Everything You Need to Know About Blood Glucose Homeostasis

In the body, both too little and too much glucose can have negative consequences for metabolic health. Whether you’ve just eaten a large meal or have been fasting for many hours, it’s easy to take for granted all your body does behind the scenes to help keep your blood sugar levels stable.

The process by which the body works to maintain this balance in the face of our ever-changing environment is known as blood glucose homeostasis.

So, what exactly does this process involve? Let’s take a look! 

What is Blood Glucose Homeostasis?

One of the main ways your body works to keep you alive and thriving is through ensuring your blood sugar levels stay within a tight range required to keep your cells fueled without flooding them with too much fuel.

When you eat, you often consume far more calories than are required to keep you alive during the short time you are eating. You also naturally fast for longer periods of time while sleeping or experiencing times of scarcity. In both cases, the body’s priority is the same: stability and balance of blood glucose levels.

Even in the absence of foods providing glucose and energy through glucose metabolism and processes such as glycolysis, some tissues still demand a continuous glucose supply. These include parts of the kidney and eye, brain, red blood cells, testes, and skeletal muscles during exercise.

Glucose is the primary source of fuel for the brain in both the fed and fasted states with the exception of extended fasting, in which case the brain can begin to metabolize ketones. Some sources suggest that the brain will use roughly 70 percent of the total glucose made by the liver during a fasting period.

So, how does your body maintain this balance within such a dynamic environment full of unpredictable fluctuations? To better understand glucose utilization and regulation in the body, we’ll break the process down into four main phases.

The Four Phases of Blood Glucose Homeostasis

The phases of blood glucose homeostasis are sometimes referred to as the Fed/Fast Cycle. The different phases can be broken down into four parts, including: 

• The Fed State 
• The Post-Absorptive State
• The Fasting State
• The Prolonged Fasting State or Starvation State

Below, we’ll take a closer look at what each of these phases involves and how they are unique.  

1) The Fed State (Absorptive State)

This is the phase where food intake begins and lasts until around three hours after eating. Pancreatic beta cells will produce insulin and insulin levels start to rise.

Insulin helps the body move glucose from the blood into the cells. Your body’s release of insulin depends on many things, such as the presence of carbohydrates and protein in your meal and how your pancreas is functioning. If you have insulin resistance, your cell receptors have a difficult time responding to the action of insulin.

Insulin will have many jobs to do in the fed state. The effects of insulin includes:

• Assisting the muscles and liver with glucose uptake

• Helping the muscle and liver to make glycogen from unused glucose
• Stopping the liver and muscle from breaking down any glycogen stores they already have

The glucose that comes from ingestion of carbohydrates entering the blood is first grabbed up by the red blood cells (RBCs) and central nervous system (CNS) after passing through the liver. Both the RBCs and CNS use that glucose to make energy immediately. 

However, the liver will convert some leftover postprandial (or unused) glucose to glycogen. When glycogen capacity is maxed out, the liver is also capable of turning glucose into fatty acids, which can then be stored in adipose or fat tissue. This allows the body to keep a source of fuel stashed away later down the line if needed. 

Muscle is also a welcoming destination for incoming glucose and will happily use it as needed to produce energy required for muscle contractions as well as to store away as glycogen until needed in the future. 

2) Early Fasting (Post-Absorptive State)

This phase begins around three hours post-meal and continues to around 12 to 18 hours post-meal. The body no longer has access to glucose coming in directly from food you are eating and instead begins making glucose from other sources. It does this in two ways:

• Glycogenolysis. Think of this as two words = glycogen (the storage form of glucose) and lysis (to split apart, or break). This process involves the breakdown of stored glycogen and the release of glucose. This will focus mainly on the breakdown of liver glycogen stores. Glycogenesis is the opposite process: the synthesis of glycogen from glucose.‍
• Gluconeogenesis. You can think of this as three words = gluco (relating to glucose), neo (new), and genesis (the beginning or start of something). This is the process of creating new glucose molecules from non-carbohydrate sources like amino acids and other compounds.

Initially in this phase, glycogenolysis, or the breakdown of our glycogen stores, is the primary source of glucose for most people. Eventually, both glycogenolysis and gluconeogenesis will be happening simultaneously. Then, once glycogen reserves are depleted, gluconeogenesis will become the primary pathway for making glucose. 

For those who may follow a very low carb or keto diet, their glycogen stores may be lower compared to someone eating a relatively higher carb diet and this may mean that gluconeogenesis begins a lot sooner than it otherwise might. 

Some estimates suggest that around 54 percent of glucose comes from gluconeogenesis after 14 hours of fasting.

3) The Fasting State 

When your body has been fasting between 18 and 48 hours, you have officially arrived at the fasting state. Insulin levels drop and glucagon, produced by pancreatic alpha cells, begins to rise. Glucocorticoids like your primary stress hormone, cortisol, also increase.

Here, researchers have found the percentage of glucose coming from gluconeogenesis rises to 64 percent after 22 hours and then up to 84 percent after 42 hours. Alongside the liver, the kidneys lend a hand and participate in roughly 40 percent of overall gluconeogenesis activity. 

For gluconeogenesis, the body relies on compounds such as lactate, glycerol, glucogenic amino acids, and certain fatty acids as glucose sources. Glucogenic amino acids are specific amino acids that have the special ability to be converted into glucose. These include methionine and valine, among others.

Muscle protein breakdown or catabolism is a main supplier of these amino acids. Not all amino acids are glucogenic. Fatty acids once stored as triglycerides are now on the move, released from fat stores to provide additional energy. 

4) The Prolonged Fasting State or Starvation State

As your body enters a much longer period of fasting beyond 48 hours, there’s a more urgent need to preserve vital body proteins and prevent their ongoing breakdown. The proteins that must be preserved for their life-sustaining functions include immune system antibodies, certain enzymes, hemoglobin, and others.

This protein-sparing shift further increases lipolysis, or breakdown of fat stores (lipo = fat; lysis = break apart). Fatty acids along with ketones become the main source of fuel. Survival at this point will rely heavily on stored fat or lipid from adipose tissue.

Interestingly, higher levels of ketones may begin to stimulate insulin release while inhibiting the breakdown of fats to some degree. This may partially be why we may see weight loss in the first one to five days of fasting come in around one to two kilograms per day and then slow to an average of 0.3 kilograms per day over the following three weeks.

As mentioned earlier, the initial rapid weight loss may also largely be due to changes in salt and water concentrations and storage. It’s important to also consider that a lot of the research that has looked at this stage of fasting has mostly involved obese study subjects. 

Some of these processes may be altered to varying degrees in those who have lower body fat percentages. We also see higher risks for other health concerns arise in the starvation state, such as:

• Impaired endocrine function, including sex hormone and thyroid function
• Organ function impairment, including cardiac risks
• Loss of bone density
• Impaired cognitive function

And, of course, the risk of death is high if starvation continues past a certain point. 

Hormones Involved in Glucose Homeostasis

As we already know, insulin and glucagon play a central role in glucose homeostasis. Below we’ll explore some of the other hormones involved in this fascinating orchestra.

Cortisol

Cortisol is a hormone produced by the adrenal glands. You may recognize cortisol as your primary stress hormone, though it also plays an important role in modulation of the immune response and inflammation and other functions of metabolism.

Cortisol is a catabolic hormone, which means that its release will encourage your body to break down certain things like protein and glycogen stores. 

Epinephrine

When you hear people talk about adrenaline, they’re actually talking about epinephrine. Considered both a neurotransmitter and hormone, epinephrine is released when the body enters the “fight or flight” mode under acute stress.

This powerful compound is primarily made in the adrenal glands, but small amounts are also released from the ends of certain nerves. Epinephrine typically causes glucose to rise (from promoting the breakdown of glycogen stores).

It also increases free fatty acids in the blood (from promoting the breakdown of fat stores) to be used by the body as fast fuel in times of urgency. Epinephrine may also raise your blood pressure and heart rate. 

Amylin

Amylin is a hormone that, like insulin, is made primarily in the pancreas beta cells. Amylin regulates glucose homeostasis by slowing stomach emptying, inhibiting the release of the glucagon and inducing a sense of fullness after eating. This hormone helps protect against overeating and meal glucose spikes. 

GLP-1

GLP stands for glucagon-like peptides. GLP-1 is a peptide hormone made by the small intestine and helps reduce glucose levels by stimulating insulin and reducing glucagon secretion. 

lt also slows stomach emptying, so less glucose from food is released into the bloodstream. GLP-1 agonists are a class of medications often used in treatment of diabetes mellitus (or more specifically, type 2 diabetes).

Which Systems are Involved in Blood Glucose Homeostasis?

To summarize what we’ve described earlier, many different organs and glands are involved in this process, such as the brain, liver, gastrointestinal tract, and pancreas. 

There are 3 main systems participating in the dance of glucose homeostasis:

• The Nervous System
• The Endocrine System
• The Vascular System

The Nervous System

The nervous system is often considered the main communication system in the human body, though it’s not the only one. It uses specialized cells called neurons to send and receive electrochemical messages throughout the body. This communication helps you sense your environment and perform every activity necessary for life.

The Endocrine System

This is your hormonal system. Apart from other functions in the body, certain hormones such as testosterone can affect insulin sensitivity.

Hormones are chemical messengers that travel through the bloodstream to communicate with and regulate many vital life-sustaining processes. They are produced by endocrine glands such as the adrenal glands, ovaries, testes, pancreas, pituitary, thyroid, and more. 

The Vascular System

The vascular system is your primary transport system in the body, ferrying chemical substances of all kinds, including oxygen, nutrients, hormones, and other important molecules to and from different locations. 

These systems work very closely together to harmonize and overlap. The vascular system is influenced by the nervous and endocrine systems and the nervous and endocrine systems are in turn influenced by vascular function. 

They act as a collaborative unit that helps govern everything about how our body adapts to everyday life, including glucose homeostasis. 

How Do You Support Blood Glucose Homeostasis?

You can now see how the body is hard at work to maintain healthy glucose levels 24/7. So, what can you do to help support this process?

Hyperglycemia and hypoglycemia are both conditions we may be able to influence significantly with diet and lifestyle changes. Regulation of blood glucose can also help support good cardiovascular health, lower the risk of obesity and type 2 diabetes mellitus.

To read more about how to understand normal glucose levels and the diet and lifestyle choices that may impact them, check out our journal!