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
Open accessAbstract
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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In a digenic model crossing Ppp2r2a+/- mice with insulin receptor null heterozygotes, a severely aggravated overt diabetic phenotype occurred, with progressive hyperglycemia, hyperinsulinemia, glycosuria, impaired glucose tolerance, and insulin resistance.
“in a digenic model, in which these Ppp2r2a +/-mice were crossed with mice heterozygous for a null allele of the insulin receptor, a severely aggravated and overt diabetic phenotype was observed, characterized by progressive hyperglycemia, hyperinsulinemia, glycosuria, impaired glucose tolerance and insulin resistance.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [74]
These mice showed modest insulin resistance but no overt diabetes.
“These mice showed modest insulin resistance, but no overt diabetes.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [74]
Elevated FoxO1 expression and increased Pepck and G6P mRNA levels were observed in both Ppp2r2a in vitro knockdown and the digenic in vivo model.
“elevated FoxO1 expression, resulting in increased Pepck and G6P mRNA levels, were observed both in Ppp2r2a in vitro knockdown and in the digenic in vivo model [74].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [74]
Random chemical mutagenesis created a mouse model with a new splice acceptor site in Ppp2r2a intron 3, causing a premature translation stop.
“Through use of a random chemical-induced mutagenesis approach, a mouse model was created, harboring a new splice acceptor site in Ppp2r2a intron 3, resulting in the generation of a premature translation stop [74].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [74]
Heterozygous mice had 35-45% reduction in B55α transcripts and 22-43% reduction in B55α protein in white adipose tissue, liver, and skeletal muscle.
“in heterozygous mice, a 35-45% reduction in B55α transcripts and a 22-43% reduction in B55α protein expression was seen in white adipose tissue, liver and skeletal muscle.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [74]
The digenic model had decreased total AKT levels, increased basal AKT Thr308/Ser473 phosphorylation, and decreased insulin-stimulated AKT, GSK-3β, and p70 S6K phosphorylation.
“This was accompanied by decreased total AKT levels and increased basal AKT phosphorylation (Thr308, Ser473), but decreased insulin-stimulated AKT, GSK-3β and p70 S6K phosphorylation.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [74]
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References 38 · Cited by 35
- Authors
- Goldsworthy, M., Bai, Y., Li, C.-M., Ge, H., Lamas, E., Hilton, H., Esapa, C. T., Baker, D., Baron, W., Juan, T., Véniant, M. M., Lloyd, D. J., & Cox, R. D.
- Affiliations
- Medical Research Council (GB)
- Amgen (United States) (US)
- Corresponding author
- Goldsworthy, Michelle
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-02-11
- Volume
- 65
- Issue
- 5
- Pages
- 1434-1446
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5947768
- OpenAlex
- W2267011558
- Cited by
- 35
- References
- 38
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 15 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 3 · 2016: 2
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Medical Research Council
- Amgen Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- type 2 diabetes, PPP2R2A, protein phosphatase 2A, alternative splicing, splice site mutation, insulin resistance, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, Akt signaling, serine/threonine kinase, gluconeogenic gene expression, hypomorphic allele, N-ethyl-N-nitrosourea mutagenesis, mouse model
- MeSH terms
- Alleles, Animals, Cell Line, Diabetes Mellitus, Type 2, Disease Models, Animal, Heterozygote, Insulin Resistance, Male, Mice, Mutant Strains, Mutation, Receptor, Insulin, Signal Transduction, Alternative Splicing, Disease Progression, RNA Splice Sites, RNA Interference, RNA, Small Interfering, Mice, Protein Phosphatase 2, Haploinsufficiency
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