A common variant in PPP1R3 associated with insulin resistance and type 2 diabetes.
Open accessAbstract
Selected candidate genes have been analyzed in the Pima Indians of Arizona based on evidence that insulin resistance and type 2 diabetes have significant genetic determinants. An amino acid substitution at codon 905 of the glycogen-targeting subunit of type 1 protein phosphatase that regulates skeletal muscle glycogenesis was recently reported to be associated with changes in insulin action in Danish subjects. In addition to the variant at 905, we report here a novel substitution at codon 883 and common variant of an "ATTTA" element in the 3'-untranslated region (UTR) of the corresponding gene (PPP1R3). The 3'-UTR variant resembled the mRNA-destabilizing AT(AU)-rich elements (AREs) and resulted in a 10-fold difference in reporter mRNA half-life, was correlated with PPP1R3 transcript and protein concentrations in vivo, and was associated with insulin resistance and type 2 diabetes in the Pimas. The variant is more common in Pimas (0.56) than in Caucasians (0.40). Because of its apparent effect on expression of PPP1R3, it may, in part, contribute to the higher prevalence of type 2 diabetes in this Native American population.
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Known genetic mutations associated with insulin resistance are rare in healthy subjects across populations.
“Examination of groups of healthy subjects in a number of different populations has shown that known genetic mutations associated with insulin resistance are rare [20, 39, 40, 41, 42, 43, 44].”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [40]
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Kahn, S. E. (2003) · Diabetologia · doi:10.1007/s00125-002-1009-0 · Cited by 2,166 · see citing works
Newgard, C. B., Brady, M. J., O'Doherty, R. M., & Saltiel, A. R. (2000) · Diabetes · doi:10.2337/diabetes.49.12.1967 · Cited by 189 · see citing works
Genetic Studies of the Etiology of Type 2 Diabetes in Pima Indians
Baier, L. J., & Hanson, R. L. (2004) · Diabetes · doi:10.2337/diabetes.53.5.1181 · Cited by 109 · see citing works
- Authors
- Xia, J., Scherer, S. W., Cohen, P. T., Majer, M., Xi, T., Norman, R. A., Knowler, W. C., Bogardus, C., & Prochazka, M.
- Affiliations
- National Institutes of Health (US)
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1998-09-01
- Volume
- 47
- Issue
- 9
- Pages
- 1519-1524
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2044271687
- Cited by
- 86
- References
- 0
- Citations by year
- 2025: 2 · 2022: 1 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 1 · 2015: 1 · 2013: 1 · 2012: 2
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- public-domain
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin resistance, type 2 diabetes, Pima Indians, 3' untranslated region variant, AU-rich elements, mRNA stability, genetic susceptibility
- MeSH terms
- Adult, Alleles, Arizona, Base Sequence, Codon, Diabetes Mellitus, Type 2, Female, Genotype, Humans, Indians, North American, Insulin Resistance, Male, Molecular Sequence Data, Phosphoprotein Phosphatases, Polymorphism, Genetic, Regression Analysis, RNA, Messenger, Transcription, Genetic, Genetic Variation, Muscle, Skeletal
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