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 floods. 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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Acknowledgements 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).
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