ArticleDiabetes2016
Haploinsufficiency of the Insulin Receptor in the Presence of a Splice-Site Mutation in Ppp2r2a Results in a Novel Digenic Mouse Model of Type 2 Diabetes.
Article in Diabetes, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Systematic review of transcriptome and microRNAome associations with gestational diabetes mellitus.Frontiers in endocrinology · 2022Pooled it
- MicroRNAs Associated with Metformin Treatment in the Diabetes Prevention Program.International journal of molecular sciences · 2024Trial
- Targeting PP2A in cancer: an underrated option.Journal of experimental & clinical cancer research : CR · 2025Review
- PP2A B55α inhibits epithelial-mesenchymal transition via regulation of Slug expression in non-small cell lung cancer.Cancer letters · 2024Article
- Article
- Identification of key DNA methylation changes on fasting plasma glucose: a genome-wide DNA methylation analysis in Chinese monozygotic twins.Diabetology & metabolic syndrome · 2023Article
- Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies.Signal transduction and targeted therapy · 2023Review
- The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.The EMBO journal · 2023Article
- Ser/Thr phosphatases: One of the key regulators of insulin signaling.Reviews in endocrine & metabolic disorders · 2022Review
- Identification and Validation of miR-222-3p and miR-409-3p as Plasma Biomarkers in Gestational Diabetes Mellitus Sharing Validated Target Genes Involved in Metabolic Homeostasis.International journal of molecular sciences · 2022Article
- Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus.The Journal of biological chemistry · 2021Article
- Article
- Impaired insulin signaling in the B10.D2-American journal of physiology. Endocrinology and metabolism · 2019Article
- The Oncogenic Functions of MASTL Kinase.Frontiers in cell and developmental biology · 2018Review
- Compartmentalized gene expression profiling of receptive endometrium reveals progesterone regulated ENPP3 is differentially expressed and secreted in glycosylated form.Scientific reports · 2016Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Insulin resistance in mice typically does not manifest as diabetes due to multiple compensatory mechanisms. Here, we present a novel digenic model of type 2 diabetes in mice heterozygous for a null allele of the insulin receptor and an N-ethyl-N-nitrosourea-induced alternative splice mutation in the regulatory protein phosphatase 2A (PP2A) subunit PPP2R2A. Inheritance of either allele independently results in insulin resistance but not overt diabetes. Doubly heterozygous mice exhibit progressive hyperglycemia, hyperinsulinemia, and impaired glucose tolerance from 12 weeks of age without significant increase in body weight. Alternative splicing of Ppp2r2a decreased PPP2R2A protein levels. This reduction in PPP2R2A containing PP2A phosphatase holoenzyme was associated with decreased serine/threonine protein kinase AKT protein levels. Ultimately, reduced insulin-stimulated phosphorylated AKT levels were observed, a result that was confirmed in Hepa1-6, C2C12, and differentiated 3T3-L1 cells knocked down using Ppp2r2a small interfering RNAs. Altered AKT signaling and expression of gluconeogenic genes in the fed state contributed to an insulin resistance and hyperglycemia phenotype. This model demonstrates how genetic changes with individually small phenotypic effects interact to cause diabetes and how differences in expression of hypomorphic alleles of PPP2R2A and potentially other regulatory proteins have deleterious effects and may therefore be relevant in determining diabetes risk.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.