Periodic food shortage is one of the biggest challenges organisms face in natural habitats. How animals cope with nutrient limited conditions is an active area of study, of particular relevance in the context of the current increasing destabilization of global climate. Caves represent an extreme setting where animals have adapted to nutrient-limited conditions, as most cave environments lack a primary energy source. Here we show that cave-adapted populations of the Mexican Tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin resistant compared to the river-adapted population. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro. Surface/cave hybrid fish carrying the allele weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation similarly have increased body weight and insulin resistance. Higher bodyweight may be advantageous in the cave as a strategy to cope with infrequent food. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and dramatically reduced life-span. However, cavefish have a similar lifespan to surface fish (of greater than fourteen years) and do not accumulate advanced glycated end products (AGEs) in the blood that are typically associated with progression of diabetes-associated pathologies. Our findings raise the intriguing hypothesis that cavefish have acquired compensatory mechanisms that allow them to circumvent the typical negative effects associated with failure to regulate blood glucose.

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