Enrico Tiepolo
Glucose control
From a general physiological point of view, the issue is where glucose goes, what use we make of glucose,
and why glucose levels get higher or lower.
Insulin
Insulin is a relatively big peptide that comes from a pro-hormone,
called pro-insulin. Pro-insulin in turn comes from an even longer
peptide called pre-pro-insulin, made of a signal peptide, A and B
chains and a connection peptide. Firstly, the signal peptide is removed
and pro-insulin is formed.
The pro-insulin then folds, and a bond is formed between two
cysteines from two different portions of the chain. The final hormone
is obtained when the connection peptide is cut, and you end up
with two peptide chains (A and B) linked by two cysteine bonds.
1. Insulin is known as the hormone that lowers glycemia
(reduces glucose levels in the blood).
2. However, another equally important function of insulin is to allow cells to use glucose to
perform anabolism.
The main signal for the release of insulin is glycemia itself. However, the organism also has an
anticipatory response of insulin, that is activated when we see or smell food (since we imagine that
we are soon going to eat). The endocrine pancreas in fact receives parasympathetic innervation
from the vagus nerve (X), which activates muscarinic receptors on beta cells of Langerhans islets: these
receptors, coupled to Gq, favor the increase of calcium within the cells and the consequent release
of insulin.
• This first insulin release is called the cephalic phase (stimulated
by vagus nerve).
• Then, after we eat and the stomach is filled, a vagal reflex is
activated to induce stomach secretions and induce a second release
of insulin: this is called gastrointestinal phase.
Meanwhile we start absorbing glucose, and the levels of glucose in beta
pancreatic cells increase. This happens because when the levels of glucose
are high, cells let more glucose in (except for the intestine and the kidneys,
in which glucose usually moves in the cells through active transport).
Therefore: + glucose in blood = + glucose in cells = + oxidative
phosphorylation = - balance between ATP/ADP (more ATP which
indicates abundance of glucose) à blocks specific ATP-sensitive potassium
channels à triggering the release of insulin.
In fact, these channels have a subunit called sulfonylurea receptor
(SUR), which responds to ATP and some drugs, called sulfonylureas
causing the cell to release insulin.
Once insulin is released, the further increase of
glycemia that would occur after the meal can be
regulated.
33 Body At Work II
, Enrico Tiepolo
Actions of insulin
Insulin acts through IRS1 (Insulin Receptor Substrate 1), a cytosolic peptide which is
phosphorylated by the insulin receptor (a tyrosine kinase receptor).
This produces a chain of activation:
• PI3K (the kinase of phosphatidylinositol) is phosphorylated and activated: this causes
phosphorylation of PIP2 (Phosphatidyl Inositol Phosphate) --> transcriptional effects
• AKT (Protein Kinase B) is phosphorylated and activated --> transcriptional effects
• GSK (glycogen synthase kinase) is phosphorylated and so inactivated: this causes
dephosphorylation and so activation of glycogen synthase (it’s the inhibition of an inhibitor).
The result is the activation of glycogen synthesis.
For glycogen synthesis to occur effectively, glucose has to be phosphorylated into glucose-6-phosphate:
this is performed by hexokinase. Phosphorylated glucose can then be used for any anabolic/catabolic
process.
• The more glucose-6-phosphate is consumed, the more glucose is subtracted from the cytoplasm,
the more glucose will enter the cell, the more hexokinase will produce glucose-6-phosphate.
• Instead, if glucose-6-phosphate is not used it accumulates in the cell and hexokinase does not
phosphorylate any more glucose.
It’s a mechanism of autoregulation.
The limiting factors are:
1) glycemia, that should be maintained at a reasonable level and cannot fall down
2) glucose entry in the cell, which should occur at the same rate glycogen is produced
3) glycogen synthase, which should be able to convert glucose into glycogen to accumulate it
Hexokinase usually does not represent a limiting factor because it’s very active.
1) Skeletal muscles
Skeletal muscles constitute a huge component of body mass: glucose uptake in muscles would represent
a very effective mechanism of glucose storage. However, if it was always active there would be a risk of
hypoglycemia. So, the rate of glucose entry in muscles and of glucose accumulation into glycogen has to
be regulated by insulin.
This occurs through 2 mechanisms:
1) activation of glycogen synthase ß by phosphorylation of glycogen synthase kinase (inhibitor)
2) favor the expression of GLUT4 on the surface of cells = transcriptional effect
GLUT4 is a very high-capacity transporter: it works not by pumping glucose inside the cell, but by
opening a wider gate for glucose to enter the cell (it’s useful for this gate to be open only when glycemia
is high, but otherwise to be always closed since muscles would uptake all blood glucose).
Insulin favors the expression and relocalization of GLUT4 on the membrane:
• Expression when the increase in glycemia is persistent,
• Relocalization when increase in glycemia is transient (guaranteeing a rapid response, as there
would be no time for de novo synthesis of the transporter).
2) Liver
Glucose regulation in the liver is different, as hepatocytes have to be in continuous and easy
communication with the blood (so it’s not possible to have an open/closed gate for glucose as in skeletal
muscles).
Hepatocytes have a constitutive expression of GLUT2, a low-affinity, high-capacity glucose transporter
(also present in beta pancreatic cells). Glucose freely flows in and out of hepatocytes, in order to be stored
34 Body At Work II
Glucose control
From a general physiological point of view, the issue is where glucose goes, what use we make of glucose,
and why glucose levels get higher or lower.
Insulin
Insulin is a relatively big peptide that comes from a pro-hormone,
called pro-insulin. Pro-insulin in turn comes from an even longer
peptide called pre-pro-insulin, made of a signal peptide, A and B
chains and a connection peptide. Firstly, the signal peptide is removed
and pro-insulin is formed.
The pro-insulin then folds, and a bond is formed between two
cysteines from two different portions of the chain. The final hormone
is obtained when the connection peptide is cut, and you end up
with two peptide chains (A and B) linked by two cysteine bonds.
1. Insulin is known as the hormone that lowers glycemia
(reduces glucose levels in the blood).
2. However, another equally important function of insulin is to allow cells to use glucose to
perform anabolism.
The main signal for the release of insulin is glycemia itself. However, the organism also has an
anticipatory response of insulin, that is activated when we see or smell food (since we imagine that
we are soon going to eat). The endocrine pancreas in fact receives parasympathetic innervation
from the vagus nerve (X), which activates muscarinic receptors on beta cells of Langerhans islets: these
receptors, coupled to Gq, favor the increase of calcium within the cells and the consequent release
of insulin.
• This first insulin release is called the cephalic phase (stimulated
by vagus nerve).
• Then, after we eat and the stomach is filled, a vagal reflex is
activated to induce stomach secretions and induce a second release
of insulin: this is called gastrointestinal phase.
Meanwhile we start absorbing glucose, and the levels of glucose in beta
pancreatic cells increase. This happens because when the levels of glucose
are high, cells let more glucose in (except for the intestine and the kidneys,
in which glucose usually moves in the cells through active transport).
Therefore: + glucose in blood = + glucose in cells = + oxidative
phosphorylation = - balance between ATP/ADP (more ATP which
indicates abundance of glucose) à blocks specific ATP-sensitive potassium
channels à triggering the release of insulin.
In fact, these channels have a subunit called sulfonylurea receptor
(SUR), which responds to ATP and some drugs, called sulfonylureas
causing the cell to release insulin.
Once insulin is released, the further increase of
glycemia that would occur after the meal can be
regulated.
33 Body At Work II
, Enrico Tiepolo
Actions of insulin
Insulin acts through IRS1 (Insulin Receptor Substrate 1), a cytosolic peptide which is
phosphorylated by the insulin receptor (a tyrosine kinase receptor).
This produces a chain of activation:
• PI3K (the kinase of phosphatidylinositol) is phosphorylated and activated: this causes
phosphorylation of PIP2 (Phosphatidyl Inositol Phosphate) --> transcriptional effects
• AKT (Protein Kinase B) is phosphorylated and activated --> transcriptional effects
• GSK (glycogen synthase kinase) is phosphorylated and so inactivated: this causes
dephosphorylation and so activation of glycogen synthase (it’s the inhibition of an inhibitor).
The result is the activation of glycogen synthesis.
For glycogen synthesis to occur effectively, glucose has to be phosphorylated into glucose-6-phosphate:
this is performed by hexokinase. Phosphorylated glucose can then be used for any anabolic/catabolic
process.
• The more glucose-6-phosphate is consumed, the more glucose is subtracted from the cytoplasm,
the more glucose will enter the cell, the more hexokinase will produce glucose-6-phosphate.
• Instead, if glucose-6-phosphate is not used it accumulates in the cell and hexokinase does not
phosphorylate any more glucose.
It’s a mechanism of autoregulation.
The limiting factors are:
1) glycemia, that should be maintained at a reasonable level and cannot fall down
2) glucose entry in the cell, which should occur at the same rate glycogen is produced
3) glycogen synthase, which should be able to convert glucose into glycogen to accumulate it
Hexokinase usually does not represent a limiting factor because it’s very active.
1) Skeletal muscles
Skeletal muscles constitute a huge component of body mass: glucose uptake in muscles would represent
a very effective mechanism of glucose storage. However, if it was always active there would be a risk of
hypoglycemia. So, the rate of glucose entry in muscles and of glucose accumulation into glycogen has to
be regulated by insulin.
This occurs through 2 mechanisms:
1) activation of glycogen synthase ß by phosphorylation of glycogen synthase kinase (inhibitor)
2) favor the expression of GLUT4 on the surface of cells = transcriptional effect
GLUT4 is a very high-capacity transporter: it works not by pumping glucose inside the cell, but by
opening a wider gate for glucose to enter the cell (it’s useful for this gate to be open only when glycemia
is high, but otherwise to be always closed since muscles would uptake all blood glucose).
Insulin favors the expression and relocalization of GLUT4 on the membrane:
• Expression when the increase in glycemia is persistent,
• Relocalization when increase in glycemia is transient (guaranteeing a rapid response, as there
would be no time for de novo synthesis of the transporter).
2) Liver
Glucose regulation in the liver is different, as hepatocytes have to be in continuous and easy
communication with the blood (so it’s not possible to have an open/closed gate for glucose as in skeletal
muscles).
Hepatocytes have a constitutive expression of GLUT2, a low-affinity, high-capacity glucose transporter
(also present in beta pancreatic cells). Glucose freely flows in and out of hepatocytes, in order to be stored
34 Body At Work II
