Letter | Published:

Insulin resistance in cavefish as an adaptation to a nutrient-limited environment

Nature volume 555, pages 647651 (29 March 2018) | Download Citation


Periodic food shortages are a major challenge faced by organisms in natural habitats. Cave-dwelling animals must withstand long periods of nutrient deprivation, as—in the absence of photosynthesis—caves depend on external energy sources such as seasonal floods1. Here we show that cave-adapted populations of the Mexican tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin-resistant compared to river-adapted populations. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro and contributes to hyperglycaemia. Hybrid fish from surface–cave crosses carrying this mutation weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation have increased body weight and insulin resistance. Higher body weight may be advantageous in caves as a strategy to cope with an infrequent food supply. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and reduced lifespan. However, cavefish have a similar lifespan to surface fish and do not accumulate the advanced glycation end-products in the blood that are typically associated with the progression of diabetes-associated pathologies. Our findings suggest that diminished insulin signalling is beneficial in a nutrient-limited environment and that cavefish may have acquired compensatory mechanisms that enable them to circumvent the typical negative effects associated with failure to regulate blood glucose levels.

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We thank Y. Chinchore and C. Sengel for technical advice; X. Gao for bioinformatics support; Z. Zakibe for photographs of the fish; the Aquatics facility at Stowers for fish maintenance and support; the cell culture core at Stowers for cell line maintenance and advice; the molecular biology core at Stowers for design, execution and validation of the CRISPR constructs; the proteomics core; M. Levy for advice and computational modelling of the insulin receptor; A. Herman for help with the genome scan; the Microscopy Resources on the North Quad (MicRoN) core at Harvard Medical School; M. Miller for illustration; and S. Williams, F. Damen, S. Xiong, E. Kingsley and K. Fox for feedback on the manuscript text. This work was supported by a grant from the NIH to C.J.T. (HD089934) and institutional funding to N.R. M.R.R. was supported by a National Research Service Award (DK108495) and R.P. was supported by a grant from the Deutsche Forschungsgemeinschaft (PE 2807/1-1).

Author information

Author notes

    • Misty R. Riddle
    •  & Ariel C. Aspiras

    These authors contributed equally to this work.


  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Misty R. Riddle
    • , Ariel C. Aspiras
    • , Brian Martineau
    • , Megan Peavey
    • , Julius A. Tabin
    •  & Clifford J. Tabin
  2. Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA

    • Karin Gaudenz
    • , Robert Peuß
    • , Jenny Y. Sung
    • , Andrew C. Box
    •  & Nicolas Rohner
  3. College of Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108, USA

    • Suzanne McGaugh
  4. Department of Biology, New York University, New York, New York 10003, USA

    • Richard Borowsky
  5. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA

    • Nicolas Rohner


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M.R.R., A.C.A., C.J.T. and N.R. conceived the project and designed research with additional contributions from K.G., R.P. and A.C.B. M.R.R., A.C.A., K.G., R.P., J.Y.S., B.M., M.P., A.C.B., J.A.T., S.M., R.B. and N.R. performed the research. M.R.R., A.C.A., C.J.T. and N.R. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Clifford J. Tabin or Nicolas Rohner.

Reviewer Information Nature thanks K. Kavanagh, S. O’Rahilly and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Figure

    This file contains raw uncropped film for the western blot shown in Figure 1F. Both films were from the same set of membranes which were stripped and reprobed. Red outline denotes gels used for the figure and yellow outline shows cropping used.

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    Supplementary Information

    This file contains names of the rivers in which surface Astyanax mexicanus were sampled and the numbers of individual samples collected.

  4. 4.

    Supplementary Information

    This file contains extended text describing the population genomic approach to test the insra locus for signatures of selection.

HTML files

  1. 1.

    Supplementary Data

    This file contains Sequence information of the genes from the insulin signaling pathway (http://www.genome.jp/kegg-bin/show_pathway?hsa04910) from Astyanax mexicanus in FASTA format.

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