Glucagon…Insulin’s Partner

If you run a search on the internet for the word “glucagon,” then follow it up with a search for the term “insulin,” it is easy to see which receives all the attention based on the search results. Insulin is what diabetics are most concerned about on a day-to-day basis, but glucagon plays an important role in the blood sugar control process too. In fact, the glucagon hormone plays a very significant role in diabetes and therefore is every bit as important as insulin. Research has begun to explore this role in depth in terms of protein metabolism[1] and how insulin and glucagon interact.[2]

Though the medical aspects of the intimate relationship of glucagon and insulin are complex, having a basic understanding of how your body is working to maintain the appropriate blood glucose levels is important.

What is Glucagon?

Glucagon is a counter regulatory hormone produced in the alpha cells (α-cells) of Langerhan’s insula or islet.[3] The islets are scattered throughout the pancreas. They consist of three major types of cells:

  • Alpha cells – produce the hormone glucagon which raises blood glucose levels
  • Beta cells – produce insulin which lowers blood glucose levels
  • Delta cells – produce the hormone somatostatin which is believed to influence action of alpha and beta cells

All three, as research indicates, interact and react with each other in response to blood sugar when it reaches a specific level.[4] The alpha cells, or A cells, are small in number. The glucagon produced by the alpha cells in the pancreas act on the liver leading to the conversion of glycogen into glucose which is why blood glucose levels are raised during this conversion process. Beta cells are the glucose detectors and will produce insulin when detecting that blood glucose levels are rising. The delta cell hormone production is believed to react with the alpha and beta cells as the hormone reduces the rate of intestinal food absorption.

  • Glucose enters the bloodstream after eating
  • The glucose is stored in the liver as glycogen (glycogenesis)
  • Blood sugar levels decline
  • Liver uses glucagon to convert glycogen back to glucose (glycogenolysis)
  • Glucose re-enters the bloodstream
  • When reserves of glucose are exhausted, amino acids and certain forms of carbohydrates are synthesized into glucose (gluconeogenesis)

Studies clearly indicate that glucagon responds to low levels of blood sugar as it attempts to maintain a steady level of glucose in the bloodstream. This is referred to as the process of glucose homeostasis.[5] Glucose homeostasis is merely the complex process in which just the right amount of glucose level is maintained. The specific goal of glucagon then is to prevent hypoglycemia – severe, low blood glucose.

Exploring the Process of Glucose Generation Further

A liver in healthy condition converts excess glucose into glycogen. In doing so, it is retaining a certain back-up amount of ready energy in the form of glycogen. When it is necessary, glucagon acts as the catalyst to reverse the energy storage so that energy is released. The liver takes all the glycogen it has in storage, exhausts the supply and makes it available to the bloodstream.

After the process of conversion from glycogen to glucose in the liver seems to be complete, glucagon continues to work. In other words, just because the liver has used up all of the glycogen reserves, amazingly it continues to produce glucose. Except now it accomplishes this by setting into motion specific mechanisms that synthesizes glucose from other building blocks. This is the pathway referred to as gluconeogenesis.

The Liver and Fat and Protein Metabolism

The liver, which plays such a large role in glucose production, also is involved in fat metabolism. In basic terms, the liver is the most important site in the body for converting both proteins and carbohydrates into triglycerides and fatty acids.  The converted material is then transported to and stored in adipose tissue as fat.

Diabetics are known to experience one or more of three fat metabolism disturbances as a result of their disease. The first disturbance is the impairing of fatty acid synthesis. A person with this disturbance will experience severe loss of weight or emaciation which is why this is considered a symptom of diabetes.

The second possible disturbance is the accumulation of fats or lipids in different tissues throughout the body. This leads to excessive weight gain, fatty liver, heart disease and other fat related health conditions.  These are more symptoms of diabetes.

The third fat metabolism disturbance is characterized by an increase in the release of tissue stored fat. In this case triglycerides tend to rise in what is called lipolysis. The fatty acids are released from the liver due to glucagon activated pancreatic enzymes called lipase within adipose or fatty tissues. Therefore, high triglycerides also qualify as a diabetes symptom.

Another simple way to look at this process is that a person who doesn’t eat for a while experiences a reduction in fatty acid synthesis. When the diabetic eats some carbohydrates, the process of reduction is reversed. In a diabetic it appears that their physical response to carbohydrates is exaggerated. Glucose is not utilized and something akin to carbohydrate starvation or deficiency develops.

The liver also is involved in protein metabolism. Protein amino acids are converted to glucose or lipids through enzyme action. That is why liver enzymes are measured to determine if liver damage has occurred.

Glucagon Secretion – Controlling Factors

The major trigger spurring glucagon into action is very specific. The trigger is the amount of sugar in the blood stream. If blood glucose levels are high, glucagon will not respond and thus glucose is not produced. However, when the blood sugar level after a fasting period (like when someone doesn’t eat for a while) is equal to or falls below 60 mg/dl, glucagon gets to work triggering the production of glucose in an attempt to restore the right glucose levels. It increases glucose secretions in order to prevent hypoglycemia (too little blood sugar.)

While the same trigger, a blood glucose level, produces an insulin reaction, the reaction is different from that of glucagon in the liver. Insulin is a reaction to high blood glucose and is produced by pancreas beta cells; glucagon reacts to low blood glucose and is produced by pancreas alpha cells.  The ultimate goal of both reactions is to produce normal blood glucose levels. However, neither insulin nor glucagon ever completely stops no matter what the glucose level in the bloodstream may be. The hormones are secreted at a basal level, meaning they are secreted even when blood glucose levels are correct.

Another possible stimulus for glucagon is an increase in the levels of sugar in the blood that occurs when an individual is exercising. The exact mechanisms are not yet fully understood though. It is not yet certain which of two factors actually stimulates glucagon. Is it the exercise itself or the depletion of glucose through exercise which causes the triggering of glucagon?  More research is needed and ongoing.

What is known is that, if you want to inhibit the secretion of glucagon, you can do so by increasing the level of blood sugar. This can be done through diet or through drugs. Your body may also call upon another hormone to go into action – the somatostatin produced by the delta cells mentioned earlier and which also reside in the islets of Langerhan in the pancreatic duct system.

Conclusion

Glucagon is a pancreatic hormone which works to raise blood sugar when necessary. Produced by the alpha cells, it is triggered when blood sugar is detected as being too low. Glucagon does not act alone in regulating glucose homeostasis though. It works in conjunction with insulin hormones. However, a lot more research needs to be done to gain a better understanding of how glucagon and insulin interact so that more effective means of control in diabetics can be achieved.

 

References

[1] Scot R Kimball, SR; Siegfried, BA; and Jefferson, LS (2004) Glucagon Represses Signaling through the Mammalian Target of Rapamycin in Rat Liver by activating AMP-Activated Protein Kinase. The Journal of Biological Chemistry, 279 (52):54103-9.

[2] Baum, JI; Kimball, SR; and Jefferson, LS (2009). Glucagon acts in a Dominant Manner to Repress Insulin-Induced Mammalian Target of Rapamycin Complex 1 Signaling in Perfused Rat Liver. American Journal of Physiology Endocrinology and Metabolism, 297 (2): E410-E415.

[3] Henquin, J-C; Accili, D; Ahrén, B; Boitard, C; Seino, S; and Cerasi, E (2011). Long in the Shade, Glucagon Re-Occupies Centre Court. Diabetes, Obesity and Metabolism, 13 (Suppl. 1): v-viii.

[4] Hellman, B; Albert Salehi, Gylfe, E; Dansk, H; and Grapengiesser, E (2009).  Glucose Generates Coincident Insulin and Somatostatin Pulses and Antisynchronous Glucagon Pulses from Human Pancreatic Islets. Endocrinology, 150 (12):5334-5340.

[5] Bansal, P; and Wang, Q (2008). Insulin as a Physiological Modulator of Glucagon Secretion.  American J Physiology Endocrinology and Metabolism, 295 (Oct.):E751-E761.

[6]  Murray, R.K;  Bender, DA; Botham, KM; Kennelly, PJ; Rodwell, VW; and Weil, PA (2009). Harper’s Illustrated Biochemistry 28th ed. New York: Lange McGraw Hill.

This article was originally published July 12, 2012 and last revision and update of it was 9/10/2015.