Paris. The summer of 1848. Mobs filled the streets, building barricades just like in Les Mis. If they’d had cars, they probably would have been set on fire. In February of that year, the King, Louis-Phillipe, had abdicated in yet another French Revolution. There was a new government, what is called the Second Republic, but whatever it tried to do, it didn’t make anybody happy and there was more unrest. At the Collège de France, faculty complained that it had “slackened the zeal for research among all of the chemists, and all of their time … is absorbed by politics.”
Figure 1. The Revolution of 1848. Barricades on the Rue Soufflot (Horace Vernet)
Not all of them. Claude Bernard realized that nothing that could happen in the street would be as revolutionary as the results from his experiments on digestion in dogs. He had found sugar in a dog that he had been dissecting. But the dog hadn’t been fed any sugar. Where did the sugar come from? At the time, everybody assumed that any sugar in an animal came from their diet and that the sugar would ultimately be destroyed by oxidation. Animals eat sugar (or any food) for energy and the energy comes from oxidation of the food just as if you were burning food in a furnace. The dog hadn’t eaten any sugar. Strange as it seemed, the only possible explanation was that the dog was making its own sugar. It must have been making sugar from something else.
This was a revolution. Animals burned their food for energy. Lavoisier showed that. More than 100 years before the Second Republic he had built a whole animal calorimeter, a device that measures the heat generated by an animal. He showed that food was burned in an animal in roughly the same way that metals or other substances are oxidized.
Figure 2. Claude Bernard, 1858
Sugar is a food. How did it wind up undigested in the animal? Bernard was amazed. His first reaction was that there might be something wrong with the reagent that he had used to detect the sugar. But that was not it: the dog really was making its own sugar. In fact, he soon found that if he fed a dog only meat, there was as much sugar in that animal as there was in another dog that had been fed on a “sugary soup.”
Glycogen and Gluconeogenesis
“Although Bernard’s experimental findings were occasionally at fault… his strength appears to lie in his ability to discard a theory once its experimental basis had been undermined… he was apt not to state frankly that he had been wrong, he nevertheless did change his ideas. “
— quoted by F.G. Young.
It took some doing to show that the sugar was actually being produced in the dog’s liver but, by 1857, Claude Bernard had isolated the matière glycogene, what we call today glycogen. We understand its structure, as Bernard didn’t — it is a polymer of glucose, highly branched, highly structured. — it is a storage form of carbohydrate which allows glucose to be mobilized when needed and supplied in the blood.
Figure 3. Structure of glycogen. Each of the small units is a glucose molecule which can be clipped off from the end of each chain. The structure is highly branched (has a lot of ends). The multi-colored object in the center is the protein glycogenin around which the molecule is built.
Bernard emphasized the supplier idea, its ability to provide glucose to the tissues. He was not clear on how it got there. We now understand that sugar that we eat can be burned for energy or can be stored in glycogen. Most people are familiar with “carbohydrate loading” before a marathon, the pasta and beer dinner that will build up glycogen (at least if you just practiced by running a half marathon) and that that will support greater endurance (depending on what else you’ve been doing). But, of course, Bernard’s dogs hadn’t eaten any sugar at all. He knew that glycogen didn’t come from fat but, in fact, feeding protein seemed to be even better than feeding sugar (he used fibrin, the blood coagulation protein). The picture that evolved at that time, not quite correct, was that protein was the source that supplied glycogen which, in turn, could produce glucose, although, in 1858, it was unknown how this could be accomplished.
Figure 4 The first mention of the word glycogen as recorded by Claude Bernard in 1857
Today, we emphasize the need to keep blood glucose constant; we understand that almost all cells in the body use glucose as an energy source so too little is not good. It turns out that too much is also not good because glucose has some chemical reactivity and will react with proteins in the blood and in the tissues to form what are called advanced glycation end-products or AGEs.
The liver is a kind of command center for metabolism. The liver takes up glucose when blood levels are high and releases glucose from glycogen if levels fall. The liver is also the major site of the process is known as gluconeogenesis (GNG) whereby new glucose is made from other metabolites mostly amino acids from protein. GNG will also replenish any glycogen that is used up. In some sense, Bernard had discovered at least the idea of gluconeogenesis, (which would not be clearly demonstrated for another hundred years) even though in his animals, most of the glucose was coming from glycogen.
We now understand that the immediate source of blood glucose is usually from glycogen although GNG is going on almost all the time (contrary to the suggestion in some textbooks that GNG is a last-ditch effort after glycogen is gone). In other words, glucose made in GNG may be in the form of the metabolite glucose-6-phosphate (G-6-P) that can go into synthesis of glycogen and only later appear in the blood. The bottom line: glucose uptake into the liver, glucose release into the blood, glycogen synthesis and breakdown and gluconeogenesis all go on at the same time, are directly connected. It is really all one process defining blood glucose control (Figure 5).
Figure 5. Components of Hepatic Control of Blood Glucose.
Gluconeogenesis and the crisis in nutrition
It’s more than basic physiology. Control of glucose production, glycogen metabolism and GNG are right at the center of the confusion in nutrition and dietary recommendations that we confront today. For forty years, we focused on the supposed dangers of high dietary fat and it was absolute dogma that fat, or at least saturated fat, and cholesterol were unambiguous risks for cardiovascular disease. (Supermarkets are still stocked with low-fat, cholesterol-free producta which are “healthy,” “smart,” and “lite” (which foreign students think is how you spell “light.”) The possibility that the real problem was the excesses of the dietary carbohydrate that replaced the fat was rejected and the implication arose that somehow there was a requirement for carbohydrate. Fat and carbohydrate is what it is all about. So, how much carbohydrate do you need? How much do you need to eat to survive and how much to be healthy?
We now understand that animals (including humans) don’t need any carbohydrate. Whatever you think is a desirable amount of sugar and starch, whatever tastes good to you or appears to be a fundamental feature of your life style, you have to know that you don’t need to obtain any carbohydrate from what you eat. In the course of his experiments, Claude Bernard tested animals that had been fasted, and he soon established the idea that hepatic output of glucose is one of the processes that allows animals to live for long periods without food. (The other, naturally, is the ability to store fat and call upon the fat stores when needed). It is hard to exaggerate the importance of this discovery for people who want to understand nutrition and who want to control their own health.
If you think about it, you already knew that you don’t need to take in carbohydrate. We don’t store all that much glycogen. The average person has a storage of energy in the form of glycogen of under 1,000 calories, less than half of what is in normal dietary consumption. Fat storage is typically more than 100 times greater — even with carbohydrate loading, marathon runners run mostly on fat. If you had to rely on glycogen for energy, you would be exhausted in a day or so. If people really needed to consume carbohydrate, they would not come out alive after being stranded in the Andes for two weeks. That there is no dietary requirement for carbohydrate most of us learned in high school, or should have. The dietitians say “carbohydrate is an important source of energy” — your brain and other tissues require glucose — but if challenged will admit that it does not have to be dietary carbohydrate.
Claude Bernard lucks out
Sometimes luck is on our side. Sometimes we make the right mistake. Bernard measured the amount of sugar in the portal vein which brings blood from the digestive tract to the liver — it’s not a true vein (red in Figure 6.) He measured, as well, the amount of glucose leaving the liver in the hepatic veins (blue). His original observations showed that there was little or no glucose in the inputs from the portal vein but he was able to identify sugar in the hepatic veins leaving the liver. In other words, no glucose was coming into the liver but some was coming out. This pretty much made his case that the liver was a sugar-producing organ and that glycogen was being made form something else, rather than being assembled from blood sugar. Some of his scientific rivals, however, said that he was wrong, that they had also detected sugar coming into the liver in the portal vein.
Figure 6. Liver anatomy. The portal vein supplies blood (not truly a vein; red). Blood is carried ot the heart via the hepatic vein (blue).
They were right, of course — we now know that there is sugar throughout the circulation and glycogen is assembled from blood glucose. Bernard had made a mistake . He had let some of his dissections sit around too long and the sugar in the portal vein had been metabolized. His basic idea was right — usually, more sugar is leaving the liver than is coming in (the liver does produce glucose) but the differences are not that great and, given the methods that he had, he might have missed it. It was his error that led him to the role of metabolism and he had effectively discovered gluconeogenesis. He got it slightly wrong and had to modify his ideas later but he identified glycogen and had inadvertently brought out the idea of gluconeogenesis. Sometimes we luck out.