Reinforcing that diabetes management is complex, research from Sweden’s Uppsala University confirms that people with type 2 diabetes produce too much glucagon in addition to producing too little insulin.

Past research already established that a significant 60 percent of people with type 2 diabetes are challenged by “beta-cell dysfunction” which means their pancreas does not produce enough insulin. This latest research looks at how the “alpha-cell” function is also impaired with type 2 diabetes.

The research team set out to determine if the cells responsible for glucagon production were dysfunctional on their own or if once separated from other pancreatic tissue, they would be able to properly regulate glucagon output again.

Let’s take a closer look.

What is Glucagon?

Glucagon is a hormone secreted by alpha-cells produced by your pancreas.  Insulin, on the other hand, is produced by the beta-cells in your pancreas.

Glucagon is a hormone that tells your liver to release glycogen, sugar from your bloodstream that has been stored in your liver as back-up fuel to keep your brain functioning.  When glycogen is released it is converted into glucose, enters your bloodstream, and provides your body with that additional fuel. 

Glucagon essentially prevents low blood sugar levels in non-diabetic healthy people by providing that second-by-second supply of glycogen when you are between meals, exercising, or asleep.

Glucagon counteracts the effects of insulin by instructing the liver to release stored glucose into the blood.”

Normal and Non-Normal Function

After eating, your body is supposed to block the release of glucagon to prevent the unnecessary release of glycogen from the liver. 

In non-diabetic people, insulin signals the body to absorb glucose to provide energy to tissues and stops the release of glycogen, thereby reducing sugar in the blood. 

This process fails in diabetic patients and too much glucagon contributes to a vicious cycle that boosts their already high blood sugar levels.  

Study Methods

The study first conducted experiments to demonstrate that:

• Glucagon production is highest when blood sugar levels are lower (like between meals, during exercise, and when you’re sleeping)
• Higher blood sugar levels (like after eating a meal) block the release of glucagon

In people with type 2 diabetes, this regulatory process is ‘disturbed’ and high blood sugar levels were no longer properly blocking the release of glucagon. 

To test this theory, researchers at Uppsala did the following:

• Separated alpha-cells from the other pancreatic tissue
• Test the behavior of these isolated alpha-cells and found that they secreted glucagon even when blood sugar levels were still high. 

This confirmed that those alpha-cells are dysfunctional, much like the beta-cells responsible for insulin production.

Study Findings

In patients with type 2 diabetes, the glucose-absorbing tissues become resistant to insulin which leads to elevated blood glucose. 

The ongoing production of glucagon by alpha-cells is normally blocked by insulin.  In a person with diabetes, this cell-to-cell communication is lost and glucagon secretion proceeds even when it should not.

One would assume, however, that once the alpha-cells are separated from the other pancreatic tissue, that they would behave normally. And this wasn’t the case.

“It turns out that the αlpha-cells in type 2 diabetes become resistant to insulin, much like liver, fat, and muscle,” explains the study. 

The result is that glucagon release is no longer inhibited during the mealtime rise in blood glucose, and this leads to elevated levels of the hormone in type 2 diabetes.”

Liver Signaling Medications

There are two classes of drugs in today’s market that tell your liver to produce less glycogen (sugar). DPP-4 Inhibitors and biguanides. 

DPP-4 Inhibitors (dipeptidyl peptidase-4 inhibitors)

• Januvia (sitagliptin)
• Nesina (alogliptin)
• Onglyza (saxagliptin)
• Tradjenta (linagliptin)

DPP-4 Inhibitors reduce your liver’s release of glycogen and increase your pancreas’ insulin production.

Biguanides

• Glucophage (metformin)
• Glucophage Extended-Release (metformin XR)

Biguanides reduce your liver’s release of glycogen and increase your sensitivity to the insulin you do produce.

Common side-effects of both drug types include upset stomach, gas, diarrhea, heartburn, and muscle weakness. Taking the “XR” (eXtended Release) version of metformin can significantly help alleviate these digestive symptoms

Causality

Does diabetes damage beta & alpha-cell function or does something else damage the beta and alpha cells which then causes diabetes?

In the ongoing effort to better treat, prevent, “reverse,” and cure type 2 diabetes, researchers must study the foundation cause. 

• Do lifestyle habits and weight-gain damage the healthy production and function of beta-cells and alpha-cells? 
• Does something first damage the production and function of those cells and that, in turn, leads to higher blood sugar levels and a diabetes diagnosis?

Far more is known about beta-cell function and dysfunction than alpha-cell function.

The relationship between beta-cell function and insulin resistance still comes with many questions despite extensive research.

“Beta-cell dysfunction and insulin resistance are inherently complex with their interrelation for triggering the pathogenesis of diabetes also somewhat undefined,” explains 2013 research. “Both pathogenic states induce [high blood sugar levels] and therefore increase insulin demand.” 

As the cells have decreased ability to sense rising levels of glucose, the pancreas produces more insulin to help manage blood sugar levels, until the demand for insulin is more than the body can sustain.

But where does alpha-cell dysfunction fit into this picture?

Some research suggests that while the dysfunction in the alpha-cells’ response to glucose may actually contribute to the dysfunction of beta-cells, the dysfunction starts with beta-cells. 

With this understanding, Uppsala hopes their latest research will continue to aid in the development of more effective treatment options for people with type 2 diabetes.