A blind cave fishZachary Zakibe

Millions of years ago, a small, unremarkable fish called the Mexican tetra started swimming into the caves of eastern Mexico. In the all-encompassing darkness of these limestone caverns, the tetras’ eyes, which take a lot of energy to build and maintain, were useless luxuries. Over several generations, the cave fish lost them entirely. Today, they are born with small eyes that gradually waste away as they get older.

The tetras’ eye sockets, however, don’t go to waste; they can use them to store fat. Blind cave fish are stockier than their cousins that live on the surface, and some have fat-filled humps. “You dissect them and you see that their body cavity is full of visceral fat that surrounds their organs,” says Misty Riddle, from Harvard Medical School. Some of them eat more than their sighted relatives, but even when the two groups are fed the same amounts of food, the blind ones put on more weight. These are sensible adaptations for living in caves, where food is scarce and starvation is always just around the corner.

Now, Riddle and her colleague Ariel Aspiras have discovered another bizarre metabolic trick that may help the cave fish cope with a world of little food. They’ve relinquished the tight control that most animals exert over the levels of glucose (sugar) in their blood. Instead, they allow those levels to fluctuate wildly, in a way that’s reminiscent of type 2 diabetes. And yet, these fish have none of the health problems that diabetic humans experience.

When humans eat a meal, our blood sugar spikes. Our pancreas reacts by releasing insulin, a hormone that tells the liver and other organs to start absorbing the extra glucose. When we fast, our blood glucose drops, and the pancreas releases glucagon, a different hormone that prompts the liver to release glucose instead. Through the actions of these two hormones, we keep our blood sugar at an even keel.

In the blind cave fish, that keel is broken. Their blood glucose, rather than swelling and dipping in gentle waves, spikes and crashes instead. It typically stays at a much higher level than that of the surface fish. It remains high if the cave fish go without food for a day. And it falls off the charts if they starve for a week.

That’s not because they have something wrong with their pancreas. Instead, their muscles are unusually insensitive to insulin. In humans, insulin resistance and high blood sugar are two of the defining traits of type 2 diabetes—a disorder that can lead to long-term problems like heart disease, strokes, and kidney failure. But the cave fish “are happy, normal, and healthy despite having this extreme elevation in their blood glucose,” Riddle says. “We were really shocked to see that.”

Her surprise deepened when she and her colleagues worked out why the fish are resistant to insulin. The hormone works by sticking to a protein called the insulin receptor, like a key entering a lock. The cave fish have a mutation in this receptor, which likely changes the shape of the lock so that the insulin key no longer fits. Riddle and Aspiras confirmed this by using a gene-editing technique called CRISPR to introduce the same mutation into the insulin receptor of zebra fish—a species that’s commonly used in laboratory studies. These modified zebra fish became insulin-resistant and put on more weight, just like the blind cave fish.

This is a very strange result, for two reasons. First, insulin is a growth hormone that’s important in the development of fat cells. Humans who have broken insulin receptors are typically extremely thin, as if they were in a permanent state of starvation. In tetras, those same broken receptors seem to have the opposite effect.  

Second, the very same mutation that Riddle and Aspiras found in the cave fish causes Rabson–Mendenhall syndrome in humans—a severe, diabetes-like illness that manifests in infancy and typically kills people before their third birthday. The cave fish, however, can live as long as their surface-dwelling cousins—if not longer. Some of the animals in Riddle’s lab have been alive for at least 14 years. “At that age, they look similar to a surface fish that’s 3 years old,” she says. “We don’t really have high enough numbers of the old fish to say that they age more slowly, but it certainly seems that they’re not aging prematurely.”

Indeed, the cave fish probably have several such adaptations. Riddle and Aspiras did most of their work on tetras from two caves, Tinaja and Pachón, which are part of the same mountain range. But in Molino cave, which is part of a different range, the cave fish evolved independently. They also have high blood-sugar levels, but they don’t have the same insulin-receptor mutations. They must have their own unique techniques for changing their response to insulin.

By learning more about these adaptations, the team hopes to better understand how diabetes manifests in people, and perhaps find ways of treating it. It wouldn’t be the first time, either. Byetta, a drug that’s commonly used to manage type 2 diabetes, was developed after studying the saliva of the Gila monster lizard.

“The [cave fish] study supports the idea that using therapies to enhance insulin sensitivity may prevent or delay the onset of type 2 diabetes,” says Juleen Zierath, from the Karolinska Institute. Still, she notes that most humans live in a very different world to that of the cave fish—one of ample nutrients. When we cut down on calories, we tend to become more sensitive to insulin, not less. As such, it’s unclear what lessons we can draw from the cave fish.

Anna Krook, also from the Karolinska Institute, agrees. After all, she notes that even mammals like mice and humans can react to the same insulin-receptor mutations in very different ways, which should give us pause before extrapolating from one animal to another. “We can and should use this opportunity to gain important insights about life with high glucose, but in the end it may not always translate across species,” she says.

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