Our body’s priority is preventing hypoglycemia, not hyperglycemia

An adult human has about 5 l of blood in circulation. Considering a blood glucose concentration of 100 mg/dl, this translates into a total amount of glucose in the blood of about 5 g (5 l x 0.1 g / 0.1 l). That is approximately a teaspoon of glucose. If a person’s blood glucose goes down to about half of that, the person will enter a state of hypoglycemia. Severe and/or prolonged hypoglycemia can cause seizures, comma, and death.

In other words, the disappearance of about 2.5 g of glucose from the blood will lead to hypoglycemia. Since 2.5 g of glucose yields about 10 calories, it should be easy to see that it does not take much to make someone hypoglycemic in the absence of compensatory mechanisms. An adult will consume on average 6 to 9 times as many calories just sitting quietly, and a proportion of those calories will come from glucose.

While hypoglycemia has severe negative health effects in the short term, including the most severe of all - death, hyperglycemia has primarily long-term negative health effects. Given this, it is no surprise that our body’s priority is to prevent hypoglycemia, not hyperglycemia.

The figure below, from the outstanding book by Brooks and colleagues (2005), shows two graphs. The graph at the top shows the variation of arterial glucose in response to exercise. The graph at the bottom shows the variation of whole-body and muscle glucose uptake, plus hepatic glucose production, in response to exercise. The full reference to the Brooks and colleagues book is at the end of this post.

Note how blood glucose increases dramatically as the intensity of the exercise session increases, which means that muscle tissue consumption of glucose is also increasing. This is particularly noticeable as arm exercise is added to leg exercise, bringing the exercise intensity to 82 percent of maximal capacity. This blood glucose elevation is similar to the elevation one would normally see in response to all-out sprinting and weight training within the anaerobic range (with enough weight to allow only 6 to 12 repetitions, or a time under tension of about 30 to 70 seconds).

The dashed line at the bottom graph represents whole-body glucose uptake, including what would be necessary for the body to function in the absence of exercise. This is why whole-body glucose uptake is higher than muscle glucose uptake induced by exercise; the latter was measured through a glucose tracing method. The top of the error bars above the points on the dashed line represent hepatic glucose production, which is always ahead of whole-body glucose uptake. This is our body doing what it needs to do to prevent hypoglycemia.

One point that is important to make here is that at the beginning of an anaerobic exercise session muscle uses up primarily local glycogen stores (not liver glycogen stores), and can completely deplete them in a very localized fashion. Muscle glycogen stores add up to 500 g, but intense exercise depletes glycogen stores locally, only within the muscles being used. Still, muscle glycogen use generates lactate as a byproduct, which is then used by the liver to produce glucose (gluconeogenesis) to prevent hypoglycemia. The liver also makes some glycogen (glycogenesis) during this time. This means that it is not only pre-exercise liver glycogen that is being used to maintain blood glucose levels above whole-body glucose uptake. This makes sense, since the liver stores only about 100 g of glycogen.

The need to prevent hypoglycemia at all costs is the main reason why there are several hormones that increase blood glucose, while apparently there is only one that decreases blood glucose. Examples of hormones that increase blood glucose are cortisol, adrenaline, noradrenaline, growth hormone, and, notably, glucagon. The only hormone that decreases blood glucose levels in a significant way is insulin. These hormones do not increase or decrease blood glucose directly; they signal to various tissues to either secrete or absorb glucose.

Evolution typically prioritizes processes that have a higher impact on reproductive success, and one must be alive to successfully reproduce. Hypoglycemia causes death. Often those processes that have a significant effect on reproductive success rely on redundant mechanisms. So our evolved mechanisms to deal with hypoglycemia are redundant. Evolution is not an engineer; it is a tinkerer!

What about hyperglycemia – doesn’t it cause death? Well, not in the short term, so related selection pressures were fairly small compared to those associated with hypoglycemia. Besides, there were no foods rich in refined carbohydrates and sugars in the Paleolithic - e.g., white bread, bagels, doughnuts, pasta, cereals, fruit juices, regular sodas, table sugar. Those are the foods that contribute the most to hyperglycemia.

Reference:

Brooks, G.A., Fahey, T.D., & Baldwin, K.M. (2005). Exercise physiology: Human bioenergetics and its applications. Boston, MA: McGraw-Hill.