Courtney Stanczak

Dr. Huffman
Biochemistry 361
11 November 2016
Literature Project
1) Li, C., Liu, C., Nissim, I., Chen, J., Chen, P., Doliba, N., Naji, A. (2013). Regulation
of Glucagon Secretion in Normal and Diabetic Human Islets by -Hydroxybutyrate and
Glycine. The Journal of Biological Chemistry, 288(6), 39383951.
http://doi.org/10.1074/jbc.M112.385682
2) Abstract, Introduction, Experimental Procedures, Results, Discussion, References
3) Glucagon: A peptide hormone released from pancreatic -cells; among its effects are
increasing the level of glucose in blood via the breakdown of liver glycogen
Insulin: A peptide hormone released from pancreatic -cells; among its many effects is
the promotion of glucose uptake into the cells of certain target organs (muscle and
adipose tissue)
Tricarboxylic acid (TCA) cycle: Series of enzyme catalyzed chemical reactions that form
a key part of aerobic respiration in cells.
Glycolysis: The enzymatic pathway that convers a glucose molecule into two molecules
of pyruvate: the anaerobic process generates energy in the form of two ATP molecules
and two NADH molecules
Oxidation: The removal of electrons

The main objective of this study was to examine paracrine signaling that occurred in the
-cells and -cells. Particularly in relation to how it impacted the glucagon response on the cells
with high or low levels of glucose in the blood. -cells are an insulin producing cell which have a
more understood pathway than the -cells that release glucagon. However, glucose does help
with suppression of glucagon secretion, but this is not the only factor that can explain glucose
suppression from glucagon. A metabolomic approach was used by trailing the response of amino
acids and other potential neurotransmitters to see how it affected -cells and -cells in regulation
of glucagon secretion.
This study concludes that the neurotransmitter -hydroxybutyrate (GHB) is released from
the -cells when glucose is present. GHB has an inhibitory paracrine signal affect on the -cells.
It comes from the GABA shunt due to increased activity of glucose carbons that go into the TCA
cycle pathway during glucose stimulated insulin secretion (GSIS). In type 2 diabetics, there was
a depletion of the GABA shunt enzymes and metabolites that ultimately affected glucose
suppression from glucagon. Non-diabetic individuals on the other hand had an increase in GHB
released when glucose was found in the blood. Researchers further demonstrated GHBs effects
on glucose suppression of glucagon by using a GABA transaminase inhibitor called vigabatrin.
Resultantly, glucose was released from glucagon when using vigabatrin.
Furthermore the evidence shows that -cells are controlled by factors released from cells during GSIS causing glucagon suppression release. When carbon atoms from glucose go
into glycolysis as well as the TCA cycle, the -cells increase the ATP/ADP ratio. This in turn
stimulates the release of insulin. At the same time, glucose is in the oxidized form and combines
with the substrates from the TCA cycle. This increases the amount of GHB released from
GABA. The GHB binds to the GHB receptor on the -cell decreasing glucagon release. In

normal human islets amino acids are released to increase glucagon during times of
hypoglycemia. Leucine, an amino acid, is released turning into glycine that binds to the glycine
receptor on the -cell. When glycine binds on the -cell, it stimulates the increase in glucagon
release and does not activate a secretion of insulin. All in all, this indicates that glycine is a
counterbalance to GHB being the inhibitory effector.
Another component that was highly researched was -cells being controlled by insulin.
Results from the study found that type 2 diabetics had a normal suppression of glucagon by
glucose even though insulin secretion was impaired. The experiment concluded that the release
of insulin does not directly suppress glucagon; therefore, evidence shows the metabolic signal
from the -cells controls the glucagon secretion from the -cells making GHB the primary
signal.
Further evidence supporting that GHB suppresses glucagon release is shown in
individuals with SSA dehydrogenase deficiency. They have increased levels of GHB and have a
higher risk of hypoglycemia. SSA converts into GHB by SSA which binds onto the -cell
receptor inhibiting glucagon release.
I found this article fascinating due to learning about the role of how glucagon is either
suppressed or released. I never imagined anything but insulin being the main factor in regulating
glucose suppression from glucagon. Lastly, these new findings will lead to further areas of
research on potential drug treatment options for type 2 diabetics in order to suppress
hyperglucagonemia.