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Glucagon Secretion & Physiology

Notes

Glucagon Secretion & Physiology

Sections

GLUCAGON

  • Peptide hormone secreted pancreatic alpha cells
  • Counterregulatory hormone: opposes insulin action
  • Other counterregulatory hormones: epinephrine, norepinephrine, cortisol, growth hormone
  • Binds G-protein coupled receptors in specific tissues (i.e. liver)
  • Short half-life

PANCREAS

Islets of Langerhans (1-2% of pancreatic beta cells)

  • Beta cell: secretes insulin
  • Alpha cell: secretes glucagon (opposes insulin)

GLUCAGON SECRETION

Pancreatic alpha cell

  • Glucagon: single polypeptide chain
  • Preproglucagon: cleaved to produce diff. products in diff. tissues (i.e. intestinal GLP-1)
  • Preproglucagon --> --> --> glucagon

Activate secretion:

  • Low blood glucose (primary stimulus)
  • Stress hormones: (nor)epinephrine override alpha cell's response during physiologic stress
  • Amino acids: high protein meal stimulates glucagon secretion (counters insulin secretion)

INSULIN VS. GLUCAGON

  • Glucose levels maintained in tight range
  • Healthy adult fasting blood glucose: < 100 mg/dL

GLUCAGON MECHANISM OF ACTION

Hepatocytes: receptors for glucagon and epinephrine

  • Counterregulatory hormones control same processes, but respond to other stimuli (i.e. stress)
  • Muscle cells: only receptors for epinephrine NOT glucagon
  1. Binds G-protein coupled receptor on hepatic cell
  2. Alpha subunit exchanges GDP for GTP
  3. Alpha subunit activates adenylyl cylase, which activates PKA
  4. PKA phosphorylates downstream enzymes
  5. Activates glycogen & lipid breakdown, and gluconeogenesis
  6. Inhibits glycogen, protein and lipid synthesis
  • Long-term response: increases transcription of gluconeogenic enzymes (~hours/days)

CLINICAL CORRELATION

Hypoglycemia

  • Acute drop in blood glucose levels to below 60 mg/dL
  • Symptoms range from dizziness to coma and even death
  • Brain and red blood cells depend on glucose for energy

Full-Length Text

  • Here we will learn about glucagon, a regulatory hormone in metabolism.
  • To begin, start a table to learn some key features of glucagon.
  • Denote that it is a peptide hormone secreted by pancreatic alpha cells.
  • It is a counterregulatory hormone: it promotes catabolic pathways in the body that oppose the actions of insulin.
    • Denote that other counterregulatory hormones include epinephrine, norepinephrine, cortisol and growth hormone.
    • Like other counterregulatory hormones, it binds G-protein coupled receptors (not receptor tyrosine kinases like insulin) in specific tissues, primarily the liver.

We will learn each of these points and draw comparisons between glucagon and insulin as we proceed.

First, let's illustrate where and how glucagon is secreted.

  • Draw a pancreas and label a cluster of cells in its periphery "Islets of Langerhans."
    • They comprise about 1% of pancreatic cells.

Let's take a closer look at these cells.

  • Show that they include beta cells, alpha cells and blood vessels.
  • Indicate that the beta cells secrete insulin and the alpha cells secrete glucagon.
  • Thus, these two regulatory hormones are secreted in close proximity.
  • Now, draw a representative alpha cell.
  • Within it, draw a glucagon as a single polypeptide chain.
    • Note that this is unlike insulin, which comprises two polypeptide chains joined by disulfide bonds.
  • Indicate that the glucagon derives from the precursor preproglucagon, which we will not illustrate here.
  • Preproglucagon is cleaved several times to produce glucagon, much like preproinsulin.
    • As a side point, preproglucagon is cleaved to produce different products in different tissues, unlike insulin. For example, it is cleaved to produce glucagon like protein-1 in intestinal cells, not glucagon.

Now, return to our alpha cell.

  • Indicate that glucagon, like insulin, has a short half-life.
  • Show that the following factors stimulate glucagon secretion:
    • Low blood glucose, which is the primary stimulus.
    • Stress hormones
    • Amino acids.

Let's review each of these stimuli, starting with low blood glucose.

  • To begin, recall that insulin is secreted when blood glucose levels are high.
  • Glucagon is secreted when they are low.
  • Thus, imagine that insulin and glucagon are in a continuous tug of war.
    • Insulin lowers blood glucose when it is high and glucagon increases it when it is too low.
    • Write that this tug of war keeps glucose levels within a tight range. In a normal, healthy adult, fasting blood glucose is less than 100 mg/dL.
  • When would an average, healthy adult require the most glucagon secretion?
    • When he or she is asleep! During such a prolonged fast, glucagon must maintain blood glucose to prevent hypoglycemia.
  • As a clinical correlation, write that hypoglycemia, or an acute drop in blood glucose levels to below 60 mg/dl can produce symptoms ranging from dizziness to coma and even death.
    • Our brain and red blood cells depend on glucose for energy, without glucagon, they would starve every time we went to sleep!

Now for the stress hormones.

  • Indicate that epinephrine and norepinephrine override the alpha cell's response to glucose levels during periods of physiologic stress.
    • Thus, even when glucose levels are not low, alpha cells secrete glucagon.

And for amino acids.

  • Indicate that after a high protein meal, amino acids can stimulate glucagon secretion to counter the insulin that is also secreted after a high protein meal (remember the tug-of-war).

Finally, let's illustrate the mechanism of glucagon action.

  • To do this, draw the membrane of a hepatic cell with a G-protein coupled receptor (GPCR) embedded within it.
  • Now, draw adenylyl cyclase also in the membrane.
  • Step 1: Show that glucagon binds the GPCR.
  • Step 2: Indicate that this causes the alpha subunit to exchange GDP for GTP.
    • Show that the alpha subunit then activates adenylyl cyclase, which increases intracellular cAMP.
  • Step 3: Show that cAMP activates protein kinase A.
  • Step 4: Indicate that protein kinase A phosphorylates a number of downstream enzymes.
    • Show that this activates catabolic enzymes and inactivates anabolic enzymes.
  • Specifically, indicate that the following processes are activated:
  • Glycogen and lipid breakdown
  • Gluconeogenesis
  • Indicate that glycogen, protein and lipid synthesis, however, are inhibited.
    • Again, these actions oppose that of insulin, which promotes anabolic processes and glucose storage.
  • Note that the other counterregulatory hormones control the same processes, but do so in response to other stimuli.
    • For example, epinephrine activates these pathways in response to physiologic stress.
  • As an important point, indicate that our hepatocyte has G-protein coupled receptor's for both glucagon and epinephrine.
  • Next, indicate that muscle cells only have receptors for epinephrine, not glucagon!
  • To emphasize this point return to our table and denote that glucagon does not bind GPCR's in the muscle.

Now, we have covered the short-term responses of glucagon in a hepatocyte.

  • What about the long-term responses?
    • Return to our diagram and write that much like insulin, glucagon has a long-term response at the transcriptional level: it produces an increase in the number of gluconeogenic enzymes over the course of hours/days.