PHYSIOLOGY OF THE PANCREAS .

 PHYSIOLOGY ENDOCRINE PANCREAS :
Anatomical and functional unit of the endocrine pancreas is the islet of Langerhans
, whose mass corresponds to 1 % of the total weight of the organ. They synthesize
insulin ( beta cells ) , glucagon (alpha) and somatostatin (delta) . Islets have a thin
vascular network and are provided with a facing portal venous system type from
the beta cells , to the alpha and delta . They are innervated by the autonomic
nervous system and intercellular communications exist .
BETA CELLS AND INSULIN :
 Synthesis of Insulin:
The gene is responsible for synthesis in the short arm of chromosome 11. The first
peptide synthesis is the "pre- proinsulin " . In the endoplasmic reticulum with 2
folds spatially disulfide bonds , forming the " proinsulin " . In Golgi membrane
structure around a number of molecules , forming a granule. By the action of
proteolytic enzymes, pro-insulin produces equimolar amounts of insulin and Cpeptide Additionally, there uptake zinc, forming zinc insulin molecules. The
progression of the granules to the plasma membrane is via microtubule driven
contractile filaments ciliary electroquímico.Los potential gradients granules fuse
with the cell membrane and are secreted by exocytosis. Insulin in the form of
monomers , together with the C-peptide are diffused into the capillaries in
equimolar manner . There is also a small proinsulin secretion (10% insulin).
 Regulation of Insulin Secretion :
Insulin secretion is regulated by the interaction of substrates, autonomic nervous
system , hormones and cell signaling ( paracrine ) . Glucose , amino acids (
arginine and leucine) , keto acids and fatty acids are the primary stimuli . When
metabolized , increase the concentration of ATP , inhibit ATP -sensitive potassium
channel and promote the influx of calcium into cytosol electrosensibles opening
their channels . Calcium binds to a protein - the calmomodulina - it interacts with
other proteins such as protein kinase C , which in turn activates the synthesis
promoting cytoskeleton to form myosin contractile cilia . Potentiating agents such
as glucagon , secretin, pancreozymin , gastric inhibitory peptide (GIP ) and
acetylcholine , stimulates adenylate cyclase and thus increase the concentration of
cyclic AMP which in turn activates AMP -dependent protein kinases .

The neurotransmitters epinephrine, norepinephrine, somatostatin, which act as
inhibitors exert their effect by modulating the inositol metabolism in the membrane ,
producing diacylglycerol , which regulates the activation of protein kinases . The
autonomic nervous system is an important modulator of insulin secretion . The
parasympathetic and sympathetic stimulation inhibits it . Adrenergic effect is
complex because stimulation of the α 2 receptors inhibits secretion while chronic
stimulation of beta receptors increases it. L cells secreted in the ileum and jejunum
K respectively, after food intake , stimulate insulin secretion mediated glucose
levels . Are important regulators of postprandial hyperglycemia . The
interregulation between glucose and insulin is able to maintain blood glucose levels
within a narrow physiological range . The beta cell has the sensitivity to perceive
small changes in glycemia , responding immediately with a proportional insulin
secretion . Under normal conditions, when there is more demand for a sustained
elevation of glucose, increases sensitivity to it and then is able to stimulate beta cell replication . These effects have a different temporal sequence : in seconds
responds to changes in glycemia in minutes ensemanas increases sensitivity and
adapts increasing cell mass . Response is biphasic insulin secretagogues : an
early stage and quickly that lasts 10 minutes later and again less intense and
sustained . The first is presumably due to secretion of preformed granules and the
second to de novo biosynthesis . It has been shown that this biphasic response is
essential for the homeostasis of glucose. Circulation and Metabolism of insulin :
The pancreas secretes insulin and equimolar amounts of peptide C. Measuring the
concentrations of C-peptide or glucagon stimulation post is a good expression of
the synthesis and secretion of insulin, which can be measured even in patients
receiving exogenous insulin , since the latter has no cross reaction with peptide C.
The half-life of insulin is 4.8 and their degradation takes place in the liver and
kidney and somewhat C-peptide and proinsulin in the kidney . Insulin in a high
percentage is captured in its first pass through the liver , but not the peptide C.
Catabolism is initiated by the rupture of the disulfide bridges by the action of
glutathione insulintransferasa , then initiated proteolysis , releasing inactive
peptides . The biological activity of proinsulin is about 10% of insulin and C-peptide
is completely inactive.
 Insulin Receptors :
The biological action of insulin is through its interaction with specific receptors. Are
composed of two alpha units , responsible for the recognition of insulin and two
beta units , location within the membrane, with the function of transmitting the
message to intracellular effectors . Receptors are constantly degraded and
resynthesized . The number of receptors is negatively contrarregulado the
concentration of insulin and its affinity is reduced by the action of other hormones,

among which the catecholamines , glucagon , growth hormone , corticosteroids ,
estrogen, progesterone and placental lactogen . It has been established that the
maximum insulin bioefecto can be maintained even at a concentration of 10% of
recipients.
 Post- receptor Effect of Insulin :
The binding of insulin receptor autophosphorylation generates beta units (position
tyrosine) which activates transcription factors and protein kinases that stimulate or
inhibit gene transcription , and the action of enzymes involved in the metabolism of
substrates induce translocation proteins, increased protein synthesis and the
transport of glucose , aminoacids and ions. For example, insulin activates glucose
transport through the cell membranes of adipose tissue and muscle by increasing
the synthesis and translocation of GLUT4 transport operator . Insulin increases
hepatic glucokinase action of stimulating the transcription of the enzyme gene and
directly activates pyruvate dehydrogenase , acetyl Co A carboxylase and glycogen
synthase. Furthermore, directly inhibits the intracellular lipase and phosphorylases
responsible for the mobilization of endogenous substrates ( fatty acids from the
adipocyte glucose from the liver).

ALPHA CELLS AND GLUCAGON :
 Synthesis of Glucagon :
Glucagon is a peptide hormone synthesized and secreted by the alpha cells of the
pancreas. Brain , salivary glands and intestine synthesize and secrete peptides
glucagon related immunologically . Prohormone , proglucagon , is able to release
other peptides through a process of post- translation specific tissue. Predominantly
synthesized pancreas glucagon. The intestine can not be synthesized glucagon ,
glicentin oxytomodulina instead generates , GLP-1 and GLP-2 .Glucagon acts on
the metabolism of energy substrates and GLP-1 is the most important signal to
induce intestinal synthesis and secretion of insulin in the pancreas .
 Regulating Glucagon Secretion :
Glucagon secretion is also interregulada for substrates, for the autonomic nervous
system , by hormones and signaling. The concentration of glucose is essential
physiological signal : the low levels stimulated while raising glucose, inhibited.
Amino acids stimulate glucagon secretion . Both the system and the sympathetic
and vagal gastric inhibitory peptide in physiological concentrations are also
stimulators . For potential paracrine mechanisms , insulin and somatostatin exert
an effect . The lack of inhibition of glucagon secretion secondary to hyperglycemia

conditions insufficient insulin is due to a reduction lainsulina inhibitory effect , which
under normal conditions is effected through the venous system and portal type
paracrine .
 Metabolism of Glucagon :
Pancreatic glucagon appears to be degraded mainly in the kidney , since the renal
failure there is a significant elevation of serum levels .
 Glucagon Receptor :
Specific receptors have been identified and it is likely that much of its biological
effects are due to the hormone-receptor interaction , stimulating adenylate cyclase
, and induction of cyclic AMP proteinkinasas .
DELTA CELLS AND SOMATOSTATIN :
 Synthesis of Somatostatin :
Somatostatin was originally isolated from the hypothalamus , is widely distributed
in neurons of the central nervous system and intestine and delta cells of the gastric
mucosa, intestinal , colon, and in the islets of Langerhans. The prohormone , pro somatostatin is subjected to a process of differential posttranslational specific
tissue which affects its expression. Locating somatostatin bodies intended
digestion, absorption and utilization of nutrients received through food, has been
suggested that this hormone plays a role in the homeostasis of nutrients.
 Regulation of Somatostatin Secretion :
Glucose stimulates secretion with a dose-response relationship . Also make amino
acids and ketone bodies . The enterohormonas ( gastrin , cholecystokinin , secretin
and GIP ) stimulate somatostatin secretion , inhibits glucagon while possibly by a
paracrine mechanism . ß The cholinergic and adrenergic agents stimulate it and α
2 adrenergic receptors , inhibit it.
METABOLIC EFFECTS OF PANCREATIC HORMONES :
 Effects of Insulin :
Insulin has an important role in metabolic regulation . Is defined as an anabolic
(promotes the deposition of energy substrates and protein synthesis ) and
anticatabolic ( mobilization slows substrates ) . Secretion increased after a meal,
induces vasodilation ( for its effect of nitric oxide synthesis by stimulating
endothelial oxodo synthase ) that facilitates the distribution of substrates to the
tissues. Although its effects are more evident in the regulation of glucose

homeostasis , has a key role in the metabolism of amino acids, fatty acids, keto
acids and lipoproteins. Its physiological effects in vivo should be considered in the
context of their relationship to hormones called catabolic ( glucagon ,
catecholamines , glucocorticoids and growth hormone ) .
 Effects on the metabolism of carbohydrates :
Promotes glucose utilization (oxidation and deposit) and slows their endogenous
production . In muscle and adipose tissue stimulates glucose transport through the
membrane and increases glucose oxidation by activating pyruvate dehydrogenase
. In the liver , where glucose transport is independent of insulin, glucokinase and
activates glycogen synthase , favoring oxidation and storage as glycogen .
Glycogenolysis and depresses neoglycogeny and consequently the hepatic
glucose production . Glucose inhibits phosphatase that regulates glycogenolysis .
The brake is reduced because neoglycogeny muscle catabolism and alanine flow
to the liver and inhibits enzymes responsible for the passage of
phosphoenolpyruvic to glucose.
 Effects on lipid metabolism :
Promotes the synthesis of triglycerides and slows its hydrolysis. Decreases the
concentration of free fatty acids in plasma and delivery to the liver. Inhibits hepatic
ketogenesis and peripheral utilization facilitates ketoacids .Triglyceride synthesis is
stimulated by a higher concentration of glycerophosphate and acetyl-CoA derived
from glycolysis and also by increased formation of NADPH , derived from the
metabolism of glucose via the pentose . Insulin inhibits the hormone - sensitive
lipase and thereby reduces intracellular hydrolysis of triglycerides and free fatty
acid flux to the liver. Increases malonyl CoA inhibitor, acyl carnitine transferase ,
thus reducing the penetration of that WILL fatty acids into the mitochondria , the
beta- oxidation and subsequent transformation into keto . It stimulates the use of
the latter on the periphery. Insulin is defined as a hormone anticetogénica ,
reducing the mobilization of fatty acids to the liver, reducing its penetration into the
mitochondria and promotes its incorporation into the Krebs cycle and triglyceride
synthesis .
 Effects on protein metabolism :
Increases amino acid uptake in muscle , promotes protein synthesis and inhibits
proteolysis. Reduces the concentration of branched chain amino acids in blood ,
degradation of amino acids and proteins to oxidation.

 Effects on lipoprotein metabolism :
Insulin stimulates lipoprotein lipase , favoring the catabolism of triglyceride-rich
lipoproteins ( VLDL and chylomicrons ) . It also reduces the catabolism of HDL .
 Glucagon Actions :
It is a catabolic hormone and has an important role in the mobilization of
substrates. Stimulates glycogenolysis neoglycogeny and activating the
endogenous hepatic glucose production . Activates lipolysis and fatty acid transport
to the liver. It has a key role in hepatic ketogenesis by increasing the levels of
carnitine and reducing levels of malonyl CoA. This accelerates the passage of fatty
acids into the mitochondria and insulin deficiency conditions , its transformation
into keto . A muscular level , promotes the degradation of proteins into amino acids
, its output to the liver and its subsequent conversion to glucose ( neoglycogeny )
 Somatostatin Actions :
Its main effect is to modulate the intestinal absorption of substrates, as it inhibits
the endocrine , exocrine and gastrointestinal tract motor . It is possible that
indirectly regulate the proportional response of insulin and glucagon in accordance
with the requirements , supply and availability of energy substrates . This is
because there is a complex interregulation between the three hormones ,
somatostatin exerting an inhibitory effect on the insulin and glucagon .

 PHYSIOLOGY EXOCRINE PANCREAS :
Exocrine pancreas is the main source of digestive enzymes that act in the small
intestinal lumen (ID). Human pancreatic enzyme synthesis is about 10g protein /
day. This gland makes two types of secretion , one rich exocrine bicarbonate and
digestive enzymes expressed in the light of the ID , and other endocrine formed by
insulin and glucagon , hormones that are secreted into the portal circulation to
exert its main action on the physiology of the liver , where they are in higher
concentration than in the rest of the systemic circulation. Pancreatic exocrine
secretion is controlled neurohormonal digestive system , entering game stimulating
vagal innervation and sympathetic vasoconstrictor , and hormones such as
secretin duodenal stimulating basic electrolyte secretion and CCK and gastrin
secretion stimulating enzymatic .

MORPHO - FUNCTIONAL ASPECTS :
Exocrine secretory cells are pancreatic acini gathered in that drain into intercalated
ducts , which in turn drain into interlobular ducts , and do so in turn extralobular
ducts , which in turn do in collecting duct higher , up to the main pancreatic duct or
which normally binds bile duct ( bile duct ) , forming the ampulla of Vater , which
opens to the duodenal lumen through the sphincter of Oddi . ( there may be an
accessory pancreatic duct called Santorini ) . These cells secreting
embriolágicamente endoderm derived unlike the endocrine cells that make neural
crest . Cells centroacinar ducts and are responsible for the secretion rich aqueous
sodium bicarbonate . Appropriate parasympathetic innervation vagal fibers
innervating cells both exocrine and endocrine for exerting a stimulatory action
through ACh. The sympathetic vasoconstrictor action exerted , reducing therefore
the volume of the exocrine secretion .
GENERAL FEATURES PANCREATIC EXOCRINE SECRETION :
Colorless and odorless liquid with density between 1007-1024 and a pH between
7.6 and 8.2 , with an average volume of 1.5 to 2.0 liters / day. It has a rich
hidrosalino bicarbonate component and an organic component rich in digestive
proenzymes . Electrolyte concentration varies with the rate of secretion . Cation
concentrations remain constant while the Cl- and bicarbonate vary inversely with
the increase in secretion rate . Osmolality flow does not change .
LOCATION AND MECHANISM :
Hidrosalino component centroacinar cells derived from ductal very rich and
carbonic anhydrase. Cells is thought to perform centroacinar plasma ultrafiltered so
at baseline electrolyte composition of pancreatic juice is similar to the plasma.
Under stimulated conditions (for secretin ) , centroacinar cells do not alter
practically the ultrafiltrate , while the ductal cells activated increases chloride
bicarbonate exchange , hence the image of the graph, thereby maintaining
equivalence between cations and anions , given that the cations are kept constant
and equal to the plasma . Bicarbonate concentration ranging from 25 mEq / L at
baseline to 150 meq / l under stimulated conditions . The origin of this bicarbonate
ductal cells in the carbonic anhydrase activity of these cells that transforms into
CO2 and water and this carbonic dissociates into bicarbonate and hydrogen ions .
Bicarbonate is exchanged for chloride level luminal membrane , while the level of
the hydrogen ion basolateral resulting exchanged for sodium , with the motor of
this exchange the sodium / potassium pump characteristic . Chloride out again
through a chloride channel , which draws water and sodium . Alteration of this
channel by altering the gene encoding the protein which forms the channel (CFTR :

conductance regulator gene for cystic fibrosis transmembrane , multisystemic
disease involving the formation and accumulation of thick, sticky mucus )
determines a decrease hidrosalina important and bicarbonate secretion , which
occurs at a mucous plug braking enzyme secretion . Another important source of
bicarbonate is secreted from the plasma , not being clear about the mechanism
used nFor the cell. The intracellular cAMP is the mediator of the stimulating action
of secretin in ductal cells , increasing PKA phosphorylates chloride channels ,
favoring the exit thereof , and therefore the exchange with the bicarbonate .
Calcium and magnesium are at higher concentrations in the plasma ( from 25 to
35% more) , which means secretion thereof. These ions are secreted in acinar
cells with enzyme secretion .
SECRETION ORGANIC :
Organic secretion is formed by a wide range of proenzymes that under basal
conditions is very small , whereas stimulated conditions is increased and besides
selective excess depending on the type of food eaten . Assumes organic secretion
from 6 to 20 g / day in two liters of secreción.Todas enzymes secreted in an
inactive form and the most important , being instrumental in the process of
activation of other enzymes ( proteases ) pancreatic are secreted together with
inhibitors that prevent accidental activation that could cause digestion of the
pancreatic duct . These factors are Kunitz stable and unstable under alkaline
conditions and under acidic conditions of Katzal , specific inhibitor of trypsin.
Colipase is another factor released by the pancreas and prevents inhibitory effect
on bile acids have lipase . In addition to these factors , pancreatic factors are
provided in the natural diet that act as inhibitors of these proteolytic type enzymes .
Thus we soy, egg white, Ascaris lumbricoides , etc. . Activation of these enzymes
prior passes duodenal pancreatic trypsinogen activation , thanks to the existence in
the duodenal mucosa of enterokinase in the presence of calcium ( from the same
pancreatic secretion ) and an alkaline pH converts the trypsinogen to trypsin ,
which is responsible for activating the other pancreatic proenzymes .

REGULATION:
 Cephalic phase :
The sensory , psychological and even mechanical esophageal vagal pathway
activated enzyme secretion to 50 % of the total.

 Gastric phase :
It is in active gastric distension reflexes vagovagales favoring enzyme secretion but
not alkaline . At this stage no gastrin intervenes .
 Intestinal phase :
It is the most important. Chyme entry into the duodenum entails the activation of
the different sensors which duodenal and jejunum following reflections generated
vagovagales activation ( duodenal distension ) and the release of different
hormones. Increased duodenal acid ( pH 4.5 ) and the presence of fatty acids with
more than 8 carbons and bile acids stimulate secretion by cells of the duodenum
and jejunum S secretin new product , specifically peptide hormone that stimulates
bicarbonate secretion and water in the ductal cells and to a lesser extent the
enzyme . The effect of this hormone is performed through the cAMP pathway is
enhanced by the presence of another hormone cholecystokinin duodenal origin
(CCK) new product , which is not by itself able to stimulate alkaline secretion .
Performed similar effect ACh and VIP (the latter is perhaps the most important
regulator of exocrine pancreatic secretion ) . The presence of fatty acids duodenal
light over 8 carbons, their monoglycerides, amino acids such as phe, val , met and
tryp and calcium ion release stimulated by cells I ID , cholecystokinin pancreomicina ( CCK ) peptide hormone (very similar to gastrin ) that acts
preferably on pancreácticas acinar cells to stimulate enzyme secretion , through
the increase of intracellular ionized calcium . Action is enhanced markedly by the
least ACh and secretin . PLG neuropeptide ( gastrin-releasing polypeptide )
pancreatic nerve terminals is an important activator enzyme secretion by acinar
cells (also bombesin ), but increases their effectiveness in the company of
cholinergic stimulation . Neurotensin , acts synergistically in the pancreas so that
the power secretin enzyme secretion and reduces bicarbonate . With the CCC ,
reduce enzymatic and increases bicarbonate . Decrease endogenous opioids
stimulated pancreatic secretion hormones. There is evidence that sympathetic
stimulation in addition to its vasoconstrictor effects , appears to directly stimulate
pancreatic enzyme secretion . Moreover, it has been found that increasing the
concentration of trypsin in the duodenum is a decrease of pancreatic enzyme
secretion , possibly mediated by CCK . For example, providing a high dose of
dietary soy is a pancreatic hypertrophy because soybean is a protease inhibitor ,
which reinforces the idea of a concentration retrocontrol between active proteases
and pancreatic secretion . Also appears to be a control on the types of pancreatic
enzymes secreted depending on the nutritional characteristics of the diet , given
that high protein diets , proteases are multiplied by 3 by 2.5 lipase and amylase is
divided by 6 . In fat diets , lipases are multiplied by 7 and high-carbohydrate diets is
multiplied amylase between 1 and 5 . The mechanisms are unknown, but possibly

hormonal factors intervene consequential to the presence of these nutrients in the
blood, or perhaps the same nutrients . For example, it has been shown that insulin
appears to have a potentiating effect of CCK on pancreatic amylase secretion . In
fasting for more than 48 hours there is a significant decrease in pancreatic mass .
And very prolonged fasting pancreatic regression can be irreversible.