[Editor's note: This story was updated on Sept. 22, 2017, to state that geneticist Cliff Tabin's remarks were made as part of his scientific talk.]
For months fish that live in dark caves in Mexico go without food. They have gone far longer—millennia—without light, evolving to lose their eyes and skin pigments.
Now researchers have discovered these strange creatures have another oddity. To survive their food-scarce environment, the fish have evolved extreme ways of turning nutrients into energy. These features create symptoms like large blood sugar swings that, in humans, are precursors of type 2 diabetes. But in the fish these changes are adaptations, not a disease. These cave fish lead long and healthy lives.
Understanding how the fish remain healthy in spite of these ominous symptoms may lead to new therapeutic approaches for treating diabetes in people, notes Cliff Tabin, a geneticist at Harvard Medical School. Tabin identified these features and described them last month at a meeting of the Pan-American Society for Evolutionary Developmental Biology in Calgary. And he and his colleagues are beginning to get clues about how cave fish pull off this feat.
In humans and other mammals one of the first signs of type 2 diabetes risk is poor control of blood sugar (glucose). This happens because cells resist insulin, the hormone that signals cells to take in glucose from the bloodstream. If the problems continue, they progress into full-blown diabetes characterized by blood glucose levels of 140 milligrams per deciliter or higher, organ failure, leaky blood vessels, damaged nerves and heightened risk of stroke and heart disease. The illness kills 3.4 million people worldwide every year. Diet, drugs and insulin injections are the current treatments and, too often, do not work. (Weight loss surgery recently has become another option, but it carries the risks of any major operation.)
The cave fish Astyanax mexicanus has, apparently, figured out another solution. The fish were washed from rivers into caves about a million years ago. It was a big change. Rivers were full of food but caves have only what is washed in by seasonal floods—some small aquatic crustaceans, decomposing matter and detritus in the mud. The caves have no light (therefore, no plants or photosynthesis) and little oxygen in the water. But there are also no fish predators. “In the caves, the good news is no one wants to eat you. The bad news is you have nothing to eat,” Tabin said in his talk.
Because cave fish go many months without food, researchers hypothesized they evolved a metabolism that efficiently stores the calories they could scrape up as fat, similar to animals that store fat before winter to tide them over during the lean months. To test that idea, Tabin and his team compared the cavefish with river fish raised under identical conditions in the lab. They found the cavefish do store more visceral fat than their riverine relatives. But the cave dwellers also had much larger, fatty livers, which resembled diabetes-linked fatty liver disease in humans. “But you don’t see destruction of the liver in these guys,” Tabin said. “It’s very curious.”
The discovery of one prediabetic feature in healthy fish prompted Tabin to look at other aspects of their metabolism. Blood sugar control was one. When the river fish were fed glucose, he saw, insulin kicked in to control their blood glucose levels. But in the cave fish blood glucose shot up. Then, during starvation, cave fish blood glucose levels dropped off the charts. “We’ve got what would be a diabetic response in humans, but the cave fish do not get diabetes,” Tabin said.
A close look at fish muscles—major glucose consumers—showed the cave fish appear to be insulin resistant at a cellular and biochemical level. Surface fish muscle cells take up more glucose than does cave fish muscle, given the same amount of insulin.
Genetic analysis revealed a reason for this: The fish had a unique mutation in the insulin receptor gene, and the change helped the fish gain weight. Tabin and his team used genetic-engineering methods to insert the cave fish insulin receptor into normal zebra fish. Sure enough, those fish became heavier than regular zebra fish. “We are finding that a lot of genes under selection in the cave fish are involved in metabolism,” says Suzanne McGaugh of the University of Minnesota, who studies the population genetics of the species and was not involved with the research.
Together, these findings suggest the cave fish have evolved an extremely “thrifty” metabolism. But how do they escape the ill effects of that kind of food processing? The fish “have had time to counterevolve, or coevolve, factors that allow them to negate the problems associated with poor blood glucose control, fatty livers and insulin resistance,” says Nicolas Rohner, who was a postdoctoral fellow in Tabin’s laboratory and now leads his own group at the Stowers Institute for Medical Research.
In other words, evolution in these cave fish has zeroed in on potential solutions to diseases like diabetes and obesity. Cave fish researchers are now working to find out how the fish do it. “The only piece of total speculation I'll give you is that the metabolic rate is lower in the cave fish” than in their river fish relatives, says Alex Keene of Florida Atlantic University, who was not part of the study. There might be something about slow energy use in cells that protects against diabetes, he says. Finding that something will, like fishing, require some patience.