In my last blog I went over a study that casts some doubt on the notion that the liver is critical for blood glucose control. In this study, they found that mice who had their liver blocked from contributing to blood glucose control adapted by shifting that duty over to the kidneys and intestine(1). The assumption that the liver is king as far as blood glucose control is a fairly widely held concept due to the fact that it can store 100g of glucose and produce glucose from non-carbohydrate sources. The problem arises when you take in to account that easy access to carbohydrates is a fairly recent phenomenon. Taken together with other scientific evidence, it appears that the intestine should likely play a larger role in blood glucose regulation than it does today, and the modern diet prevents this from happening.
In this study the kidneys took on a much larger role in blood glucose regulation during times of fasting as the gene crucial for blood glucose regulation increased in expression. The intestine also saw an increase in expression of this gene, but the total expression of this gene was 50x greater in the kidney. These results may understate the importance of the intestine in blood glucose regulation, especially in the non-fasted state.
When you compare the diet of ancestral, pre-agricultural humans to that of today, one glaring difference is the fiber content of the diet. Today, the average human diet contains less than 20g of fiber per day. In his book The Story of the Human Body, Dr. Dan Lieberman's assessment of the literature points to the consumption of 100-150g of fiber per day by pre-agricultural humans. This number is in line with what previous research has shown(2) as well as Jeff Leach's experience living with modern day hunter gatherers. While the difference in fiber intake may not seem important when you consider humans don't absorb fiber, when you look at what it does to the microbiome and the effect it has on blood glucose regulation you can see that it is likely very important.
When bacteria in the intestine break down fiber, they make short-chain fatty acids(SCFAs), specifically butyrate and propionate. Both of these SCFAs promote intestinal gluconeogensis in complementary ways(3). Gluconeogenesis is the generation of blood glucose from non-carbohydrate sources and it allows the intestine to participate in blood glucose regulation through the fermentation of fiber by bacteria in the gut. Interesingly, when gluconeogenesis is shut off in the intestine, all of the metabolic benefits of a high fiber diet are lost despite having a similar microbiome. So, in a population where people consume low amounts of fiber, the intestine likely has a negligible role in regulating blood glucose. Ironically, in this population, blood glucose tends to run high. In a population where fiber is consumed in large quantities, the intestine likely takes on a much larger role in regulating blood glucose. In this population, blood glucose tends to remain low. This is not the only piece of the puzzle, however.
There is another issue that arises when bacteria in the intestine don't ferment fiber in to butyrate. Butyrate is the fuel of choice for cells of the colon(4), but they are able to metabolize glucose as well. A problem occurs when there isn't enough butyrate for the cells of the colon(Colonocytes), they must rely on glucose as a source of energy(4, 5). When colonocytes are provided enough butyrate, they break it down in to the ketone beta-hydroxybutyrate which can be further broken down for energy. When there isn't enough butyrate, they are forced to metabolize glucose which colonocytes break down in to lactate. Colonocytes cannot metabolize lactate so it is sent to the liver to undergo gluconeogenesis. In a mouse model of colitis, this is how colonocytes metabolize energy(5). Unfortunately, glucose is unable to provide enough energy for efficient gastrointestinal function in this manner(4).
In addition to having an effect on gluconeogenesis by the intestine, SCFAs also stimulate secretion of a hormone called glucagon-like peptide 1(GLP-1)(6). GLP-1 has several roles in the body, but of interest to our discussion is it's role in insulin and glucagon secretion. Insulin lowers blood glucose by causing cells to take it in while glucagon causes blood glucose to increase by increasing gluconeogenesis in the liver, kidney and intestine as well as causing those organs to release glucose. GLP-1 stimulates insulin secretion in a glucose dependent manner, when glucose levels are high GLP-1 stimulates more insulin than when glucose levels are low while it causes glucagon levels to fall independent of glucose levels. It is worthy to note that carbohydrate consumption also causes GLP-1 to be secreted, but since carbohydrate consumption will cause blood glucose levels to rise, it will cause more insulin secretion than one would see going the fiber route.
People with Type 2 diabetes tend to have a large amount of insulin in their blood, but their cells don't respond to it because they have become resistant. This causes their blood glucose to run high because insulin can't do it's job of lowering blood glucose. Since glucagon increases blood glucose and runs high in Type 2 diabetics, it is believed that lowering glucagon levels can help correct the high blood glucose levels associated with the disease. Metformin, the Type 2 diabetes medicine of choice, works by causing the liver to make less glucose, which causes the same effect as lowering glucagon. GLP-1 and drugs that mimic it accomplish the same thing, are being used as pharmaceutical therapies, and the result is lower blood glucose levels(7, 8).
The positive effect of administering GLP-1 to improve blood glucose regulation brings up a few interesting questions. Is the intestine a more important component of blood glucose regulation than we give it credit for? Is bacterial fermentation of fiber in to butyrate the first step in blood glucose regulation given how important it likely was for blood glucose regulation in ancestral humans? Finally, is administering pharmaceutical GLP-1 merely restoring an ancient signal from the intestine to the liver saying, "I have your back" with regard to gluconeogenesis and blood glucose regulation? While we are unlikely to find answers to these questions any time soon, it is very interesting that higher fiber intake is very protective against Type 2 diabetes (9, 10, 11, 12). Furthermore, people with Type diabetes tend to have more disturbances within the digestive tract than healthy people(13, 14) with the most common disturbance being constipation.
Between the evidence provided above and comparisons of the ancestral diet to our modern one, it seems likely that the modern diet may be presenting an environment that causes blood glucose to be regulated in a way that is not efficient for humans. Our long history of high fiber consumption likely selected for people who were good at using the fermentation of fiber by resident bacteria as the first step of blood glucose regulation that involved the intestine to a much larger degree than it does today. The modern diet puts a much larger burden on the liver to make and regulate blood glucose due to the high carbohydrate and low fiber content of the diet. This provides less fuel to allow the intestine to participate in blood glucose regulation and may be a contributing factor to Type 2 diabetes and the increased occurrence of GI disorders associated with the disease.
