YSM Issue 93.4 Full Magazine

FOCUS
Biochemistry
A MOLECULAR
WHODUNIT
IN THE LIVER
What molecules cause hepatic insulin resistance?
BY ALICE HUANG
IMAGE COURTESY OF SHUTTERSTOCK
What happens to the carbs we eat?
Carbohydrates are one of the
main sources of energy for cells
in the human body. After eating a meal,
carbohydrates pass through the digestive
system, traveling from the stomach to the
small intestines, and are broken down into
their basic unit, the monosaccharide (such
as glucose, fructose, and galactose), along
the way. Upon their arrival in the small
intestines, monosaccharides are transported
into the bloodstream, increasing glucose
concentrations in the blood and prompting
the pancreas to secrete the essential hormone
insulin to promote tissue glucose uptake and
suppress endogenous glucose production.
This process provides tissues access to glucose
for energy production and storage as well as
maintains a healthy concentration of blood
glucose to prevent hyperglycemia.
Hyperglycemia, or abnormally high blood
sugar levels, can become dangerous since the
body will turn to excessively breaking down
fats when glucose cannot be accessed by
tissues for energy production. This process
of rapid fat breakdown produces excessive
ketones, the buildup of which could be lifethreatening.
Additionally, hyperglycemia
can cause damage to multiple tissues, such
as the retina, kidneys, limb extremities,
and cardiovascular system, which could
lead to severe downstream complications,
including vision loss, renal diseases, limb
extremity necrosis and amputation, and
cardiovascular diseases. Disruption of
the insulin signaling pathway may lead
to hyperglycemia in type 2 diabetes, a
condition where the body not only exhibits
lowered response to insulin but also does
not produce enough insulin in chronic
conditions. Researchers have conducted
many studies investigating the pathways
responsible for the development of insulin
resistance. Recently, the Shulman Lab
at Yale has come forth with a potential
mechanism for the development of insulin
resistance in the liver, also known as hepatic
insulin resistance (HIR).
Significance of the study
The Shulman Lab, led by Gerald Shulman,
the George R. Cowgill Professor of Medicine
and Cellular & Molecular Physiology at
Yale, has been extensively studying HIR
and its contribution to type 2 diabetes for
the past few years. “Insulin resistance is
the primary determinant of whether or not
someone develops type 2 diabetes. [Type 2
diabetes] is going to impact half a billion
people within ten years’ time and is the
leading cause of blindness and end-stage
renal disease, as well as a huge economic
cost to society,” Shulman said. His research
team has been dedicated to investigating
the role of liver fat accumulation in insulin
action disruption and hepatic insulin
resistance. In a paper recently published
in Cell Metabolism, the Shulman Lab
presented its newest discovery: a possible
pathway by which certain molecules,
called diacylglycerols (DAGs), might be
responsible for inducing HIR. Kun Lyu, a
graduate student in the Shulman Lab and
first author of the paper, explains that the
pathway had been discovered step-bystep
from decades of work, and that with
its history, had had its fair share of debate
and controversy. “Over the past two or
three years, we have developed new tools
and models to specifically address this
controversy,” Lyu said.
Major results
The pathway the team discovered describes
how accumulation of plasma membrane sn-
1,2-diacylglycerols (PM sn-1,2-DAGs) leads
to HIR. These DAGs are a group of plasma
(cell) membrane-bound stereoisomers
(compounds composed of the same atoms
differing only in their orientations) of DAG
that was found to activate the Protein Kinase
C- (PKCε) pathway, which has the ability to
disrupt insulin signaling. PKCε activation
results in phosphorylation—a type of
chemical tagging—of a critical amino acid
residue (a specific chemical building block of
a protein) on insulin receptor kinase (IRK).
By tagging this amino acid residue, PKCε
then disrupts the downstream signaling
pathway and can lead to insulin resistance.
The research team was able to establish
the role of DAGs in inducing HIR by
removing functioning copies of an enzyme
called DGAT2, which converts DAGs to
triglycerides, in mice—a model known as
DGAT2 knockdown (KD). To determine the
effects of high DAG content on liver insulin
action, the researchers subjected regular
chow-fed rats to a treatment that decreases
DGAT2, allowing DAG to accumulate. They
then subjected these acute hepatic DGAT2
KD rats to a hyperinsulinemic-euglycemic
clamp, a method used to infuse high levels
of insulin (“hyperinsulinemia”) to mimic
insulin levels after ingestion of carbohydrates
while maintaining normal blood-glucose
concentrations (“euglycemia”). The
researchers found that this model impaired
insulin’s suppression of endogenous glucose
production by impairing the insulin
signaling pathway, suggesting that DAGs
could play a role in HIR.
12 Yale Scientific Magazine December 2020 www.yalescientific.org