Glucose Regulation and Utilization in the Body

On the last page, we traced the process of digesting the carbohydrates in a slice of pizza through the gastrointestinal tract, ending up with the absorption of monosaccharides across the cells of the small intestine and into the bloodstream. From there, they travel to the liver, where fructose and galactose are converted to glucose.

After any meal containing carbohydrates, you experience a rise in blood glucose that can serve as fuel for cells around the body. But during the periods between meals, including while you're sleeping and exercising, your body needs fuel, too. To ensure that you have enough glucose in your blood at any given time, your body has a finely-tuned system to regulate your blood glucose concentration. This system allows you to store glucose when you have excess available (when your blood glucose is high) and to pull glucose out from your stores when needed (when your blood supply gets low).

Your body's ability to maintain equilibrium or a steady state in your blood glucose concentration is called homeostasis. It's a critical part of normal physiology, because if your blood glucose gets too low (called hypoglycemia), cellular function starts to fail, especially in the brain. If blood glucose gets too high (called hyperglycemia), it can cause damage to cells.


 Hormones Involved in Blood Glucose Regulation

Central to maintaining blood glucose homeostasis are two hormones, insulin and glucagon, both produced by the pancreas and released into the bloodstream in response to changes in blood glucose.

 

The image below depicts a mouse islet of Langerhans, a cluster of endocrine cells in the pancreas. The beta-cells of the islet produce insulin, and the alpha-cells produce glucagon.

A mouse pancreatic islet is seen as a cluster of cells, sitting next to a blood vessel. Cell nuclei both inside and outside the islet are stained blue so are seen as circular shapes throughout the pancreatic section. Insulin is stained red so makes the entire islet appear red. Blood vessels are stained green.

Fig. 5.1. A mouse islet of Langerhans, visualized with immunofluorescent microscopy. In this image, cell nuclei are stained blue, insulin is stained red, and blood vessels are stained green. You can see that this islet is packed with insulin and sits right next to a blood vessel, so that it can secrete the two hormones, insulin and glucagon, into the blood. Glucagon is not stained in this image, but it's there!

In the figure below, you can see blood glucose and insulin throughout a 24-hour period, including three meals. You can see that when glucose rises, it is followed immediately by a rise in insulin, and glucose soon drops again. The figure also shows the difference between consuming a sucrose-rich food and a starch-rich food. The sucrose-rich food results in a greater spike in both glucose and insulin. Because more insulin is required to handle that spike, it also causes a more precipitous decline in blood glucose. This is why eating a lot of sugar all at once may increase energy in the short-term, but soon after may make you feel like taking a nap!

The figure shows a line graph, with time over 24 hours on the x-axis and with blood glucose concentrations on the left y-axis and blood insulin concentrations on the right y-axis. The graph shows 3 peaks during the day for meals, with insulin level closely matched to glucose level. The effects of a sugar-rich meal shows a higher glucose and insulin peak and a more precipitous decline in glucose in response.

Fig. 5.2. Typical pattern of blood glucose and insulin during a 24-hour period, showing peaks for each of 3 meals and highlighting the effects of consumption of sugar-rich foods.

Let's look a little closer at how insulin works, illustrated in the figure below. Insulin is released by the pancreas into the bloodstream. Cells around the body have receptors for insulin on their cell membranes. Insulin fits into its receptors (labeled as step 1 in the figure), kind of like a key in a lock, and through a series of reactions (step 2), triggers glucose transporters to open on the surface of the cell (step 3). Now glucose can enter the cell, making it available for the cell to use and at the same time lowering the concentration of glucose in the blood.

Schematic showing insulin binding to its receptors on the cell membrane, triggering GLUT-4 glucose transporters to open on the membrane. This allows glucose to enter the cell, where it can be used in several ways.

Fig. 5.3. Insulin binds to its receptors on the cell membrane, triggering GLUT-4 glucose transporters to open on the membrane. This allows glucose to enter the cell, where it can be used in several ways.

The figure also shows several different ways glucose can be used once it enters the cell.

In addition to its role in glucose uptake into cells, insulin also stimulates glycogen and fat synthesis as described above. It also stimulates protein synthesis. You can think of its role as signaling to the body that there's lots of energy around, and it's time to use it and store it in other forms.

 

On the other hand, when blood glucose falls, several things happen to restore homeostasis.

  1. You receive messages from your brain and nervous system that you should eat. If that doesn't work, or doesn't work fast enough….

  2. Glucagon is released from the pancreas into the bloodstream. In liver cells, it stimulates the breakdown of glycogen, releasing glucose into the blood.

  3. In addition, glucagon stimulates a process called gluconeogenesis, in which new glucose is made from amino acids (building blocks of protein) in the liver and kidneys, also contributing to raising blood glucose.

How Glucose Provides Energy

Now let's zoom in on how exactly glucose provides energy to the cell. We can trace this process in the figure below.

Schematic showing an overview of glucose metabolism in the fed state, when there is adequate glucose available. Glucose can be used to generate ATP for energy (going through glycolysis, Krebs cycle, and the electron transport chain), or it can be stored in the form of glycogen or converted to fat for storage in adipose tissue.

Fig. 5.4. Overview of glucose metabolism in the fed state, when there is adequate glucose available. Glucose can be used to generate ATP for energy, or it can be stored in the form of glycogen or converted to fat for storage in adipose tissue.

  1. Glucose, a 6-carbon molecule, is broken down to two 3-carbon molecules called pyruvate through a process called glycolysis.

  2. Pyruvate enters a mitochondrion of the cell, where it is converted to a molecule called acetyl CoA.

  3. Acetyl CoA goes through a series of reactions called the Krebs cycle. This cycle requires oxygen and produces carbon dioxide. It also produces several important high energy electron carriers called NADH2 and FADH2.

  4. These high energy electron carriers go through the electron transport chain to produce ATP -- energy for the cell!

  5. Note that the figure also shows that glucose can be used to synthesize glycogen or fat, if the cell already has enough energy.

What Happens When There Isn't Enough Glucose?

We've already talked about what happens when blood glucose falls: glucagon is released, and that stimulates the breakdown of glycogen as well as the process of gluconeogenesis from amino acids. These are important mechanisms for maintaining blood glucose levels to fuel the brain when carbohydrate is limited. Hypoglycemia (low blood glucose) can cause you to feel confused, shaky, and irritable, because your brain doesn't have enough glucose. If it persists, it can cause seizures and eventually coma, so it's good we have these normal mechanisms to maintain blood glucose homeostasis!

What happens if your carbohydrate supply is limited for a long time? This might happen if a person is starving or consuming a very low carbohydrate diet. In this case, your glycogen supplies will become depleted. How will you get enough glucose (especially for the brain) and energy? You'll have to use the other two macronutrients in the following ways:

  1. Protein -- You'll continue to use some amino acids to make glucose through gluconeogenesis and others as a source of energy through acetyl CoA. However, if a person is starving, they also won't have extra dietary protein. Therefore, they start breaking down body proteins, which will cause muscle wasting.

  1. Fat -- You can break down fat as a source of energy, but you can't use it to make glucose. Fatty acids can be broken down to acetyl CoA in the liver, but acetyl CoA can't be converted to pyruvate and go through gluconeogenesis. It can go through the Krebs cycle to produce ATP, but if carbohydrate is limited, the Krebs cycle gets overwhelmed. In this case, acetyl CoA is converted to compounds called ketones or ketone bodies. These can then be exported to other cells in the body, especially brain and muscle cells.

These pathways are shown in the figure below:

Schematic showing that during starvation or when consuming a low-carbohydrate diet, protein (amino acids) can be used to make glucose by gluconeogenesis, and fats can be used to make ketones in the liver. The brain can adapt to using ketones as an energy source in order to conserve protein and prevent muscle wasting.

Fig. 5.5. During starvation or when consuming a low-carbohydrate diet, protein (amino acids) can be used to make glucose by gluconeogenesis, and fats can be used to make ketones in the liver. The brain can adapt to using ketones as an energy source in order to conserve protein and prevent muscle wasting.

Ketone production is important, because ketones can be used by tissues of the body as a source of energy during starvation or a low carbohydrate diet. Even the brain can adapt to using ketones as a source of fuel after about three days of starvation or very low carbohydrate diet. This also helps to preserve the protein in the muscle.

Ketones can be excreted in urine, but if ketone production is very high, they begin to accumulate in the blood, a condition called ketosis. Symptoms of ketosis include sweet-smelling breath, dry mouth, and reduced appetite. People consuming a very low carbohydrate diet may be in ketosis, and in fact, this is a goal of the currently popular ketogenic diet. (Ketones are acidic, so severe ketosis can cause the blood to become too acidic, a condition called ketoacidosis. This mainly happens with uncontrolled diabetes.)

Is following a ketogenic diet an effective way to lose weight? It can be, but the same can be said of any diet that severely restricts the types of foods that you're allowed to eat. Following a ketogenic diet means eating a high fat diet with very little carbohydrate and moderate protein. This means eating lots of meat, fish, eggs, cheese, butter, oils, and low carbohydrate vegetables, and eliminating grain products, beans, and even fruit. With so many fewer choices, you're likely to spend more time planning meals and less time mindlessly snacking. Being in ketosis also seems to reduce appetite, and it causes you to lose a lot of water weight initially. However, studies show that being in ketosis doesn't seem to increase fat-burning or metabolic rate. There are also concerns that the high levels of saturated fat in most ketogenic diets could increase risk of heart disease in the long term.  Finally, it's a very difficult diet to maintain for most people, and reverting back to your previous dietary patterns usually means the weight will come back. The ketogenic diet is also very similar to the Atkins diet that was all the rage in the 1990's, and we tend to be skeptical of such fad diets, preferring to focus instead on balance, moderation, and enjoyment of a wide variety of foods.

The following video reviews the concepts just covered: Glucose Regulation and Utilization in the Body

Diabetes

Diabetes is a chronic disease in which your normal system of regulating blood glucose doesn't work. There are three main types of diabetes: type 1, type 2, and gestational diabetes.

Type 1 Diabetes:

This is an autoimmune disease in which the beta-cells of the pancreas are destroyed by your own immune system. Without the beta-cells, you can't make enough insulin, so in type 1 diabetes, you simply don't have enough insulin to regulate your blood glucose levels. Remember how we said insulin is like the key that lets glucose into the body's cells? In type 1 diabetes, you're missing the key, so glucose stays in the blood and can't get into cells.

Schematic showing that in type 1 diabetes, the pancreas does not make enough insulin, so glucose transporters (GLUT-4) do not open on the cell membrane, and glucose is stuck outside the cell.

Fig. 5.6. In type 1 diabetes, the pancreas does not make enough insulin, so glucose transporters (GLUT-4) do not open on the cell membrane, and glucose is stuck outside the cell.

Common symptoms include weight loss and fatigue, because the body's cells are starved of glucose. Excess glucose from the blood is also excreted in the urine, increasing urination and thirst.

Once diagnosed, type 1 diabetics have to take insulin in order to regulate their blood glucose. Traditionally, this has required insulin injections timed with meals. New devices like continuous glucose monitors and automatic insulin pumps can track glucose levels and provide the right amount of insulin, making managing type 1 diabetes a little easier. Figuring out the right amount of insulin is important, because chronically elevated blood glucose levels can cause damage to tissues around the body. However, too much insulin will cause hypoglycemia, which can be very dangerous.

Type 1 diabetes is most commonly diagnosed in childhood, but it has been known to develop at any age. It's much less common than type 2 diabetes, accounting for 5-10% of cases of diabetes.

The following video, from the charity Diabetes UK, provides a nice review of type 1 diabetes: https://youtu.be/C3AQIfgthh4

Type 2 Diabetes:

Development of type 2 diabetes begins with a condition called insulin resistance. At least initially, the pancreas is producing enough insulin, but the body's cells don't respond appropriately. It's as if you still have the insulin key but can't find the keyhole to unlock the doors and let the glucose in.

Schematic showing that in type 2 diabetes, the cell does not respond appropriately to insulin, so glucose is stuck outside the cell.

Fig. 5.7. In type 2 diabetes, the cell does not respond appropriately to insulin, so glucose is stuck outside the cell.

The result is the same: high blood glucose. At this point, you may be diagnosed with a condition called prediabetes. The pancreas tries to compensate by making more insulin, but over time, it becomes exhausted and eventually produces less insulin, leading to full-blown type 2 diabetes. According to the CDC, 100 million Americans are living with diabetes (30.3 million) or prediabetes (84.1 million).

Although people of all shapes and sizes can get Type 2 diabetes, it is strongly associated with abdominal obesity. In the past, it was mainly diagnosed in older adults, but it is becoming more and more common in children and adolescents as well, as obesity has increased in all age groups. In the maps below, you can see that as obesity has increased in states around the country, so has diabetes.   

The figure shows maps of the U.S. from 1994, 2000, and 2015, showing that the prevalence of both obesity and type 2 diabetes have increased over time. In general, states with greater obesity also have greater incidence of type 2 diabetes.

Fig. 5.8. Data from the CDC show the increasingly prevalence of both obesity and type 2 diabetes between 1994 and 2015.

The complications of type 2 diabetes result from long-term exposure to high blood glucose, or hyperglycemia. This causes damage to the heart, blood vessels, kidneys, eyes, and nerves, increasing the risk of heart disease and stroke, kidney failure, blindness, and nerve dysfunction. People with uncontrolled Type 2 diabetes can also end up with foot infections and ulcers because of impaired nerve function and wound healing. If left untreated, this results in amputation.

This video, also from Diabetes UK, reviews the causes, complications, and treatments for type 2 diabetes: https://youtu.be/4SZGM_E5cLI

The link between obesity and type 2 diabetes is explored in this video, part of the Weight of the Nation series by HBO: https://youtu.be/l5rYq-G1A5M

Gestational diabetes:

Gestational diabetes is diabetes that develops during pregnancy in women that did not previously have diabetes. It affects approximately 1 to 2 percent of pregnancies in the U.S. It can cause pregnancy complications, mostly associated with excess fetal growth because of high blood glucose. Although it usually goes away once the baby is born, women who have gestational diabetes are more likely to develop type 2 diabetes later in life, so it is a warning sign for them.

This video from Kahn Academy does a nice job of explaining the causes of the different types of diabetes: https://youtu.be/c9LwwQK5588

Diabetes Management:

All of the following have been shown to help manage diabetes and reduce complications. Diabetes management, as well as prevention (particularly if you've been diagnosed with prediabetes), starts with lifestyle choices.

Self Check

How does your body respond to high blood glucose? (Select all that apply)

[mark all correct answers]

 
 
 
 
 
 

When might ketone production be high? (Select all that apply)

[mark all correct answers]

 
 
 
 

There is strong evidence that a ketogenic diet is a superior eating pattern for weight loss and a good choice for most people for the long term.

 
 

Match the items.

The task is to match the lettered items with the correct numbered items. Appearing below is a list of lettered items. Following that is a list of numbered items. Each numbered item is followed by a drop-down. Select the letter in the drop down that best matches the numbered item with the lettered alternatives.

a. An autoimmune disease in which the immune system attacks the pancreas and there is not enough insulin production.

b. Begins with insulin resistance and strongly associated with obesity.

c. Develops in pregnancy.

 

People with diabetes should eliminate carbohydrates from their diet as much as possible.

 
 

References

  1. Salway, J.G., Metabolism at a Glance, Blackwell Publishing, 2004.

  2. Smolin, L. and Grosvenor, M. 2016. Nutrition Science and Applications. John Wiley and Sons.

  3. Gibson, A.A. et al. 2015. Do ketogenic diets really suppress appetite? A systematic review and meta-analysis, Obesity Reviews, 16(1):64-76, https://www.ncbi.nlm.nih.gov/pubmed/25402637

  4. Hall, K.D. et al. 2016. Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men. Am. J. Clin. Nutr. 104(2):324-33. https://www.ncbi.nlm.nih.gov/pubmed/27385608

  5. Abassi, J. 2018. Interest in Ketogenic Diet Grows for Weight Loss and Type 2 Diabetes, JAMA 319(3):215-217. https://jamanetwork.com/journals/jama/article-abstract/2669724

  6. Belluz, J. 2018. The Keto Diet, Explained. Vox.com, https://www.vox.com/science-and-health/2018/2/21/16965122/keto-diet-reset

  7. CDC, Diabetes Basics, https://www.cdc.gov/diabetes/basics/index.html

Image Credits

  1. Fig. 4.1. Mouse islet image by Jakob Suckale, Wikipedia, CC BY-SA 3.0

  2. Fig. 4.2. Glucose/insulin patterns in 24-hours figure by Jakob Suckale and Michele Solimena, CC BY 3.0, https///commons.wikimedia.org/wiki/File/Suckale08_fig3_glucose_insulin_day.png.

  3. Fig. 4.3. Insulin action figure by Meiquer, Wikipedia, CC BY-SA 3.0, with additions by Alice Callahan, CC BY-NC-SA 4.0

  4. Fig. 4.4. Glucose metabolism figure by Alice Callahan, CC BY-NC-SA 4.0, with ATP star by Anastasia Latysheva from the Noun Project

  5. Fig. 4.5. Gluconeogenesis and ketogenesis figure by Alice Callahan, CC BY-NC-SA 4.0, with brain by monstara and liver by maritacovarrubias, both from Open Clip Art, public domain

  6. Figs. 4.6 and 4.7 by Brian Lindshield, from "Kansas State University Human Nutrition (FNDH 400) Flexbook" (2018). NPP eBooks. 19.

  7. Fig. 4.8 from CDC, public domain, https://www.cdc.gov/diabetes/data/center/slides.html

 


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