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The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes

Nature Genetics volume 24, pages 291–295 (2000)Cite this article

Abstract

Type 2 diabetes is a polygenic and genetically heterogenous disease1. The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2,3,4,5). We evaluated the role of IB1 in β-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma β-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IB1 protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on 149 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (S59N) that segregated with diabetes. In vitro , this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of β-cell function.

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Figure 1: Effect of MAPK8IP1 antisense RNA in INS1 cells.
Figure 2: Segregation analysis of MAPK8IP1 S59N and IPF1 Q59L mutations in pedigree F514.
Figure 3: The MAPK8IP1 S59N mutation is a weaker inhibitor of the JNK-activated repression of INS and is associated with an accelerated pro-apoptotic program.

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Acknowledgements

We thank J. Oberholzer for freshly isolated human pancreatic islets; P. Fontana for help in statistical analysis; and P. Gallina for collecting diabetic families and patient data. G.W., C.B. and V.M. are supported by the Swiss National Science Foundation (grants 32-48916.96, 32-94471.95 and 32-54119.98) and the Placide Nicod and Botnar Foundations.

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Authors and Affiliations

  1. Departments of Internal Medicine CHUV-University Hospital, Lausanne, Switzerland

    Gérard Waeber, Christophe Bonny, Vincent Mooser, Myriam Steinmann, Christian Widmann, Anne Maillard, Gérard Waeber, Pascal Nicod & Philippe Froguel

  2. Department of Pathology, CHUV-University Hospital, Lausanne, Switzerland

    Judith Miklossy

  3. Institute of Biology-CNRS EP10, Pasteur Institute, Lille, France

    Jérôme Delplanque, Christian Dina, El H Hani, Jérôme Delplanque, Nathalie Vionnet, Philippe Boutin & Philippe Froguel

  4. Institute of Morphology and Cellular Biology, Lausanne University, Switzerland

    Christian Widmann

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Correspondence to Gérard Waeber.

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Waeber, G., Delplanque, J., Bonny, C. et al. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat Genet 24, 291–295 (2000). https://doi.org/10.1038/73523

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