2.

INSULIN SECRETION
Insulin is an important hormone required for normal metabolism. The gene engaged of insulin
synthesis is de INS gene (located on chromosome 11p15.5).

Insulin secretion is a very complex process: it involves the interaction of many external and internal
stimuli which activate or inhibit insulin release.
The insulin transduction pathway is a biochemical pathway by which insulin increases the
absorption of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver.

1. Pancreatic beta cells

Insulin is synthetized by the pancreatic beta cells. In
people with type 1 diabetes this cells are damaged.
The pancreas has endocrine structures called the
islets of Langerhans, where beta cells produce,
store and release insulin. A damage in the secretion
processes leads to insufficient insulin release, which
contributes to the development of type 2 diabetes.

In addition, beta cells also secrete an hormone

called Amylin, which slows the rate of glucose
entering the bloodstream.
Beta cells control the secretion of insulin thanks to the calcium ion channels and ATP- sensitive ion
channels they have in their membrane. Through this channels potassium ions diffuse out of the cell,
creating a potential difference.

2. SIGNALING FACTORS INVOLVED IN INSULIN RELEASE

Insulin secretion can be stimulated by different substrates; glucose is evolutionarily the primary
stimuli for insulin release in some animal species, because it is a principal food component and can
accumulate immediately after food ingestion. In humans, insulin secretion induced by glucose is
much larger compared with the stimulation by amino acids or fatty acids.

GLUCOSE

When the blood levels of glucose are increased after a meal its increased the release of the
insuline from the pancreatic beta cells. That occurs because there is an enzyme called glucokinase
that works as a glucose sensor in beta cells.

Glucose takes part of the regulation of insulin at different levels; it increases mRNA concentration,
its stability and its avarage lifetime, so glucose stimulates insulin transcription. Glucose also
regulates the begining in translation of preproinsulin mRNA and the translocation of new
preproinsulin chains mediated by SPR ( Signal Racognition Particle) and their enlongation.

FATTY ACIDS

Fatty acids and other lipid molecules are important for many cellular functions, including vesicle
exocytosis. Faty acids are esencial for glucose-stimulated insulin secretion. They have enormous
capacity to amplify glucose-stimulated insulin secretion, which is particularly operative in situations
of beta-cell compensation for insulin resistance. It has been discovered a fatty acid receptor in beta
cells, free factty acid receptor (FFAR), so the fatty acids can influence the function of the beta cells.

AMINO ACIDS

Physiological concentrations of amino acids arent able

to stimulate insulin secretion. However, certain
combinations of amino acids at physiological
concentrations or higher can augment glucose-stimulated
insulin secretion (GSIS).
For example, glutamine alone does not stimulate insulin
secretion or increase GSIS, but a combination of
glutamine with leucine can enhance GSIS from -cells.
Leucine can activate glutamate dehydrogenase, which
converts glutamate to -ketoglutarate. Glutamine, after
converted into glutamate by glutaminase in the cytosol,
can enter the TCA cycle via -ketoglutarate, which
results in ATP production, thereby enhancing insulin
secretion.

Moreover, some amino acids can indirectly influence -cell insulin secretion. Free amino acids,
including alanine and glutamine, are released into the blood and strenghten the secretion of glucagon.
This involves a elevatation of blood glucose levels, which then triggers insulin secretion.
This picture shows the influence of leucine and glutamine in the insulin secretion.

HORMONES

Some hormones can increase the production of insulin. The incretin effect is estimated to account
for approximately 50-70% of the total insulin secreted following oral glucose administration. Thus,
incretins are hormones that are secreted from the gastrointestinal tract into the circulation in response
to nutrient ingestion that enhance glucose-stimulated insulin secretion. Gastric inhibitory polypeptide
(GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the
intestine after the ingestion of glucose and other nutrients. Glucagon-like peptide (GLP)-1 is a gut
hormone that stimulates insulin secretion, gene expression, and -cell growth. The hormone GIP is
also responsible for the incretin effect.
Their mechanism of action starts with the activation of a G-protein that activates adenylyl cyclase in
order to increase cAMP in beta cells. cAMP, like ATP, is a signal that regulates insulin secretion by
activation of the protein kinase A (PKA), an enzyme that phosphorylates other substrates to turn on
(or off) vital cell functions.

Several other peptide hormones, nutrients, bile acids, and lipid amides are also secreted following
nutrient ingestion, bind to receptors on islet b-cells and stimulate glucose-dependent insulin
secretion.

Another hormone that is involved in insulin secretion is glucagon. Glucagon is produced by alpha
cells in the pancreas and elevates the concentration of glucose in the blood by promoting
gluconeogenesis and glycogenolysis. Glucagon elevates the blood levels of glucose, so it
stimulates the secretion of insulin in order to reduce glucose levels.

AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system influences many of the functions of the body, including the insulin
secretion. In fact, the parasympathetic nervous system and the sympathetic nervous system have
opposing effects on insulin secretion; parasympathetic nervous system stimulates insulin secretion,
whereas sympathetic nervous system inhibits insulin secretion. Moreover, it has been reported that
the autonomic nervous system is one of the important factors that regulate pancreatic regeneration.

3. Intracellular signaling pathways involved in the secretion of insulin

The mechanisms behind insulin secretion are not very clear. Nevertheless, certain features of this process
have been clearly and repeatedly demonstrated, establishing the following biphasic model: first, theres a
basal secretion phase, rapid; and then, other less intense and sustained.

First phase: Triggering Pathway This response is activated rapidly because -cells have insulin accumulated

in its pellets, so is not necessary to synthesize new molecules.

1. Glucose is transported into the -cell by facilitated diffusion through a glucose transporter (GLUT2),
elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose
within the -cells.

2. During the glycolysis, the glucose molecule is phosphorylated by glucokinase, obtaining glucose-6-P. This
proceeding is remarkable in the whole glycolysis because its velocity controls the final insulin
secretion. Finally, we obtain pyruvate from this oxidation via.

3. Intherespiratorycycle,thepyruvateisoxidizedbythepyruvate dehydrogenase complex and the resulting

acetyl-CoA is oxidized in the tricarboxylic acid cycle. The derivate NADH and FADH 2 are oxidized by
an oxidative phosphorylation machinery. Consequently, huge amounts of ATP are obtained.
4. The ATP-sensitive potassium channel (KATP channel) is inhibited as a result of the increased ATP level
inside -cells. Potassium ions cant diffuse to the outside while its channel is closed.

5. This implies a depolarization on the cellular membrane because K+ ions remain inside the cell and
accumulate.Therefore, the cells potential becomes more positive.

Due to this depolarization, Ca++ voltage dependent channels open increasing the amount of this ion
in the cytosol because calcium ions from outside the cell diffuse in down their concentration
gradient.

6. The altered level of calcium activates the Phospolipase C, which transforms phospholipids from
the cell membrane (phosphatidylinositol 4,5-biphosphate inositol 1,4,5-biphsophate (IP3)
and diacylglicerol (DAG)

7. The IP3 bounds to a receptor in the endoplasmic reticulum and produces the release of calcium
ions from the RE to the cytosol, increasing even more the Ca++ concentration inside the
cell.

8. Synaptotagmin (a Ca++ sensor in the membrane) is activated and favour the insulin release (that
has been previously synthesized and stored in pellets).

The pellets approximate to the cell membrane and fuse with it (following the exocitosis procedure).
Thats how its content (insulin) is secreted outside the cell. Second phase: Amplifying
Pathways This phase is longer than the first one, because is related to a constant production and
slower release of new insulin molecules. This second phase can take place thanks to the entrance
of calcium in the -cells. These ions activate the transcription of the INS gene that contains the
information for the synthesis of insulin.

The insulin synthesis is stimulated by high sugar blood levels, as is proved by researches. The
release of insulin in bloodstream in the above mentioned conditions allows the organism to maintain
the glucose balance. Its also necessary to increase the mean life or mRNA that contains the INS.
This picture describes not only the insulin signaling pathways, but also the rate of insulin secretion.
In five minutes from the start, we see an exponentially growth of releasing (what means that plasma
insulin is dramatically increased) and its due to preformed insulin. However this situation finish
rapidly, and it takes a while to synthesize and secrete insulin. The second secretion will be
progressive, in order to allow the homeostasis.

4. Phases of insulin secretion and their physiological meaning

Formerly, it was believed that insulin secretion was controlled almost entirely by the blood glucose
concentration. However, as more has been learned about the metabolic functions of insulin for protein and fat
metabolism, it has become apparent that blood amino acids and other factors also play important roles in
controlling insulin secretion.

When theres a normal level of blood glucose (of 80 to 90 mg/100 ml), the rate of insulin secretion is minimal,
a level that has only slight physiologic activity. If the blood glucose concentration is suddenly increased to a

level two to three times normal and kept at this high level afterwards, insulin secretion increases substantially
in two stages:

1.- Plasma insulin concentration increases almost 10-fold within 3 to 5 minutes after the significant elevation
of the blood glucose; this results from immediate release of preformed insulin from the -cells. However, the
initial high rate of secretion is not maintained; instead, the insulin concentration decreases about halfway back
toward normal in another 5 to 10 minutes.

2.- Beginning at about 15 minutes, insulin secretion rises a second time and reaches a new plateau in 2 to 3
hours, this time usually at a rate of secretion even greater than that in the initial phase. This secretion results
both from additional release of preformed insulin and from the synthesis and secretion of new insulin.

As the concentration of blood glucose rises above 100 mg/100 ml of blood, the rate of insulin secretion rises
rapidly, reaching a peak some 10 to 25 times the basal level at blood glucose concentrations between 400
and 600 mg/100 ml. Thus, the increase in insulin secretion under a glucose stimulus is dramatic both in its
rapidity and in the tremendous level of secretion achieved.

Furthermore, the turn-off of insulin secretion is almost equally as rapid, occurring within 3 to 5 minutes after
reduction in blood glucose concentration back to the fasting level. This response of insulin secretion to an

elevated blood glucose concentration provides an extremely important feedback mechanism for regulating
blood glucose concentration. That is, any rise in blood glucose increases insulin secretion, and the insulin in
turn increases transport of glucose into liver, muscle, and other cells, thereby reducing the blood glucose
concentration back toward the normal value.
(http://diabetes.diabetesjournals.org/content/53/supp(http://ajpendo.physiology.org/content/ajpendo/
287/2/E199.full.pdf)l_3/S197)
http://diabetes.diabetesjournals.org/content/55/Supplement_2/S1
(nhttp://pages.ucsd.edu/~mboyle/COGS163/pdf-files/W3-AR-
Relationships%20between%20the%20autonomic%20nervous%20system%20and%20the%20pancr
eas%20including%20regulation%20of%20regeneration%20and%20apoptosis-
%20recent%20developments.pdf)
https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-
textbook/endocrine-system-16/the-pancreas-159/insulin-secretion-and-regulation-of-glucagon-799-
345/