PANCREAS

Cell Types in Pancreatic Islets of Langerhans

Cell Type
A cell 20% Glucagon,
proglucagon
B cell 75% Insulin, C
peptide,
proinsulin
D cell 3-5% Somatostatin
F cell <2% Pancreatic
polypeptide

Insulin is a small protein with a molecular

weight of 5808; composed of two amino acid chains
connected to each other by disulfide linkages;. When
the two amino acid chains are split apart, the functional
activity of insulin molecule is lost. *One sixth of the final secreted product is still in
the form of proinsulin and has virtually no insulin
activity.

TARGET CELL RECEPTORS

The insulin receptor is a combination of four
subunits held together by disulfide linkages: two alpha
subunits that lie entirely outside the cell membrane and
two beta subunits that penetrate through the
membrane, protruding into the cell cytoplasm. The
insulin binds with the alpha subunits on the outside of
the cell, but because of the linkages with the beta
subunits, the portions of the beta subunits protruding
into the cell become autophosphorylated.
Insulin receptor is an example of an enzyme-
linked receptor. Autophosphorylation of the beta
subunits of the receptor activates a local tyrosine
kinase, which in turn causes phosphorylation of multiple
other intracellular enzymes including a group called
insulin-receptor substrates (IRS). Different types of IRS
(e.g. IRS-1, IRS-2, IRS-3) are expressed in different
tissues. The net effect is to activate some of these
enzymes while inactivating others. In this way, insulin
directs the intracellular metabolic machinery to produce
the desired effects on carbohydrate, fat, and protein
metabolism.

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Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012

GLUCOSE TRANSPORTERS
Na Active Transport (Na-Gluc CoTransport)
Na dependent Glucose transporter (SGLT)
SGLT 1 absorption of glucose in SI and renal tubules
SGLT2 absorption of glucose in renal tubules
Facilitated Diffusion
Glucose transporter(GLUT)
GLUT 1 basal glucose uptake (placenta, RBC, BBB,
kidneys, colon, other organs)
GLUT 2 B cell sensor, transport out of intestinal and
renal epithelial cells
GLUT 3 basal glucose uptake (brain, placenta, kidneys
and other organs
GLUT4 insulin stimulated glucose uptake (skeletal and
cardiac muscle, adipose tissue and other tissues)
GLUT 5 fructose transport (jejunum, sperm)
GLUT 6 none
GLUT 7 G-6-PO4 transporter in Endoplasmic Reticulum
(liver)
2
Dr. Gloria Marie Valerio
Pancreas
Physiology B
INSULIN
Actions of Insulin
The Insulin Receptor
-the portion of the insulin
receptor that faces externally has the
hormone binding domain
-the portion of the insulin
receptor that faces the cytosol
has tyrosine kinase activity.
When occupied by insulin, the
receptor phosphorylates itself
and other proteins
*Insulin binds to the a-subunit of its receptor,
which causes autophosphorylation of the b-subunit
receptor, which in turn induces tyrosine kinase activity.
The receptor tyrosine kinase activity begins a cascade of
cell phosphorylation that increases or decreases the
activity of enzymes, including insulin receptor
substrates, that mediate the effects of glucose on
glucose, fat, and protein metabolism. For example,
glucose transporters are moved to the cell membrane
to facilitate glucose entry into the cell.
EFFECTS OF INSULIN IN CARBOHYDRATE METABOLISM
Target cells : Muscle cells, liver cells, adipose cells
Insulin
Peripheral uptake of Glucose (primary effect of
insulin)
-glucose is taken up by peripheral
tissues via facilitated transport (a passive
transport not linked to s odium). Insulin
facilitates this uptake in some tissues.
-typically the insulin receptor causes the
insertion of glucose transporters in the
membrane.
Insulin dependent cells (membrane of these cells are
slightly permeable to glucose without insulin)
adipose cells
resting skeletal muscle(although glucose can
enter working muscle without the aid of insulin)
WBC
Insulin independent cells (membrane of these cells is
already permeable to glucose even without insulin)
-nervous tissue
-renal tubules
-intestinal mucosa
-RBC
-beta cells of pancreas
9 January 2012
transcribed for Medicine 1-B
nd
2 Semester SY 2011-2012
 Insulin accelerates but is not required for 2 conditions wherein the membrane of the muscles
glucose uptake by the liver. It does this by enhancing become highly permeable to glucose:
glucose metabolism, not by inserting new transporters after a meal
into the membrane. moderate to heavy exercise

* membrane of hepatocytes is already permeable to

glucose even without insulin, insulin will enhance Effects in ADIPOCYTES
glucose uptake not by GLUT 4 but by insulin acting on Promotes triglyceride storage
hepatic enzyme. Increase glucose transport into fat cells
thus increasing availability of alpha-
Effect in LIVER glycerol phosphate for triglyceride
anabolic effects synthesis
promotes(+) glycogenesis Inh(-) intracellular lipolysis
promotes(+) glycolysis ______________________________________________
anticatabolic effects
inh(-) glycogenolysis EFFECT OF INSULIN IN FAT METABOLISM
inh(-) gluconeogenesis Target cells : hepatocytes, adipose cell
*The end effect of all these actions is to decreased
blood glucose level. stimulates(+) lipogenesis in liver

After a meal: (blood Glucose increased) Glucose

Insulin stimulates(+) Glycogenesis ,thus; Citrate/isocitrate
Glucokinase Triglyceride
Glycogen synthase-converts gluc to glyc
Insulin inhibits(-) Glycogenolysis ,thus;
Phosphorylase splits glycogen to glucose
phosphate G-6-PO4
Glucose Phosphatase splits phosphate from Acetyl coA
glucose
Malonyl
In between meals: blood glucose level will fall thus, coA
insulin secretion will decrease.
(glycogenesis inhibited,
glycogenolysis stimulated) Glycolytic
Pathway
Effects in MUSCLE CELLS
promotes glycogen synthesis * malony coA is important in the synthesis of
increase glucose transport fatty acids. Fatty acids produced are converted to
enhances activity of glycogen synthase triglycerides and then transported to the adipose cells.
inhibits activity of phosphorylase In the adipose cells(outside):

Triglyceride --> FA + alpha-Glycerophosphate

(+) insulin (-) insulin via enzyme : Lipoprotein Lipase
HSL (-) (+)
Phospholipids dec inc The FA and a-GP is then transported inside of
Ketone bodies (-) (+) the adipocyte. Inside the adipocyte, a-GP will bind the
FA to once again form Triglyceride(now Triglyceride is
on the inside of adipocyte)

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Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012
 inh.(-) formation of ketone bodies
inhibits(-) hormone sensitive lipase (ketogenesis)
catalyzes breakdown of triglycerides
(lipolysis)

What happens if Insulin is deficient? peripheral receptors -> inc. respiratory activity (rapid
Increased lipolysis -> FFA, PL (ketone bodies) -> and deep)
Cholesterol (goes in the blood) Cardio effect
Respiratory effect Inc. cholesterol -> CVA(stroke), MI, HPN
Increased ketone bodies (acetoacetic acid, beta- CNS effect
hydroxybutyric acid) -> dec. pH -> metabolic acidosis Hyperglycemic Coma
(ketoacidosis) -> stimulates chemoreceptors and s/s : rapid and deep breathing, (+)
acetone breath

__________________________________________________________________________________________________

EFFECT OF INSULIN ON PROTEIN METABOLISM synthesis protein catabolism

Target cell: liver, muscle
One of the immediate effects of insulin on the target Insulin = ANABOLIC
cell is to increase uptake of amino acids.
Exagerration: if you want to have body building, it is not
2 target cells: Liver, muscle necessary to inject insulin.

The same goes with GH but involves different amino

acid.

w/o insulin 1.) catabolism of CHON called muscle

wasting, 2.) decreased resistance to infection, because
first of muscle wasting, second the antibodies that are
supposed to protect the body from infection are also
complete.

INSULIN EFFECTS ON POTASSIUM

Insulin - cellular uptake of potassium by the activity

of the Na/K-ATPase pump.

Insulin pumps K+ into cells. Although the overall process

is not well understood, Insulin increases the activity of
Na/K-ATPase in most body tissues

When amino acid goes in, lower effect of insulin will This is important in patients suffering from renal failure,
stimulate transcription as well as translation cannot throw away K+ hyperkalemia

mRNA = protein synthesis Consequence of hyperkalemia:

extracellular K+ effect on excitable cells, example
To catalyze the effect of insulin in relation to cardiac muscle cells more excitable because,
protein metabolism,

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Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012
K+ outside, concentration gradient, K+ will go -increased blood amino acids
out, less negative hypopolarize membrane of cardiac -Glucagon, GIP, Ach (glucose)
muscle cellarrythmiacardiac failure -Gastrointestinal hormones (gastrin, cholecystokinin,
secretin)-secreted after a mealincrease blood glucose
To reduce extracellular K+ - inject insulin to increase levelstimulate insulin secretion
cellular uptake of the cell -diabetogenic hormones: glucagon, growth hormone,
To protect the patient from hypoglycemia inject cortisol
glucose together with insulin -parasympathetic stimulation
-B-adrenergic stimulation
This K+ lowering action of insulin is used to treat acute, -insulin resistance: compensatory mechanism
life-threatening hyperkalemia. - obesity
-sulfonylurea drugs(glyburide, tolbutamide)
For example, sometimes hyperkalemia of renal failure is
successfully lowered by the simultaneous DECREASED INSULIN SECRETION
administration of insulin and glucose.(The glucose is
given to prevent severe insulin-induced hypoglycemia -decreased blood glucose
from developing.) -fasting
-somatostatin
PRINCIPAL ACTIONS OF INSULIN --adrenergic activity
Categorize to rapidity of action: -leptin: decrease appetitedecreased food intake

Rapid (within seconds) HORMONES INFLUENCING INSULIN SECRETION

-increases transport of glucose, amino acids, K+ Biphasic-there are 2 stages of secreting insulin: 1st and
into insulin sensitive cells 2nd stage

Intermediate (within minutes)

stimulates protein synthesis and inhibits
protein catabolism.
stimulates glycogenesis and other glycolytic
enzymes.
inhibits glycogenolysis and gluconeogenic
enzymes.

Delayed (hours)
increases mRNAs intracellular enzymes for
lipogenesis

FACTORS THAT WILL EITHER STIMULATE OR INHIBIT

INSULIN SECRETION:
1st stage increases rapidly within 2-3 mins
-occurs several minutes before blood sugar level goes
up due to release of preformed insulin
INCREASE INSULIN SECRETION

-increased blood glucose

-increased blood free fatty acids

5
Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012
If you go halfway, there is another peak secondary to
release of pre formed insulin and newly synthesized
insulin
2nd stage longer, 2-3 hrs increase and higher than the
1st peak. In diabetic, this peak is planted initially
-release of preformed insulin and newly synthesized
insulin
Most important factor that will stimulate insulin
secretion is an increase in the blood glucose level
HORMONES THAT STIMULATE INSULIN SECRETION
GH impairs glucose utilization Hyperglycemia
Insulin release
- diabetogenic: increase blood glucose level, stimulate
insulin secretion, decreases peripheral utilization of
glucose hyperglycemiaInsulin secretion
-ketogenic because due to mobilization of FA
ketogenesis
ACTH Cortisol
Gluconeogenesis Lipolysis
Insulin release Ketone bodies

GLUCAGON

Gluconeogenesis Glycogenolysis

hyperglycemia

Insulin release

blood glucose level facilitate entry of glucose into -can direct beta cells to secrete insulin
the beta cells which has GLUT2 transporter
EPINEPHRINE
Glucose will diffuse into the cell, will be phosphorylated
to G-6-PO4 by glucokinase and will be oxidized leading Glycogenolysis Peripheral Lipolysis
to an increase of ATP Utilization
of Glucose FFA
ATP will inhibit ATP dependent K+ channel No K+
efflux, hypopolarize depolarization and opening of Hyperglycemia Ketone bodies
voltage gated calcium channel, Ca efflux
Insulin Release
Opening of the voltage gated channel will lead to the
increase of intracellular calcium and there will be SOMATOSTATIN (SIF)
exocytosis of insulin
Insulin and Glucagon secretion/release
Insulin secretion is Calcium dependent.

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Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012
THYROID HORMONES hepatocytes

MECHANISM OF ACTION OF GLUCAGON

GLUCAGON - protein hormone that will bind with a

membrane receptor in the hepatocyteactivating
adenylyl cyclase formation of cAMP (2nd messenger)
Cyclic AMP will then activate protein kinase A
leading to the different actions of glucose.

GLUCAGON

ACTIONS OF GLUCAGON
Glucagon is: a peptide hormone
Secreted by alpha cells of the
pancreatic Islets
Its primary target is the liver
Precursor molecule: preporglucagon
proglucagon active form of glucagon (MW SPECIFIC ACTIONS OF GLUCAGON ON LIVER
3500)
(skeletal muscle is NOT a target tissue of Imlpication of carbohydrate metabolism:
glucagon) -Increases Glycogenolysis
Physiologic antagonist of insulin -Increases Liver Gluconeogenesis
Implication to fat metabolism:
INSULIN GLUCAGON - Increases Lipolysis in the liver
Stimulated when Stimulated when -Increases Liver ketogenesis
increase in blood decrease in blood -Decreases Liver Lipogenesis
glucose level glucose level Implication to protein metabolism:
decrease blood increase blood glucose -Decreased protein synthesis
glucose level level -Increased protein catabolism
Hyperglycemic agent Hypoglycemic agent Increases Ureagenesis
Anabolic storage of Catabolic promotes Increases Insulin secretion
glucose in target cells mobilization of
glucose Factors that regulate the secretion of glucagon:
Many several target Only one target cell - 1. Decrease in blood glucose level.
cells adipose cells, hepatocyte
muscle cells,

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Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012

In graph, glucose, plasma glucagon conc.
glucose, plasma glucagon conc.
(opposite of insulin)
OTHER FACTORS THAT REGULATE GLUCAGON
SECRETION
-adrenergic stimulation increases glucagon
secretion via cAMP
Vagal stimulation increases glucagon
CCK and gastrin increases glucagon
Secretin, FFA and ketones and insulin inhibits
glucagon
Summary of homeostatic system, regulating blood
glucose level that involves two pancreatic hormones,
insulin and glucagon.
First, if the blood glucose levels increases the pancreas
will release insulin which has 3 major target organs:
liver, adipose, and muscle cells.
8
Dr. Gloria Marie Valerio
Pancreas
Physiology B
In relation to carbohydrate metabolism, 3 target cell. In
liver, increases glycogenesis, decreases glycogenolysis.
In fats, increased glucose uptake. In muscles increased
glucose uptake, increased glycogenesis, decreased
glycogenolysis.
In relation to fat metabolism, 2 target cells, in liver and
in fats. In liver, increased lipogenesis, decreased
lipolysis, decreased ketogenesis. In fats, increased
lipogenesis, increased lipolysis.
In relation to protein metabolism, 2 target cells, liver
and muscle. Increased amino acid uptake, increased
protein synthesis, decreased protein catabolism.
Glucagon has only 1 target cell: liver cells
When the blood glucose level is low, the pancreas will
release glucagon.
Action of glucagon: In carbohydrate catabolis-
glycogenolysis, gluconeogenesis, in fat metabolism-
ketogenesis, lipolysis, in protein catabolism- decreased
synthesis, increased catabolism.
REGULATION OF SOMATOSTATIN SECRETION (after a
meal)
Increased blood glucose
Increased amino acids
Increased fatty acids
Increased concentrations of several GI
hormones
EFFECTS OF SOMATOSTATIN
Somatostatin acts locally within the Islets of
Langerhans themselves to depress the secretion
of both insulin and glucagon.
Somatostatin decreases the motility of the
stomach, duodenum, and gallbladder.
Somatostatin decreases both secretion and
absorption in the gastrointestinal tract.
Same somatostatin secreted by the
hypothalamus that will inhibit GH secretion.
Same as GHIH.
9 January 2012
transcribed for Medicine 1-B
nd
2 Semester SY 2011-2012

Consequence of insulin deficiency in
carbohydrates, fats, and protein metabolism:
No insulin, effect on protein metabolism: decrease
synthesis, increased catabolism leading to protein
depletion, muscle wasting, decreased resistance to
infection and negative nitrogen balance.
Effect of insulin deficiency on fat metabolism,
increased lipolysis, increased ketogenesis: inc
formation of ketone bodies in the blood,
ketoacidosis/metabolic acidosis, increasing
repiratory activity of the patient, called composed
respiration, depressing the CNS may lead to COMA.
Another consequence is increased cortisol
deposited in the arterial wall: hypertension,
myocardial infarction, cerebrovascular accident.
Insulin deficiency in glucose metabolism:
glucose uptake by the cell : IC glucose
EC glucose
Decreased intracellular glucose cell
starvationstimulate appetite center in
9
Dr. Gloria Marie Valerio
Pancreas
Physiology B
hypothalamusinc. appetiteinc. food
intakePOLYPHAGIA
Increased extracellular glucoseHYPERGLYCEMIA
ECF becomes hypertonic, effect on ICF: fluid will go
out from ICF to ECFthirst center POLYDYPSIA
Renal threshold: when conc. of substance in the
blood is above normal, it will start to spill in the
urine. (Renal threshold for glucose: 180mg/100ml
blood (180mg%))
If plasma glucose level exceeds renal threshold, ex.
200mg, not be able to reabsorb excess glucose, spill
glucose in the urineGLYCOSURIA
Glucose is almost completely absorbed in the prox.
convoluted tubule, should not be present in the
urine
Glucose is osmotically active will attract fluid and
electrolytes to be flushed out into the
urineOSMOTIC DIURESIS POLYURIA
If not corrected, will further dehydrate patientinc
plasma osmolalitydec blood volCIRCULATORY
SHOCK
DISORDERS OF GLUCOSE METABOLISM
DIABETES MELLITUS
Is a syndrome of disordered metabolism with
inappropriate hyperglycemia due to either an
absolute deficiency of insulin secretion or a
reduction in the biologic effectiveness of insulin
(or both)
Characterized by hyperglycemia which can be
secondary to:
Defects in insulin production
Autoimmune or other destruction of beta cells
Insulin insensitivity
Impaired action of insulin on target tisssues
9 January 2012
transcribed for Medicine 1-B
nd
2 Semester SY 2011-2012
 DIAGNOSIS OF DIABETES MELLITUS TYPE 1 DIABETES MELLITUS
-develops abruptly, within a few days or a few weeks
FBS (fasting blood sugar) px should not have -decreased or absent insulin secretion
any caloric intake for at least 8hrs before you
extract venous blood (N.V. Varies, now: 80-90 Primary Cause: destruction of the beta cells of the
mg/dl) pancreatic islet either due to autoimmune disorder or
- upper limit for normal is 110 viral infection (in some instances, theres a hereditary
- 110-125:impaired glucose tolerance: problem tendency of beta cell deterioration even without a viral
in glucose metab but not diabetic infection or autoimmune disorder)
- above 125: diabetic
75g OGTT (oral glucose tolerance test) CLINICAL FEATURES:
-1st specimen is fasting Age of onset Usually <20 years old
-give glucose 1g / kg body wt (juvenile onset) but can develop
-every 30mins, measure blood glucose level for at any age
a period of 2 hrs. Body mass low to normal
-after intake of glucose, glucose level should Plasma insulin low or absent (destruction of
normally be high 80 to 100 even up to 140. pancreatic beta cells)
-After 2 hrs, it should come back to normal. Plasma glucagon high, can be suppressed
-There should be no value above 200mg. Plasma glucose high
RBS (random blood sugar)- can take blood Insulin sensitivity normal (no problem, if given
sugar level anytime, if normal, small difference insulinwill respond)
in between meals. Therapy insulin (aka. Insulin-dependent
2hr post prandial blood glucose if normal diabetes mellitus)
functioning of beta cells: 2hrs after a meal, Ketosis prone positive(ketoacidosis)
blood glucose should return to normal
Glycated hemoglobin- does not need fasting. TYPE 2 DIABETES MELLITUS
Detects total amount of glucose that we store -develops gradually
for 2-3 months (Hb in RBC lifespan-120 -no. 1 risk factor: obesity (fewer receptors for insulin in
days/3months) the liver, adipose and muscle cells). Also, problem in cell
signaling, in the action of insulin on the target cells.
CLASSIFICATION OF DIABETES
Type 1 Diabetes Mellitus Primary problem: resistance to insulin (included in
Type 2 Diabetes Mellitus metabolic syndrome)
Gestational Diabetes - in some pregnant
women, blood glucose level increases, either METABOLIC SYNDROME TYPE2 DM
because of inc food intake rich in Factors:
carbohydrates, fats and it could also be due to 1. Insulin resistance
diabetogenic hormones eg. HCG(in 9-10 2. Obesity
pounder babies) 3. Spastic hyperglycemia
Other/Secondary diabetes cushing syndrome 4. Abnormalities in lipid metabolism
and acromegaly 5. Hypertension
Cushing cortisol diabetogenic
Acromegaly GH diabetogenic

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Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012
CLINICAL FEATURES
Age of onset Usually >30 years old
(adult onset DM)-but can
develop at any age
Body mass obese(metabolic syndrome)
*Accumulation of fat deposits
in the abdomen
Plasma insulin normal to high initially
(compensatory mechanism)
There is release of insulin but
no action of insulin on the
target cell
Plasma glucagon high, resistant to suppression
Plasma glucose high
Insulin sensitivity reduced (bec. prob. is receptor
in the target cell)
Therapy diet, exercise, oral hypoglycemic
agent (eg. Metformine-inh.
gluconeogenesis), insulin tx(beta
cells have worked out)
Ketosis prone negative
Can also affect the nerve: Atherosclerosis + Neuropathy
ulceration gangrene of lower extremity
HYPOGLYCEMIA- dec. in blood glucose level
Causes: (even not diabetic)
-fasting (hunger, headache, dizziness)
-inc. insulin therapy (in diabetics)
-adenoma in the pancreatic islets hypersecretion of
insulin
If brain cells depend on glucose for energy:
1st affected by hypoglycemia: CNS
-At 80mg FBS: almost complete insulin secretion
-If blood glucose level falls to 70mg:
hypoglycemia(hunger, headache, dizziness)
autonomic discharge
Tremors
Sweating
Hunger
Palpitation

METABOLIC FEATURES OF DM: If below 70 counter regulatory hormones

1. POLYURIA, OSMOTIC DIURESIS dehydrated
POLYDYPSIA
2. Dec. protein synthesis, inc protein catabolism
protein depletionmuscle wasting
COMPLICATIONS OF DIABETES MELLITUS
Uncontrolled blood glucose level: complication whole
body(bec first affected is blood vessel) Microvascular
and macrovascular complication
MICROVASCULAR
When blood vessels in the retina of the eyes is affected
diabetic retinopathyblindness
-secreted when glucose level falls, they will try to
increase blood glucose level.
Includes: GH, glucagon, cortisol, epinephrine
GH - decrease peripheral stimulation of glucose
Cortisol - inc gluconeogenesis
EP - glycogenolysis
Glucagon glycogenolysis, gluconeogenesis
If blood glucose levels continues to fall:
below 50: lethargic, hallucination
at level of 40: seizure
Below 40: COMA

Most commonly affected: BV of kidney (esp.

glomerulus) diuretic nepropathyRENAL FAILURE

MACROVASCULAR
Atherosclerosis hypertension, myocardial infarction,
cerebrovascular accidentSTROKE

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Dr. Gloria Marie Valerio 9 January 2012
Pancreas transcribed for Medicine 1-B
nd
Physiology B 2 Semester SY 2011-2012