ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nature 2018;555:647-651

An important model system in evolutionary developmental biology (‘evo-devo’) are the surface dwelling (surface fish) and cave adapted (cavefish) morphs which differ in numerous traits. Cavefish is a generic term for fresh water fish adapted to life in caves and other underground habitats. Living in darkness, pigmentation and eyes are useless, or even a disadvantage because of their energy requirements, and therefore cavefish are typically pale and blind. Importantly, as they are almost entirely cut off from the outside world, their subterranean homes provide no food for most of the year, and they live in prolonged starvation with the exception of food from springtime floods that sweep in nutrients in the form of worms and algae. To survive under these conditions, cavefish have evolved starvation resistance and binge eating when food becomes available. During restricted rations, they lose weight more slowly than their surface counterparts.

Here, Riddle et al. compared laboratory-raised cavefish and surface fish and found higher blood glucose levels after feeding in the cavefish. Investigation of short and long-term fasting showed higher blood glucose levels in cavefish compared to a minor decrease in surface fish; however, after 21 days, cavefish showed a marked decrease in blood glucose levels compared to a minor decrease in surface fish, suggesting that dysregulated glucose homeostasis is a feature of cave populations. To investigate the underlying genetic mechanism, the researchers sequenced all known genes in the insulin pathway. A difference was detected in the coding of the insulin receptor gene (insra gene) between surface fish and cavefish. Remarkably, this mutation is identical to a change in the Rabson-Mendenhall Syndrome, which is characterized by severe insulin resistance.

To examine the effect of this mutation in fish, the authors used CRISPR–Cas gene-editing to generate zebrafish carrying the same insra mutation.⁶ These zebrafish developed insulin resistance and overweight. The weight gain is puzzling, as humans and rodents lacking functional insulin receptors have growth retardation and low body fat. Another unexpected finding is that cavefish have a respectable lifespan of >14 years, similar to that of the surface fish. Elevated blood-glucose levels can damage tissue if the glucose bonds with proteins in a process termed glycation, which is linked to a range of health problems in patient with diabetes. However, cavefish do not have high levels of glycated proteins, so they have apparently evolved a yet-identified compensatory mechanism. Identifying this glycation-inhibiting mechanism has major potential biomedical importance.

6. Retaux S. The healthy diabetic cavefish conundrum. Nature 2018; 555(7698): 595-597.