The Mexican tetra comes in different flavors. In normal river habitats, it’s a small, standard-looking, silvery fish. But some groups within the species have made their home in dark, food-scarce caves. Evolution has quickly rid these groups of their resource-hungry eyes and turned them into pinkish, chubby, blind cavefish—with a bunch of metabolic changes that help them survive in the extreme environment.

A paper in Nature this week reports that the cavefish are resistant to insulin, a condition that can cause damage on its own and is often a precursor to diabetes. But the fish somehow don’t suffer the same kinds of tissue damage that humans do when we have insulin resistance. The authors of the paper, led by Harvard geneticist Misty Riddle, report on how they tried to get to the bottom of the genetic mutations that contribute to this metabolic mystery. Their results show just how much variety exists in how different species respond to insulin—and that studying these fish more could help our understanding of diabetes.

High blood sugar

After you eat something, your blood sugar rises, and your pancreas releases insulin to deal with the increase. The insulin binds to specialized receptors, found on the surfaces of muscle, fat, and liver cells, telling them to absorb glucose from the blood. In between meals when blood glucose levels drop, a different hormone (glucagon) prompts the liver to release its stored glucose back into the blood.

These processes get disrupted by diabetes. In type II diabetes, not enough insulin is produced, or the body doesn’t properly recognize the insulin it makes. A precursor to the latter is called insulin resistance, and the lack of an insulin response means high blood glucose levels persist for longer periods of time. This eventually leads to tissue damage and the host of health problems that come along with type II diabetes.

That is, unless you’re a cavefish, apparently. Adapting to their dark, food-scarce environment has pushed these fish to develop metabolic eccentricities: they have reduced circadian rhythms and lower oxygen consumption, and they store more fat than their surface-dwelling brethren. Riddle and her colleagues have even discovered a new metabolic oddity: cavefish have glucose levels that are all over the map.

After exploring a few possible explanations for this, the researchers dug into published genome sequencing data, finding that the cavefish have a genetic mutation that changes their insulin receptors and leaves them resistant to it. Humans with the same mutation have a severe and dangerous form of insulin resistance known as Rabson-Mendenhall syndrome.

Different species, different results

To figure out what was going on with this mutation, Riddle and her colleagues bred cavefish with surface fish and observed what happened with the offspring. They found that those with the mutation weighed more than those without, even when their diets were regulated. They also edited the gene in zebrafish, a species more amenable to genetic experimentations. These zebrafish were overweight and insulin resistant.

That’s a strange result, because insulin is a growth hormone, and mammals without functional insulin receptors have extremely low body fat. For the cavefish, higher weight is probably a good thing for living in food-scarce environments, but it’s not clear why the cavefish have such a different response to the mutation.

There wasn’t a perfect correspondence between the mutation and insulin resistance. Some of the fish with the mutation didn’t have high blood glucose, suggesting that there are likely other genetic changes at play in the fishes’ insulin resistance. And while two different populations of cavefish have this mutation, another population didn’t—yet that population still had insulin resistance, suggesting there must be another way of achieving the same result.

The most startling finding was that the cavefish seem to be in excellent health despite their insulin resistance. The researchers write that it would be easy to imagine that there had been an evolutionary tradeoff “in which physiological health is sacrificed to reap the benefits of starvation resistance.” But no: the insulin-resistant cavefish live about as long as the surface fish and even seem to age better. Where old surface fish get tattered fins, hunchbacks, and sunken skin, the cavefish remain pretty as ever. And again, unlike humans, they don't suffer tissue damage.

Right now, studies on diabetes in non-humans tend to focus on other mammals—and even then the results don’t always neatly transfer to humans. But more work on the cavefish could open up some new questions to ask plus new ways to answer those questions. Ultimately, these could help us to understand insulin and diabetes much better—plus, simply understanding how the cavefish pull this off is its own exciting mystery.

Nature, 2018. DOI: doi:10.1038/nature26136 (About DOIs).

Correction: clarified the relationship between insulin resistance and type II diabetes.