New Clues to the Way We Metabolize Sugar

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It’s well known among palaeontologists and nutrition experts that the human diet began to change after our distant ancestors transitioned from being pure hunter-gatherers to cooking their meat and, about 10,000 years ago, to cultivating crops. Unfortunately, our bodies had been evolving over millions of years to process food, and our metabolisms still haven’t adjusted to our (relatively) new diet—one reason why the modern, high-sugar diets many of us now consume can trigger insulin resistance and type 2 diabetes.

But a gene variant that arose and started spreading sometime after 450,000 BP (before the present) could help us cope, according to a recent study led by investigators at University College London and published in the journal eLife.

After a meal and the higher levels of blood sugar in the blood that follow, insulin causes a pore to appear on the surface of fat and muscle tissue, technically known as a glucose transporter, which allows sugar molecules to pass from the blood into these tissues. We want this system to function well so that sugar can be removed efficiently from the blood. If something goes wrong with the process, and too much sugar is left circulating in the blood, it can lead to diabetes.

Humans rely on a protein called CHC22 to hold the glucose transporters inside muscle and fat away from the tissue surface, while we have low blood sugar during fasting. CHC22 is a form of clathrin (so called because of its clathrate, or latticelike, structure). Triskelion-shaped clathrins are part of a cell’s internal machinery—they form a basket to carry proteins around in the cell, removing or adding pores like glucose transporters, or proteins that act as hormone detectors from the cell surface—so they are vital for the regulation of communication between cells and their environment. If clathrin pathways go wrong, the result can be cancer, nervous system defects, developmental defects or infectious diseases; some microbes can hijack clathrin pathways to enter cells.  

In humans there are two clathrin types. The more common CHC17 form is found in all tissues and handles endocytosis—moving proteins inside the cell from the cell surface—while the CHC22 form is most highly expressed in muscle and fat and is not involved in endocytosis. 

The original form of the gene that encoded CHC22, which first evolved around 450 million years ago, produced a clathrin that held the glucose transporter tightly inside muscle and fat. Somewhere between 450,000 and 12,500 years ago, however, a new variant of the gene appeared. What drove the evolution of the new variant? Its increased frequency in humans is linked with the introduction of farming and cooking and the accompanying shift to a diet more carbohydrate-rich than that of hunter-gatherer populations. This new form of the gene makes a version of CHC22 that is less effective at holding the glucose transporter in place inside tissue, so that it can make its way to the surface more easily to let in sugar molecules from the blood.

The original form of CHC22 had advantages for early humans: it helped to keep blood sugar higher during periods of fasting before we had easy access to carbohydrates. In turn, this contributed to human brain size increasing in size and complexity; more sugar circulating in the blood meant more energy for the brain to grow. But too much sugar circulating in the blood can be dangerous and even lead to type 2 diabetes. For modern humans, the new variant became more common because it is more compatible with the high carbohydrate diets we eat today, and there is still selective pressure on the gene encoding CHC22.

The new variant may make developing insulin resistance and type 2 diabetes less likely, but not everyone has the newer version of the gene; based on the genomes of around 2,000 people from the 1000 Genomes project, around three quarters of the world’s population may have the newer mutation, with one quarter having only this gene.

In mice, there is no CHC22, and they move their sugar transporters by a different mechanism, though mice produce, and can respond to, insulin. The gene encoding CHC22 originally evolved in our ancestors alongside backbones and complex nervous systems, and then it was lost in some animals, including mice, rats, sheep and cattle. CHC22 means a tighter regulation of blood sugar but the trade-off is an increased tendency to insulin resistance. Mice and rats are herbivores, and sheep and cattle are ruminants, so it makes sense that they have evolved pathways to deal with sugar that have better compatibility with their diets.

In animals that retained CHC22, there is still diet-specific adaptation within species. Bears do have CHC22, but there is variation in the protein among species. Polar bears, with very low carbohydrate diets, and brown bears, with a higher carbohydrate diet, have distinct CHC22 variants, suggesting that mutations that appear in the gene responsible for CHC22 are driven by nutritional need. Frances Brodsky, director of the Division of Biosciences at University College London, whose laboratory initiated this study, notes: “The fact that gene encoding CHC22 is lost in several species and variable in humans is an exciting example of evolution in action. And suggests that diet is a strong force in driving evolution.”  

Her group, which has studied clathrins for many years, found the mutability of CHC22 quite surprising since the more common CHC17 clathrin is highly invariant and is present in all so-called eukaryotic organisms from yeast to humans.

The way you handle blood sugar after a meal may well depend on which variant of CHC22 you produce; people with the newer version should have lower blood glucose levels. The investigators involved in this study predict that knowing which gene variant you have may help you understand your risk of developing conditions that lead to type 2 diabetes and encourage you to adjust your carbohydrate intake accordingly. Their current research is focusing on developing a test for the variation of the CHC22-encoding gene in individuals so that variation can be correlated with blood sugar levels.

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