MODULE 11: ENDOCRINE SYSTEM

Pancreas
JULIE ANNE L. GABAT MD, FPCP, DPSEDM
03/31/2020 (08:00-17:00)
PHYSIOLOGY

TABLE OF CONTENTS The pancreas is an elongated, accessory digestive gland that lies
retroperitoneally, transversely crossing L1 and L2 vertebra (Moore, 265).
I. OVERVIEW OF THE PANCREAS ................................................................................... 1 It is divided into four parts: head, neck, body and tail (Moore, 266).
A. STRUCTURES ....................................................................................................... 1 It is located in the curvature of the duodenum (12.09, 2023).
B. CELL TO CELL COMMUNICATION........................................................................ 1 • Made up of two types of tissues:
II. INSULIN STRUCTURE & SYNTHESIS ........................................................................... 2
o Exocrine: Pancreatic Acini
A. PROPERTIES OF INSULIN ..................................................................................... 2
B. SYNTHESIS OF INSULIN ....................................................................................... 2 Greater bulk of the pancreas
C. METABOLISM OF INSULIN AND C-PEPTIDE ........................................................ 2 Comprised of Acini, which produce the alkaline fluid and digestive
D. OTHER BETA CELL SECRETIONS .......................................................................... 3 juices that is secreted into the ductal system (pancreatic duct) to
III. PHYSIOLOGY OF INSULIN SECRETION ...................................................................... 3 facilitate digestion of food
A. GLUCOSE STIMULATED INSULIN SECRETION...................................................... 3  RECALL: Pancreatic duct is joined by the common bile duct, and
B. FACTORS THAT AFFECT INSULIN SECRETION...................................................... 3 eventually drains into the duodenal papilla.
C. INCRETINS ........................................................................................................... 3
Location of acini: Surrounds the ducts
D. INSULIN SECRETION............................................................................................ 4
IV. PHYSIOLOGY OF INSULIN ACTION ........................................................................... 5 o Endocrine: Islets of Langerhans
A. INSULIN RECEPTOR ............................................................................................. 5 Localized in Islets of Langerhans that are most commonly found in
B. STEPS OF INSULIN ACTION.................................................................................. 5 the tail of pancreas.
C. REGULATION OF INSULIN RECEPTION ................................................................ 5 Secretes hormones directly into the bloodstream
D. INSULIN SIGNALING ............................................................................................ 5 Location of Islets: Near the capillaries
E. INSULIN AND ITS METABOLIC EFFECT................................................................. 5
• Islets of Langerhans
V. ACTIONS OF INSULIN ................................................................................................ 5
A. EFFECT OF CARBOHYDRATE METABOLISM ........................................................ 5 o Approximately 1-2 million islets with 2,500 cells per islet
B. EFFECT ON FAT METABOLISM ............................................................................ 6 o Ovoid and organized around small capillaries into which its cells secrete
C. EFFECT ON PROTEIN METABOLISM .................................................................... 6 their hormones
D. OTHER ACTIONS ................................................................................................. 6 o Richly vascularized, and receives 10% of pancreatic blood flow
VI. ACTIONS OF INSULIN ON TISSUES ........................................................................... 6 o Accounts for ONLY 1% of the pancreatic mass
A. LIVER CELLS ......................................................................................................... 6 o Contain 4 cell types: Beta, Alpha, Delta and F/PP Cells
B. MUSCLE CELLS..................................................................................................... 7
C. ADIPOSE CELLS .................................................................................................... 7
D. TISSUES UNAFFECTED BY INSULIN ..................................................................... 7
Table 1. Cell Types in the Islets
E. METABOLISM AND EXCRETION OF INSULIN ....................................................... 7 HORMONE LOCATION
CELL TYPE % OF TOTAL
VII. GLUCAGON ............................................................................................................. 7 SECRETED
A. GLUCAGON SECRETION ...................................................................................... 7 Beta (β) Cells ≈ 60% Insulin Central
B. MECHANISM OF ACTION .................................................................................... 7 Alpha (α) Cells ≈ 25% Glucagon Periphery
VIII. DELTA CELLS: SOMATOSTATIN .............................................................................. 7 Delta (δ) Cells ≈ 10% Somatostatin Periphery
IX. F CELLS: PANCREATIC POLYPEPTIDE ........................................................................ 8
X. IMPORTANCE OF CONTROLLING BLOOD SUGAR LEVELS ......................................... 8 Pancreatic
F-cells/PP Cell < 2%
QUICK REVIEW .............................................................................................................. 8 Polypeptide
SUMMARY OF TERMS ............................................................................................. 8
SUMMARY OF PROCESSES ...................................................................................... 8
REVIEW QUESTIONS................................................................................................ 9
REFERENCES .................................................................................................................. 9
REQUIRED ............................................................................................................... 9
FREEDOM SPACE ........................................................................................................... 9

I. OVERVIEW OF THE PANCREAS

A. STRUCTURES

Figure 2. Distribution of Cells Across the Islets

B. CELL TO CELL COMMUNICATION

• Intimate relationship of cells within the islets suggests their paracrine and
counter-regulatory function
o Insulin inhibits glucagon
o Amylin inhibits insulin
o Somatostatin inhibits both glucagon & insulin
• Communication is done through:
o Gap Junctions
o Unique blood supply of the Islets
o Innervation
Figure 1. Anatomy of the Pancreas

Transcribed by TG 16: Antonio, Bantilan, Cases, Cruz, Hermoso, Lintag, Singson, Sy

YL5: 11.03
Checked by TG 4: Caraang, Dy, Gonzales, Liberato, Montaus, Ologenio, Sumang 1 of 9
Gap Junctions 2) Preproinsulin MRNA Preproinsulin synthesis
o Preproinsulin mRNA directs ribosomal synthesis (translation) of
• Connect alpha cells to each other, beta cells to each other, and alpha cells
preproinsulin, which contains 4 peptides:
to beta cells
Signal Peptide
• Allows rapid cell to cell communication via ionic current flow or transfer of
Alpha Chain
molecules (up to 1,000 MW)
Beta Chain
Connecting Peptide (C-Peptide)
Unique Blood Supply 3) Preproinsulin Proinsulin
• Islets receive 10% of total pancreatic blood flow o Preproinsulin (11,500 MW) is cleaved by microsomal enzymes in the
• Scheme: Arterioles enter the core of the islet and its fenestrated endoplasmic reticulum to form proinsulin
capillaries, and then converge into venules that carry blood to the rim of Amino-terminal signal peptide was removed almost immediately
the islet. after synthesis
• Important so venous blood carries insulin from beta cells to alpha and delta Proinsulin consists of: alpha and beta chains, C-peptide
cells found in the periphery of the islets (hormone-rich blood bathes 4) Proinsulin Transport to Golgi
structures surrounding the cell source for regulatory purposes) o Proinsulin (9,000 MW) is transported to the Golgi apparatus and is
cleaved by proteases to form the active insulin and C-peptide
Innervation 5) Active insulin + C-peptide Packaging
o Active insulin (5,805 MW) and C-peptide (3,000 MW) are packaged into
• Islets are innervated by adrenergic, cholinergic & peptidergic neurons
secretory granules
• Delta cells send dendrite-like processes to beta cells (suggestive of intra- o Mature secretory granules contain insulin and C-peptide in equimolar
islet neural communication) amounts (1 C-peptide : 1 insulin molecule)
o 5-10% of the secretory products are uncleaved proinsulin
II. INSULIN STRUCTURE & SYNTHESIS 6) Insulin Release
A. PROPERTIES OF INSULIN o Both insulin and C-peptide are released into circulation in equimolar
amounts when stimulus is present
Proinsulin
• Single chain made up of 86 amino acids
• Consists of the alpha and beta chains of the insulin molecule, and a
connecting segment of 35 amino acids

Figure 4. Proinsulin Cleaved Into Active Insulin and C-peptide within a

Secretory Granule
Figure 3. Structure of Human Proinsulin C peptides and Insulin Molecules
Connected at Two Sites by Dipeptide Links

Insulin
• A small protein composed of 51 amino acids with two peptide chains joined
by a disulfide bond
o A chain: 21 amino acids
Contains an intrachain disulfide bridge that links peptides 6 and 11
o B chain: 30 amino acids
• The functional activity of insulin is lost when the two peptide chains are
split apart
• Goal: Increases blood glucose concentration
• Storage:
o Fat synthesis and storage
o Protein synthesis
o Glycogen synthesis
• Insulin is the first hormone to:
o Be isolated from animal sources that could be therapeutically
Figure 5. Synthesis of Insulin
administered to humans
o Have its mechanism of action elucidated C. METABOLISM OF INSULIN AND C-PEPTIDE
o Be measured by radioimmunoassay
o Be synthesized from a larger precursor/prohormone • Insulin circulates in free form
o Be synthesized via recombinant DNA o t1/2 (half-life) = 6 mins
o Clearance = 10-15 mins
• A gene in the short arm of chromosome 11 (part of a superfamily of genes
that encode related growth factors) directs insulin synthesis • Inactivated by insulinase in the liver (mainly), kidneys, and muscles (lesser
amount)
• C-peptide is cleared more slowly
B. SYNTHESIS OF INSULIN o Useful marker for endogenous insulin secretion
1) Transcription factors activate preproinsulin transcription o Allows discrimination between endogenous and exogenous sources of
o Unique set of transcription factors found in β cell nucleus activates the insulin
transcription of preproinsulin mRNA from the insulin gene Evaluation of hypoglycemia and Type 1 Diabetes Mellitus

YL5: 11.03 ENDOCRINE SYSTEM: Pancreas 2 of 9

 B. FACTORS THAT AFFECT INSULIN SECRETION
D. OTHER BETA CELL SECRETIONS
• Islet Amyloid Polypeptide (IAPP) or amylin is a 37 amino acid peptide that Table 3. Factors and conditions that Increase or decrease insulin secretion
is secreted along with insulin (12.09, 2023).
o Released from beta cells as a satiation signal following food intake INCREASE INSULIN SECRETION DECREASE INSULIN SECRETION
o Slows down gastric emptying to prevent hypoglycemia a few hours after Increased blood glucose Decreased blood glucose
a meal; hence, it takes about 4 hours to fully digest a meal Increased blood free fatty acids Fasting
o Major component of amyloid fibrils found in islets of patients with Type Increased blood amino acids Somatostatin
2 Diabetes Mellitus Gastrointestinal hormones
(gastrin, cholecystokinin, secretin, -Adrenergic activity
Table 2. Stimulants, Amplifiers, and Inhibitors of Insulin Release gastric inhibitory peptide)
AMPLIFIERS OF Glucagon, growth hormone,
STIMULANTS OF INHIBITORS OF INSULIN Leptin
GLUCOSE-INDUCED cortisol
INSULIN RELEASE RELEASE
INSULIN RELEASE Parasympathetic stimulation
Neural: Alpha (Acetylcholine)
Enteric Hormones:
adrenergic effect of
Glucose GLP, GIP, CCK, -Adrenergic stimulation
catecholamines
Secretin, Gastrin Insulin Resistance (obesity)
Sulfonylurea drugs (glyburide and
Neural Amplifiers:
Humoral: tolbutamide)
Mannose Beta adrenergic
Somatostatin
stimulation
• Note that the following were emphasized by Doc last year:
Leucine Drugs: Diazoxide,
o Increased blood amino acids
Vagal Stimulation Phenytoin,
Amino Acids: Arginine Specifically arginine and lysine
Vinblastine,
Sulfonylureas , of glucose-stimulated insulin secretion
Colchicine
However, these do not stimulate insulin release in the absence of
glucose
III. PHYSIOLOGY OF INSULIN SECRETION o Gastrointestinal hormones
• Glucose is the key regulator of insulin secretion by the pancreatic beta-cell Specifically the incretins glucose-dependent Insulinotropic Peptide
o Glucose levels >70mg/dL (3.0 mmol/L) stimulate insulin synthesis by (GIP) and glucagon-like Peptide-1 (GLP-1)
enhancing protein translation and processing  Enhance the rate of insulin release in response to oral glucose
Normal Fasting Blood Glucose: 80-90mg/dL (12.09, 2023). load
• Insulin down-regulates its own receptor by decreasing the rate of synthesis  Inhibit glucagon secretion
and increasing the rate of degradation o Glucagon, growth hormone, and cortisol
These hormones have stimulatory effects on insulin secretion
A. GLUCOSE STIMULATED INSULIN SECRETION If the secretion of these hormones are prolonged and are in large
quantities, these can cause exhaustion of beta cells leading to an
• Glucose is transported into the beta cell by a facilitative glucose transporter
increased risk of diabetes mellitus
GLUT-2 (facilitated diffusion)
Glucose concentrations can also be detected by:
Glucokinase catalyzes the phosphorylation of glucose to prevent it from
 Specialized neurons of the hypothalamus and brainstem
leaving the cell (12.09, 2023).
o Rate-limiting step of glucose-stimulated insulin secretion  Glucose-sensing cells in peripheral locations (e.g. liver)
o Major mechanism for glucose sensing and control of amount of insulin o Parasympathetic stimulation through acetylcholine
secreted into the blood o Progesterone and Estrogen also have stimulatory effects on insulin
secretion but to a lesser extent
• Glucose is phosphorylated to glucose-6-phosphate, then oxidized with ATP
as one of the products
• ATP closes ATP SENSITIVE POTASSIUM CHANNELS C. INCRETINS
• Potassium conductance decreases and the membrane is depolarized • Released from the neuroendocrine cells of the gastrointestinal tract
Sulfonylurea drugs also inhibit potassium channels (12.09, 2023). following food ingestion
• Depolarization opens VOLTAGE-SENSITIVE CALCIUM CHANNELS • Amplifies glucose-stimulated insulin secretion and suppress glucagon
• Increased intracellular calcium causes exocytosis of vesicles and release of secretion
insulin into the pancreatic venous blood and systemic circulation • GLUCAGON-LIKE PEPTIDE-1
o The most potent incretin
o Released from the L cells in the small intestine
o Stimulates insulin secretion only when the blood glucose is above the
fasting level
Incretin analogues/pharmacologic agents that prolong activity of
endogenous GLP-1 enhance insulin secretion (12.09, 2023).
• Oral vs. Intravenous Glucose (12.09, 2023)
o Oral glucose leads to higher secretions of insulin due to the presence
of incretins
o Consequently, higher blood glucose fluctuations are observed when
intravenous glucose is administered

Figure 6. Mechanism of Glucose-Stimulated Secretion of Insulin in Beta Cells

YL5: 11.03 ENDOCRINE SYSTEM: Pancreas 3 of 9

 Figure 8. Approximate Insulin Secretion at Different Plasma Glucose Levels

Prandial Insulin Secretion

Figure 7. The Incretin Concept
Table 4. GLP-1 (Glucagon-like Peptide-1) vs GIP (Glucose-Dependent
Insulinotropic Polypeptide)
GLP-1
Secreted by L-cells in the distal gut
(ileum and colon)
Stimulates glucose-dependent
insulin release
Inhibits glucagon secretion in a
glucose-dependent manner
(suppresses hepatic glucose
output)
Enhances beta-cell proliferation
and survival in animal models and
isolated human islets
• First phase
o Rapid insulin peak
o Lasts 10 minutes
o Suppresses hepatic glucose production
o Not maintained
o Decreases in 5-10 minutes but does not reach the basal level
o Facilitates phase 2 release
• Second phase
o Directly related to the level of glucose elevation
o Lasts for two hours
o Covers mealtime carbohydrates
o More prolonged and more pronounced
o Amount of insulin secreted in this phase is greater than first phase
o Comes from additional release of preformed insulin and from newly
synthesized insulin from beta cells
GIP
• Third phase
Secreted by K-cells in the proximal
o 1.5 to 3 hours after exposure to glucose
gut (duodenum)
o With a spontaneous decline in secretion to 15%-25% of the amount
Stimulates glucose-dependent
released during peak secretion
insulin release
NOTE: Insulin Secretion Before and After a Meal (12.09, 2023)
o 0-60 minutes: Basal secretion (insulin release before a meal)
o 60 minutes onward: Postprandial secretion (insulin release after a meal)
Enhances beta-cell proliferation
and survival in islet cell lines

Experimentally, administration of GLP-1 above physiologic levels has

shown dose-dependent inhibition of gastric emptying (12.09, 2023).
o Furthermore, it promotes beta-cell mass through proliferative and anti-
apoptotic pathways
However, while GIP stimulates a glucose-dependent insulin response, it
does not affect gastric emptying (12.09, 2023).
o Insulinotropic activity of GIP was less in type 2 diabetic patients
o Does not appear to affect satiety or body weight

D. INSULIN SECRETION
Basal Insulin Secretion
• 50% of the total insulin secreted
• Independent of glucose intake: you produce insulin whether you eat or not
• Released in pulsatile manner
o Rapid Oscillations: occur every 8-15 minutes
o Slower Oscillations: occur at periods of 80-150 minutes from insulin-
glucose feedback mechanism
• Circadian variation of secretion in normal individuals:
o Maximal postprandial responses are observed after breakfast
o If insulin is not maximally stimulated, the secretion will be dampened
and may not reach maximum during lunch or dinner
o Not the case for people with diabetes mellitus, obesity and insulin
resistance.
Control of Insulin Secretion
• The “x” in the Fig. 8 shows the fasting level (80-90mg/100mL)
• As blood glucose rises above 100mg/100mL, secretion of insulin rises
rapidly (up to 10-25x at concentrations between 400-600 mg/ 100mL)
• Turnover of insulin is almost just as rapid, occurring within 3-5 minutes
after a reduction in blood glucose concentration back to fasting levels
Figure 9. Portal Insulin Secretion Before and After Meal Ingestion (arrow) in a
Representative Dog
Total Insulin Secretion
50% of total insulin secreted under basal conditions (12.09, 2023)
o 18-32 units per 24 hours (0.7 – 1.3 mg)
Remainder is secreted in response to meals (12.09, 2023)
o Insulin secretory response is rapid
o Increases approximately 5x over baseline to reach a peak within 60
minutes
• Clinical Correlation:
o For type 1 diabetics, you provide the entire insulin dose for both basal
& after-meals (because no insulin is synthesized at all)
o For type 2 diabetics, your beta cells can still respond to acute increases
in blood glucose
You may provide the basal dose first and then add increments of the
after-meal dose according to the patient’s need

YL5: 11.03 ENDOCRINE SYSTEM: Pancreas 4 of 9

 IV. PHYSIOLOGY OF INSULIN ACTION
A. INSULIN RECEPTOR
Figure 10. Insulin Receptor
• Composed of four subunits held together by disulfide linkages
o Two α-subunits: lie entirely outside and to which insulin binds to
o Two β-subunits: traverse the cell membrane and protrude into the
cytoplasm
• It is an enzyme-linked receptor
o Insulin binding to the α-subunits causes conformational changes that
result in the autophosphorylation of the β-subunits
o β-subunits are closely linked to tyrosine kinases that cause
phosphorylation of multiple other intracellular enzymes, including a
group called insulin-receptor substrates (IRS).
B. STEPS OF INSULIN ACTION
1) Insulin binds to the α-subunits, causing dimerization and conformational
changes
2) Conformational changes are transmitted to the β-subunits, which
autophosphorylate in the presence of ATP
o The subunits will then activate tyrosine kinase
3) Activation of tyrosine kinase leads to either the activation or inhibition of
more enzymes involved in the physiologic action of insulin via
phosphorylation
4) Insulin-Receptor complex (IRC) is taken in via endocytosis
5) Insulin Receptor can be degraded by proteases, stored, or recycled
C. REGULATION OF INSULIN RECEPTION
• Insulin binds to elements in the nucleus, the Golgi apparatus, and the
endoplasmic reticulum
o Insulin mediates gene transcription, similar to both IGF-1 and IGF-2
• Insulin downregulates its own receptor by
o Decreasing rate of synthesis
o Increasing rate of degradation
• Insulin’s ability to downregulate its own receptor becomes a problem in
Diabetes Mellitus Type 2
o Main pathophysiology: increased insulin resistance rather than lack of
insulin
o Body responds by increasing plasma insulin levels to overcome
resistance
o This, in turn, further downregulates insulin receptors, adding to the
inability of target cells to respond
o Promotes a vicious cycle
D. INSULIN SIGNALING
• Activated insulin receptor (IR) phosphorylates tyrosine kinases, which in
turn phosphorylate insulin-receptor substrates (IRS) and other enzymes
involved in the physiologic action of insulin
o Signaling leads to regulation of both lipid and glucose metabolism
YL5: 11.03 ENDOCRINE SYSTEM: Pancreas
• IRS will then activate two distinct pathways via phosphorylation
o Phosphatidyl-inositol 3-kinase (PI3K) pathway
mediates the rapid effects of insulin signaling
Primarily, this leads to the increased uptake of glucose
Increased uptake of other materials like amino acids and ions
o Mitogen-activated protein kinase (MAPK) pathway
mediates insulin’s long-term effects
Gene expression
E. INSULIN AND ITS METABOLIC EFFECT
• Insulin’s main effect: increased glucose uptake
o Marked increase in uptake is seen in 80% of cells in the body,
particularly muscle cells and adipose cells, but not in most neurons in
the brain
• Increases glycogen production and fat accumulation
• Cell membrane becomes more permeable to amino acids, potassium ions,
and phosphate ions, causing increased transport of said materials into the
cell
• Slower changes occur in the next 10 to 15 minutes
o It changes the activity level of intracellular enzymes because of
phosphorylation
• Much slower effects occur within the next hours and even days
o It affects the rate of translation from mRNA and later, the rate of
transcription from DNA—therefore, affecting the rate of protein
synthesis
V. ACTIONS OF INSULIN
A. EFFECT OF CARBOHYDRATE METABOLISM
Peripheral Uptake of Glucose
Glucose is the primary stimulus of insulin secretion (12.09, 2023).
o Glucose can’t diffuse across cell membranes
Glucose is hydrophilic, not lipophilic (12.09, 2023).
• Tissue uptake of glucose is by facilitated transport
In some tissues, insulin regulates the number of membrane transporters
(12.09, 2023).
GLUT 1 and GLUT 3
• Mediate basal glucose uptake in most tissues, including brain, neurons, and
RBC
• Its high affinities for glucose ensure glucose entry even during periods of
relative hypoglycemia
The brain has GLUT receptors, but it doesn’t need insulin to increase the
permeability of glucose (12.09, 2023).
GLUT 2
• A low affinity transporter in the hepatocytes and 𝝱 islets
Signals must be present for it to be activated (12.09, 2023).
After a meal, portal blood from the intestine is rich in glucose (12.09,
2023).
GLUT 2 captures the excess glucose primarily for storage (12.09, 2023).
When glucose concentration drops below the Km for the transporter,
much of the remainder leaves the liver and enters the peripheral
circulation (12.09, 2023).
GLUT 4
• In adipose tissue and muscles
o Responds to glucose concentration in peripheral blood
o The rate of glucose transport in adipose tissue and muscle is increased
by insulin
Insulin-dependent (12.09, 2023).
Blood Glucose Concentration
• Insulin decreases blood glucose concentration
• Increases glucose transport into target cells such as muscle and adipose
tissue by causing the insertion of glucose transporters (GLUT 4) into the cell
membranes
Excess glucose in the muscle that are not utilized are stored as glycogen
(12.09, 2023).
• Increases glycogen formation from glucose (glycogenesis) in the liver and
inhibits glycogenolysis
Insulin secretion decreases between meals when blood glucose
concentrations decrease (12.09, 2023).
o Glycogen is split back into glucose and released into the blood
Inhibits gluconeogenesis (12.09, 2023).
5 of 9
 o By increasing the production of fructose-2,6-bisphosphate, which
increases phosphofructokinase activity C. EFFECT ON PROTEIN METABOLISM
Directs substrates away from the formation of glucose
Promotes conversion of excess glucose into fatty acids Promotes Protein Synthesis and Storage
• Insulin decreases blood amino acid concentration
B. EFFECT ON FAT METABOLISM • Increases amino acid and protein uptake into cells
o most commonly transported amino acids: valine, leucine, isoleucine,
Blood Fatty Acids and Keto Acid Concentration tyrosine, and phenylalanine
• Insulin decreases blood fatty acids and keto acid concentration • Increases protein synthesis
• Inhibits mobilization and oxidation of fatty acids • Inhibits protein degradation
• Increases storage of fatty acids • Suppresses gluconeogenesis
Net Effect: Fat deposition and inhibition of lipolysis (12.09, 2023).
• Inhibits ketoacid formation (𝝱-hydroxybutyric and acetoacetic acid) in the Synergistic Interaction of Insulin and Growth Hormone
liver
o Decreased fatty acid degradation means less acetyl CoA will be
available for ketoacid formation NOTE: This section was not part of the Pancreas Handout posted in the
Google Classroom but was part of the 2023 Trans.
Promotion of Fat Synthesis and Storage
• Insulin increases the transport of glucose into the liver cells
• More glucose becomes available to form fat (acetyl CoA from pyruvate to
make fatty acids)
After the liver glycogen reaches 5-6%, glucose becomes available to form
fat (12.09, 2023).
Increased citrate and isocitrate from acetyl CoA activates acetyl CoA
carboxylase
The conversion of acetyl CoA malonyl CoA is the first stage of fatty acid
synthesis
• Most of the fatty acids are synthesized within the liver to form triglycerides
Triglycerides are carried by VLDL and LDL into adipose tissue (12.09,
2023).
Lipoprotein lipase (LPL) is activated by insulin and facilitates triglyceride
uptake and storage into fat cells (12.09, 2023).
• Insulin inhibits the action of hormone-sensitive lipase (HSL)
Lipase causes hydrolysis of already stored triglycerides (12.09, 2023).
Inactivation inhibits release of FA from adipose (12.09, 2023).
Promotes glucose transport through the membrane into the fat cells
(12.09, 2023).
o Allows glucose to be converted into fatty acids Figure 11. The Effect of GH alone, Insulin alone, and GH+Insulin on Growth in
o Forms -glycerol phosphate a Depancreatized and Hypophysectomized Rat
Supplies glycerol backbone of triglycerides
D. OTHER ACTIONS
Effects of Insulin Deficiency on Fat Metabolism • Promotes K+ uptake into cells by increasing the activity of Na-K-ATPase
This K+-lowering action of insulin is used to treat acute, life-threatening
hyperkalemia (12.09, 2023).
NOTE: This section was not part of the Pancreas Handout posted in the
• Has a direct effect on the hypothalamic satiety center independent of the
Google Classroom but was part of the 2023 Trans.
changes it produces in blood glucose concentrations

• Lipolysis of storage fat and the release of FA Table 5. Summary: Actions of Insulin
o Loss of inhibition of HSL ACTIONS OF INSULIN EFFECT ON BLOOD LEVEL
o Activation of HSL causes release of FA and glycerol into blood Increased glucose uptake into cells Decreases blood glucose
o Subsequent increase in plasma FA (within minutes), which becomes Increased glycogen formation
available as energy substitute Decreased glycogenolysis
o FAs become the main energy substrate in tissues except the brain Decreased gluconeogenesis
• Insulin deficiency increases plasma cholesterol and phospholipid Increased protein synthesis Decreases blood amino acids
concentrations (from increased fatty acid level) Increased fat deposition Decreases blood fatty acids
o Promotes conversion (by the liver) of FA into phospholipids and Decreased lipolysis Decreases blood ketoacids
cholesterol, which is released into the blood Increased K+ uptake into cells Hypokalemia
o Leads to atherosclerosis
High lipid concentration, especially cholesterol, promotes
VI. ACTIONS OF INSULIN ON TISSUES
development of atherosclerosis in people with severe diabetes
• Excess usage of fats causes ketosis and acidosis A. LIVER CELLS
o Causes excessive acetoacetic acid formation in liver cells • Glycogen storage after a meal (5-6% of liver mass, 100 grams of glycogen
o Increased 𝝱-oxidation of fats produces Acetyl CoA which then in the liver)
condenses to form Acetoacetic Acid o 60% of glucose in the meal is stored as glycogen in the liver
FAs → Increase carnitine transport → Increase 𝝱-oxidation → o Inactivates liver phosphorylase
Increase Acetyl CoA → Excess Acetyl CoA condense to form o Activates glycogen synthase
acetoacetic acid o Enhances glucose uptake by increasing glucokinase
o Absence of insulin depresses acetoacetic acid utilization in peripheral • Reduces blood glucose concentrations
tissues → Increase in Acetoacetic Acid concentration → Acidosis o Stimulates glycogenesis
o Some Acetoacetic Acid is converted to Hydroxybutyric Acid and Acetone o Increase glucose transport into cells
(Ketone Bodies) • Increase protein synthesis
o Accumulation of Ketone Bodies leads to severe Acidosis, Coma, and o Increase amino acid transport into cells
Death o Positive nitrogen balance
• Insulin Deficiency is seen in patients with Type 1 DM and can lead to death

YL5: 11.03 ENDOCRINE SYSTEM: Pancreas 6 of 9

 B. MUSCLE CELLS Table 6. Factors Affecting Glucagon Secretion
STIMULATORY FACTORS INHIBITORY FACTORS
• Increase glucose and amino acid uptake
Fasting Insulin
• Increase protein synthesis (enzymes & structural)
Decreased blood glucose
• Decrease protein degradation Somatostatin
concentration
• Increase muscle glycogen synthesis
Increased amino acid
o 2-3% of muscle Increased fatty acid and ketoacid
concentration (esp. Alanina and
o Glycogen is stored when muscle is not exercised after a meal concentration
Arginine)
o Glycogen during short periods of extreme energy →
Cholecystokinin (CCK) Increased blood glucose level
anaerobic energy → glycolysis and lactic acid
Beta adrenergic agonists
• During basal/resting state, muscle cell depends on fatty acids for energy
because the cell is only slightly permeable to glucose Acetylcholine
• 2 conditions when muscle uses up glucose Exercise
o Moderate to heavy exercise: muscle contraction increases GLUT4
independent of insulin B. MECHANISM OF ACTION
o Few hours after a meal: Insulin-mediated process

C. ADIPOSE CELLS
• Increase glucose uptake into cells
• Increase lipid formation (lipogenesis)
• Decrease lipid degradation (lipolysis)

D. TISSUES UNAFFECTED BY INSULIN

• Nervous tissue
• Kidney tubules
• Intestinal mucosa
• RBCs and β-cells of pancreas
• Insulin accelerates, but is not required for glucose uptake by the
liver

E. METABOLISM AND EXCRETION OF INSULIN

• Insulin is cleared from circulation within 10-15 minutes
• Insulin is metabolized in the liver and kidneys by enzymes that
break disulfide bonds
o Insulinase can degrade half the amount of insulin released
before it leaves the liver
• A and B chains are released (now inactive) and are excreted in the
urine
• Same metabolism and excretion for endogenous and exogenous
insulin
VII. GLUCAGON
• Hormone of starvation
• Promotes the mobilization & utilization of metabolic fuels
• Acts opposite to insulin
• Secreted from the alpha cells of the Islets of Langerhans
• Structure:
o Single straight polypeptide with 29 amino acids
o Formed by proteolytic cleavage of a larger precursor
o Preproglucagon → proglucagon → glucagon
• Same family of hormones as gastric inhibitory peptide (GIP)
A. GLUCAGON SECRETION
• Main action: to maintain the blood glucose concentration
• Factors that stimulate glucagon secretion are those that inform the
alpha cells that a decrease in blood glucose has occurred
o Low blood glucose levels stimulate glucagon secretion
Figure 13. Major Biological Actions of Insulin and Glucagon
CELLULAR MECHANISM OF GLUCAGON ACTION:
1) Glucagon binds with its receptor in the cell membrane (GPCR), which is
coupled to adenylyl cyclase via a Gs protein.
2) Causes the formation of the second messenger, cAMP
3) cAMP activates protein kinase regulator protein
4) Protein kinase regulator protein activates protein kinase
5) Protein kinase activates phosphorylase b kinase (inactive) by
phosphorylating it into phosphorylase a kinase (active)
6) Phosphorylase a kinase converts glycogen phosphorylase b (inactive) into
glycogen phosphorylase a (active) by phosphorylation.
7) Promotes the degradation of glycogen into glucose-1-phosphate (G1P)
8) G1P glucose-6-phosphate (G6P) via phosphoglucomutase.
9) G6P glucose via glucose-6-phosphatase. Then, it is released from the
liver cells.
Actions of Glucagon on the Liver
• Increases blood glucose concentration
o Stimulates glycogenolysis
o Inhibits glycogen synthesis from glucose
o Increases gluconeogenesis by decreasing the production of
fructose 2,6-bisphosphate
This decreases phosphofructokinase activity
• Increases blood fatty acid & ketoacid concentration
o Glucagon increases lipolysis and inhibits FA synthesis, which also shunts
towards gluconeogenesis
o The ketoacids β-hydroxybutyric acid & acetoacetic acid are produced
from fatty acids
• Glucagon in high concentrations also:
o Increases heart strength
o Increases blood flow to tissues especially the kidneys
o Increases bile secretion
o Inhibits gastric secretion

VIII. DELTA CELLS: SOMATOSTATIN

• Pancreatic somatostatin: polypeptide with 14 amino acids
• As opposed to GI somatostatin which has 28 amino acids
• Secreted by delta cells
• Secretion:
o Stimulated by glucagon, beta-agonists, and ingestion of all forms of
nutrients
Almost all factors related to ingestion of food stimulate
Figure 12. Structural Features of Glucagon somatostatin secretion such as:

YL5: 11.03 ENDOCRINE SYSTEM: Pancreas 7 of 9

  Increased blood glucose Weight loss,
 Increased amino acids thiazolidinediones,
Therapy Insulin
 Increased fatty acids metformin,
 Increased concentrations of several GI hormones released from sulfonylureas, insulin
the upper GI tract in response to food intake
o Inhibited by insulin through paracrine actions QUICK REVIEW
• Action:
o Inhibits secretion of insulin and glucagon via paracrine actions
SUMMARY OF TERMS
on the alpha & beta cells OVERVIEW OF THE PANCREAS
Secreted by delta cells in response to a meal and • EXOCRINE: Greater bulk of pancreas, comprised of acini
diffuses to nearby alpha and beta cells • ENDOCRINE: Islets of Langerhans most commonly found at tail of pancreas
Modulates or limits the response of insulin and glucagon • CELL TO CELL COMMUNICATION: Gap Junctions, Unique Blood Supply,
to ingestion of food Innervation
o Decreases motility of the stomach, small intestines, and
gallbladder INSULIN STRUCTURE AND SYNTHESIS
o Decreases secretion and absorption in the GI tract • PROINSULIN: Single chain of 86 amino acids composed of the alpha and
• The function of somatostatin is to increase the time in which food nutrients beta chain of insulin and a conneting segment of 35 amino acids
are assimilated into the blood and allow it to last longer • INSULIN: 51 amino acids with two peptide chains connected by a disulfide
bond
IX. F CELLS: PANCREATIC POLYPEPTIDE
PHYSIOLOGY OF INSULIN SECRETION
• Important feedback inhibitor of pancreatic secretion after a meal
• GLUCOSE: Key regulator of insulin secretion by pancreatic beta cells
• It arises from both islet and acinar cells of the pancreas
• NORMAL FASTING BLOOD GLUCOSE: 80-90mg/dL
• Release of pancreatic polypeptide (PP) by a meal, primarily
• INCRETINS: Released from the neuroendocrine cells of the GI tract
protein, occurs in a biphasic manner
following ingestion of food (functions to amplify glucose-stimulated insulin
o First rapid release: vagal stimulation
secretion and suppress glucagon secretion)
o Second, more prolonged rise (intestinal phase): in response
• GLP-1 (GLUCAGON-LIKE PEPTIDE-1): Secreted by L-cells in distal gut (ileum
to hormonal stimulation (cholecystokinin)
and colon)
• GIP (GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE): Secreted by
K-cells in proximal gut (duodenum)

PHYSIOLOGY OF INSULIN ACTION

• INSULIN RECEPTOR: An enzyme-linked receptor made up of four subunits
held together by disulfide linkages
o Two α-subunits: lie entirely outside and to which insulin binds
o Two β-subunits: traverse the cell membrane and protrude into the
cytoplasm

PERIPHERAL UPTAKE OF GLUCOSE

• GLUT 1 AND GLUT 3: Mediates basal glucose uptake in most tissues
including brain, neurons, and RBC
• GLUT 2: a low affinity transporter in the hepatocytes and 𝝱 islets
• GLUT 4: Responds to glucose concentration in peripheral blood (found in
adipose tissue and muscles)

ACTIONS OF INSULIN ON TISSUES

• LIVER CELLS: Glycogen storage after a meal (5-6% of liver mass, 100 grams
of glycogen in the liver)
• MUSCLE CELLS: Increase glucose and amino acid uptake
• ADIPOSE CELLS: Increase glucose uptake into cells
• TISSUES UNAFFECTED BY INSULIN: Nervous tissue, Kidney tubules,
Intestinal mucosa, RBCs, and β-cells of pancreas

Figure 13. Summary of the Control of Blood Glucose • GLUCAGON: Promotes the mobilization & utilization of metabolic fuels and
is secreted by alpha cells of the Islets of Langerhans
X. IMPORTANCE OF CONTROLLING BLOOD SUGAR LEVELS
• SOMATOSTATIN: Secreted by delta cells; it inhibits the secretion of insulin
• High glucose levels cause increased osmotic pressure in the ECF and glucagon via paracrine action on alpha and beta cells of the pancreas.
o Cellular dehydration • PANCREATIC POLYPEPTIDE: Important feedback inhibitor of pancreatic
• Osmotic diuresis → dehydration and depletion of electrolytes secretion after a meal that is secreted by F cells
• Vascular injury associated with uncontrolled diabetes mellitus leads to
increased risk for heart attack, stroke, end-stage renal disease, and
blindness
SUMMARY OF PROCESSES
• Presence of tissues which rely mainly on glucose for energy SYNTHESIS OF INSULIN
o Brain, retina, germinal epithelium of the gonads 1) Unique set of transcription factors found in β cell nucleus activates the
transcription of preproinsulin mRNA from the insulin gene
Table 6. Clinical Characteristics of Patients with Type 1 and Type 2 DM 2) Preproinsulin mRNA directs ribosomal synthesis (translation) of
FEATURE TYPE 1 TYPE 2 preproinsulin, which contains 4 peptides:
Age of onset Usually <20 years Usually >30 years o Signal Peptide
Low (wasted) to o Alpha and Beta Chains
Body Mass Visceral obesity o Connecting Peptide (C-Peptide)
normal
3) Preproinsulin (11,500 MW) is cleaved by microsomal enzymes in the
Normal to High
Plasma Insulin Low or Absent endoplasmic reticulum to form proinsulin
initially
o Amino-terminal signal peptide was removed almost immediately after
High, can be High, resistant to
Plasma Glucagon synthesis
suppressed suppression
o Proinsulin consists of: alpha and beta chains, C-peptide
Plasma Glucose Increased Increased
4) Proinsulin (9,000 MW) is transported to the Golgi apparatus and is cleaved
Insulin Sensitivity Normal Reduced by proteases to form the active insulin and C-peptide

YL5: 11.03 ENDOCRINE SYSTEM: Pancreas 8 of 9

5) Active insulin (5,805 MW) and C-peptide (3,000 MW) are packaged into IMPORTANT LINKS
secretory granules
o Mature secretory granules contain insulin and C-peptide in equimolar Errata Tracker: https://tinyurl.com/2024YL5ErrataTracker11
amounts (1 C-peptide : 1 insulin molecule) Trans Feedback Form: https://tinyurl.com/2024YL5TransFeedbackForm
o 5-10% of the secretory products are uncleaved proinsulin
6) Both insulin and C-peptide are released into circulation in equimolar
amount when stimulus is present

STEPS OF INSULIN ACTION

1) Insulin binds to the α-subunits, causing dimerization and conformational
changes
2) Conformational changes are transmitted to the β-subunits, which
autophosphorylate in the presence of ATP
o The subunits will then activate tyrosine kinase
3) Activation of tyrosine kinase leads to either the activation or inhibition of
more enzymes involved in the physiologic action of insulin via
phosphorylation
4) Insulin-Receptor complex (IRC) is taken in via endocytosis
5) Insulin Receptor can be degraded by proteases, stored, or recycled

CELLULAR MECHANISM OF GLUCAGON ACTION:

1) Glucagon binds with its receptor in the cell membrane (GPCR), which is
coupled to adenylyl cyclase via a Gs protein.
2) Causes the formation of the second messenger, cAMP.
3) cAMP activates protein kinase regulator protein
4) Protein kinase regulator protein activates protein kinase
5) Protein kinase activates phosphorylase b kinase phosphorylase a
kinase by phosphorylation
6) Phosphorylase a kinase converts glycogen phosphorylase b glycogen
phosphorylase a by phosphorylation.
7) Glycogen phosphorylase a promotes the degradation of
glycogen glucose-1-phosphate (G1P)
8) G1P glucose-6-phosphate (G6P) via phosphoglucomutase.
9) G6P glucose via glucose-6-phosphatase. Then, it is released from the
liver cells.

REVIEW QUESTIONS
1. Which of the following stimulates somatostatin secretion?
a) Increased fatty acids
b) Increased blood glucose
c) Increased amino acids
d) All of the above

2. Islets of Langerhans receive 1% of the pancreatic blood flow. It accounts

for only 10% of the pancreatic mass.
a) Statement 1 is True. Statement 2 is False
b) Statement 1 is False. Statement 2 is True
c) Both statements are True
d) Both statements are False

3. Which among the following is true:

a) GLUT 1 and GLUT 2 mediate basal glucose uptake in most tissues,
including brain, neurons, and RBC
b) Insulin increases glycogenesis in the liver and inhibits glycogenolysis
c) Insulin suppresses K+ uptake into cells by decreasing the activity of Na-
K-ATPase
d) None of the above

4. The third phase of prandial insulin secretion happens

a) 1.5 hours to 3 hours after exposure to glucose
b) 2.5 hours to 4 hours after exposure to glucose
c) 1.5 hours to 3 hours before exposure to glucose
d) 2.5 hours to 4 hours before exposure to glucose

ANSWERS:
1D, 2D, 3B, 4A

REFERENCES
REQUIRED
Moore, Keith L., Dalley, Arthur F., Agur, Anne M. R. Clinically Oriented
Anatomy 7th ed. Philadelphia, Wolters Kluwer, 2014.
ASMPH Batch 2023. 05/14/2019. 12.09: Pancreas lectured by Julie Anne
L. Gabat, MD, FPCP, DPSEDM.
(1) Julie Anne L. Gabat. 03/31/2020. Pancreas Handout.

YL5: 11.03 ENDOCRINE SYSTEM: Pancreas 9 of 9