When digesting a meal, blood glucose surges and ordinarily prompts the release of insulin from the pancreas, which causes tissues throughout the body to take up and store the sugar. In type II diabetes, the body becomes insensitive to insulin, meaning that blood glucose stays elevated and eventually becomes harmful. Whilst humans eat frequently throughout the day, many animals are adapted to survive for weeks without food. An extreme example can be found in Mexican caves, where some populations of Mexican tetras (Astyanax mexicanus) have independently invaded the subterranean habitat and thus rely on unpredictable seasonal floods to provision food.
The cavefish are clearly more tolerant of starvation than their surface relatives. For example, when food deprived, they remain larger than surface fish. In order to understand how cavefish are adapted to their life of feast and famine, Misty Riddle and Ariel Aspiras, from the Harvard Medical School, USA, and their colleagues investigated glucose metabolism in both cave- and surface-dwelling populations of the Mexican tetra.
The team observed that the cavefish had extremely high blood glucose levels, both immediately after feeding and after a day of fasting. In one population, blood glucose remained high after 3 weeks of starvation. However, the elevated blood glucose was not due to an inability to make insulin; the pancreas of the cavefish developed normally, and the cavefish were producing insulin as their circulating insulin levels were similar to those of their surface relatives. When the researchers injected synthetic insulin into surface fish to see how they responded to the hormone, their blood glucose dropped; however, no such change occurred in the cavefish. In addition, cavefish muscle incubated with insulin also lacked the molecular response that normally triggers glucose uptake. In effect, the cavefish state is reminiscent of type II diabetes: the pancreas can produce insulin, but the cells don't listen.
In order to identify why the cavefish were insulin resistant, the team scoured the genome sequences of the different tetra populations. They identified a mutation in the cavefish insulin receptor, which sits on cell membranes, that prevents the hormone from binding normally. To prove this was the critical mutation, they next used the fashionable gene-editing technology CRISPR to induce the cavefish mutation in a popular lab species, zebrafish. This rendered the zebrafish insulin resistant and also made them larger. Conversely, the equivalent mutation in the same receptor in humans results in diminished growth, but why fish and mammals differ so much in their response remains to be established.
The most pertinent finding of the study, however, may be peculiar to the cavefish. Despite their high blood glucose, the cavefish live healthy lives – the damage that excessive blood glucose normally wreaks couldn't be detected in the cavefish blood – and they even appear to age more slowly than their relatives that inhabit the surface. The team therefore concludes that, to compensate for their insulin resistance, cavefish must have evolved compensatory adaptations. The specific nature of these adaptations is as yet unknown, but understanding them could eventually have major implications for diabetes research.
