":"0000-0003-0869-9699","position":6,"is_corresponding":false},{"id":380534,"name":"Rachel J. Fenske","orcid":"0000-0002-5417-0780","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","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":[]}