title: 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.
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.
authors: Diabetes Group, Medical Research Council Harwell, Oxfordshire, U.K. m.goldsworthy@har.mrc.ac.uk.
authors: Michelle
authors: M
authors: Goldsworthy
authors: Diabetes Group, Medical Research Council Harwell, Oxfordshire, U.K.
authors: Ying
authors: Y
authors: Bai
authors: Genome Analysis Unit, Amgen Inc., Thousand Oaks, CA.
authors: Chi-Ming
authors: CM
authors: Li
authors: Genome Analysis Unit, Amgen Inc., Thousand Oaks, CA.
authors: Huanying
authors: H
authors: Ge
authors: Genome Analysis Unit, Amgen Inc., Thousand Oaks, CA.
authors: Edwin
authors: E
authors: Lamas
authors: Protein Core Facility, Medical Research Council Harwell, Oxfordshire, U.K.
authors: Helen
authors: H
authors: Hilton
authors: Protein Core Facility, Medical Research Council Harwell, Oxfordshire, U.K.
authors: Christopher T
authors: CT
authors: Esapa
authors: Genome Analysis Unit, Amgen Inc., Thousand Oaks, CA.
authors: Dan
authors: D
authors: Baker
authors: Genome Analysis Unit, Amgen Inc., Thousand Oaks, CA.
authors: Will
authors: W
authors: Baron
authors: Genome Analysis Unit, Amgen Inc., Thousand Oaks, CA.
authors: Todd
authors: T
authors: Juan
authors: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA.
authors: Murielle M
authors: MM
authors: Véniant
authors: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA.
authors: David J
authors: DJ
authors: Lloyd
authors: Diabetes Group, Medical Research Council Harwell, Oxfordshire, U.K. r.cox@har.mrc.ac.uk.
authors: Roger D
authors: RD
authors: Cox
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D057895:Haploinsufficiency; D006579:Heterozygote; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D022821:RNA Splice Sites; D034741:RNA, Small Interfering; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D022821:RNA Splice Sites; D034741:RNA, Small Interfering; D011972:Receptor, Insulin; C581986:Ppp2r2a protein, mouse; D054648:Protein Phosphatase 2