Devilish details of glucagon regulation

One of the difficult things about teaching science (or any subject, I imagine) is deciding which details to leave out. On one hand, it’s often the details that make things interesting. On the other hand, each layer of complexity often requires more background for it to make sense, and the amount of information necessary for comprehension expands exponentially. As a result, we often present things as cut and dry when they are anything but. I imagine that this often gives students the impression that everything is known. Given that I’m teaching subjects that are a bit outside what I studied in graduate school, I sometimes get to experience this myself as I delve into the research literature. I’m often surprised to find out what we don’t know. As an example, take the regulation of the hormone glucagon.

Glucagon is a hormone produced and secreted by α-cells of the pancreas. The basic role of glucagon is to prevent low blood sugar – it helps maintain adequate levels of glucose in the blood. In effect, glucagon opposes the action of insulin. Insulin decreases blood glucose, glucagon raises it. It does this by triggering the release of glucose from the liver.

According to a common anatomy and physiology text (Tortora & Derrickson):

Decreased blood level of glucose, exercise and mainly protein meals stimulate [glucagon] secretion; somatostatin and insulin inhibit secretion.

From reading that, you might think the regulation of glucagon seems pretty straightforward. But if that’s true, then why did the Endocrine Society publish an article earlier this year by Jesper Gromada and colleagues titled “α-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains.” (The paper is available online for free as an “author manuscript pdf” here.) Clearly, things aren’t as cut and dry as the textbook leads one to believe.

So, what do we know about glucagon regulation? Before I answer that, perhaps I should mention why this is of anything more than academic interest. If you follow the news, you’ve probably heard discussions of a diabetes epidemic. NPR recently broadcast a story about type 2 diabetes showing up in people in their teens and twenties, much younger than once was common. Traditionally, diabetes is portrayed as a problem with the hormone insulin, but actually, high levels of glucagon also play a role. Moreover, problems with glucagon regulation in people with type 1 or advanced type 2 diabetes lead to problems with low blood sugar (hypoglycemia). In short, being able to control glucagon could help diabetics maintain normal blood glucose levels. (This is important because many of the complications associated with diabetes are a result of chronic high blood glucose.)

Back to what we know about glucagon regulation. From the article in Endocrine Reviews:

The control of glucagon secretion is multifactorial and involves direct effects of nutrients [like glucose and amino acids] on α-cell stimulus-secretion coupling as well as paracrine regulation by insulin and zinc as well as other factors secreted from neighboring β- and δ-cells within the islet of Langerhans. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system.

Some of that bears explaining. Paracrines can be thought of as local hormones that affect cell types different from the type of cell that made and secreted the paracrine. A regular hormone (as opposed to a paracrine) can be thought of as a circulating hormone – meaning that it circulates throughout the body, not just a local area. β- and δ-cells are other cell types in the pancreas. β-cells release insulin and δ-cells release somatostatin (somatostatin was mentioned in the textbook description of glucagon regulation). Lastly, the islets of Langerhans are clusters of cells including α-, β-, and δ-cells that make up the endocrine pancreas. It’s referred to as the endocrine pancreas because it’s the part of the pancreas that releases hormones (as part of the endocrine system). The rest of the pancreas (the exocrine pancreas) releases digestive enzymes into the small intestine.

If we know all of these things influence glucagon regulation, then what’s the enigma referred to in the article’s title? The uncertainty lies in the relative influence of the factors:

Since the early 1970’s, the mechanism underlying the regulation of glucagon secretion by glycemia has puzzled scientists. The debate continues whether α-cells directly sense and respond to fluctuations in plasma glucose or whether the response is mediated by the autonomic nervous system and/or the paracrine/endocrine effects of secretory products from other islet cell types. Currently, a large body of research favors the latter ‘paracrine/endocrine’ hypothesis.

The ‘paracrine/endocrine’ hypothesis can be summarized briefly as the idea that a drop in insulin triggers the release of glucagon. This portion of the broader paracrine/endocrine hypothesis is often called the β-cell ‘switch-off’ hypothesis because insulin is secreted by β-cells. High levels of insulin inhibit glucagon, so the decline of insulin in the blood will free α-cells from inhibition.

The rest of the paper goes over the evidence for the various controlling factors, explaining why the authors think the ‘paracrine/endocrine’ hypothesis is most likely the major factor regulating glucagon release. One complication seems to be that research conducted on different species can be difficult to compare. Apparently, there are subtle species-specific differences in glucagon regulation. Just because α-cells of mice react a certain way doesn’t necessarily mean that rats (or humans) will too. So, research on one organism doesn’t necessarily translate perfectly to other organisms.

Having written all this, however, I haven’t really gotten much beyond what the textbook said. (Perhaps a good indication that the extra detail isn’t worth going into at the level of class I teach.) But there is something that an inquiring mind still might be wondering: How does insulin prevent the α-cells from secreting glucagon?

This post is already far too long to delve into that in much detail, but the CliffsNotes version is this. The membranes around cells are impermeable to ions like potassium (K⁺), sodium (Na⁺), and calcium (Ca²⁺). It’s still possible for these ions (and others that I haven’t named) to enter cells, but they need passages (called ion channels) through the membrane. Using these channels, cells can control which ions get in and which ions get out. In doing so, the cells set up concentration gradients. For example, K⁺ ions are generally more abundant inside cells than outside them. The reverse is true for Na⁺. A result of this is the generation of an electrical potential across the cell membrane. Changes in the electrical potential can trigger changes in the activities of a cell. (A nerve impulse – the transmission of an action potential – is an example of what can happen when the electrical potential of a cell changes.)

So, to get to the point, insulin opens an ion channel in the membrane of α-cells. The opening of this ion channel changes the electrical potential of the cell, and this indirectly prevents the vessels containing glucagon inside α-cells from releasing the hormone. When insulin levels in the blood decrease, those ion channels close. This changes the electrical potential of the α-cells, and allows the vessels containing glucagon to release the hormone from the cell.

Next week, when I get some time, I’ll take up a new research paper that deals with this issue and comes to conclusions that differ from the ‘paracrine/endocrine’ hypothesis.