Endocrine Pancreas Lecture (Dr. Lopez)

Question 1

Endocrine Cells of the Pancreas are arranged in Clusters

Answer 1

• Endocrine Cells Secrete:
  a) Insulin
  b) Glucagon
  c) Somatostatin
• Major Function of Endocrine Pancreas:
• ** REGUALTE Glucose, Fatty Acid, and Amino Acid Metabolism
• Endocrine Cells are arranged in Clusters called ISLETS OF LANGERHANS
  a) 1 to 2% of Pancreatic Mass

b) Each Islet contains about 2,500 Cells
c) Innervated by ADRENERGIC, CHOLINERGIC, and PEPTIDERGIC Neurons

Question 2

Hormones of the Islets of Langerhans

Answer 2

1) BETA CELLS
- 60 to 65% of the Islet
- Secrete INSULIN and C Peptide
- tend to be located in the Central Core

2) ALPHA CELLS
- About 20% of the Islet
- Secrete GLUCAGON
- Tend to be located near the Periphery of the Islet

3) DELTA CELLS
- About 5 % of the Islet
- Secrete SOMATOSTATIN
- Interspersed between Alpha and Beta Cells
- Neuronal appearance, send Dendrite-like Processes to BETA Cells

Question 3

Cells of the Islets of Langerhans Communicate with each other

Answer 3

1) GAP JUNCTIONS:
- Permit RAPID cell to cell Communication
a) Alpha to Alpha
b) Beta to Beta
c) Alpha to Beta

2) BLOOD SUPPLY:
- Islets receives around 10% of the Total Pancreatic Blood Flow

• Venous Blood from One Cells Type BATHE the other Cell Types
• Venous Blood from the BETA Carries INSULIN to the Alpha and Delta
  a) Blood Flows first to Capillaries in the CENTER of the Islet and picks up INSULIN

b) Then, blood flows to the Periphery of the ISLETS, where it acts on ALPHA CELLS to INHIBIT GLUCAGON Secretion

Question 4

Insulin

Answer 4

• Major ANABOLIC Hormone
• Secreted in response to Carbohydrate and/ or Protein Containing Meals
• Glucose is the MAIN Stimulatory Factor of Insulin Secretion

Question 5

Insulin is Synthesized and Secreted in BETA Cells

Answer 5

1) PEPTIDE HORMONE:
- Structure: 2 Straight Chains linked by DISULFIDE BRIDGES

2) PREPROINSULIN —> PROINSULIN —> INSULIN
a) Preproinsulin
- 4 Peptides (Signal Peptide, A and B Chains of Insulin, and Connecting Peptide called C Peptide)

b) PROINSULIN
- No Signal Peptide

• C peptide still attached to Insulin, Disulfide Bridges form in the ER (Folded form of Insulin)
• Packed in Secretory Vesicles in the GOLGI
• During packaging, Proteases cleaved Proinsulin

Question 6

Insulin Synthesis and Release from Beta Cells

Answer 6

A) Insulin and Cleaved C Peptide are packed together in Secretory Vesicles
- Secreted in Equimolar quantities into the Blood

• C Peptide is used to TEST Beta Cell Function in Type I DIABETES MELLITUS patients Receiving Insulin Injections

Question 7

Glucose is the most Important Factor in the Regulation of Insulin Synthesis and Secretion

Answer 7

1) Transport of Glucose into the Beta Cell
2) Metabolism of Glucose inside the Beta Cell
3) ATP Closes ATP-Sensitive K+ Channels
4) Depolarization Opens Voltage-Sensitive Ca2+ Channels!!!!!!!
5) Increased Intracellular Ca2+ causes Insulin Secretion

• ***SULFONYLUREA DRUGS (Ex Tolbutamide, Glyburide) promotes the closing of ATP-Dependent K+:
• Increased Insulin Secretion
• Used in the treatment of Type II Diabetes Mellitus
• ***C Peptide is Secreted in Quimolar amount with INSULIN, and Excreted Unchanged in Urine
• C Peptide is used in Screening of Endogenous Beta Cell Function

***When INCREASE in ATP, K+ Channels Close

Question 8

Glucose and Insulin Relationship

Answer 8

• ** Glucose stimulates INSULIN Secretion in a BIPHASIC MANNER
• 1st Phase (Rapid)
• 2nd Phase (Gradual)

1) Cholecystokinin and Acetylcholine INCREASE Insulin Secretion by IP3 and Protein Kinase C
2) Somatostatin DECREASES insulin Release
3) GLUCAON INCREASES Insulin Release

Question 9

Insulin Beings its Action on Target Cells by Binding to Insulin Receptors

Answer 9

• When occupied by Insulin, Insulin Receptor Phosphorylates itself and other proteins
• *Phosphorylation either Activates or Inhibits these proteins to produce the Metabolic Actions of Insulin
• Insulin Receptor Complex is Internalized by its Target Cell
• Insulin Down Regulates its own Receptor

Question 10

Insulin Secretion and Clearance

Answer 10

• Insulin release form the Pancreas OSCILLATES with a period of 3 to 6 min, changing from Generating a Blood Insulin Concentration more than 800 mol/ L to less than 100 pmol/ L

Question 11

Peripheral Uptake of Glucose

Answer 11

• Glucose is taken up by Peripheral Cells by Facilitated Diffusion
• Insulin facilitates the Uptake in some tissues
  a) Insertion of Glucose Transporters in the Membrane (GLUT 4)

b) Adipose Tissue and Resting Skeletal Muscle requires Insulin for Effective Glucose Uptake (by GLUT 4)

Question 12

The Muscle CasE: Insulin Actions

Answer 12

MAJOR EFFECTS (Part 1):

1) INCREASE Glucose Uptake
- Increase GLUT 4 Transporter

2) INCREASE Glycogen Synthesis
- Increase Hexokinase (1)
(In Liver and Beta Cells is GLUCOKINASE)

• Activates Glycogen Synthase (2)

MAJOR EFFECTS (Part 2):

1) INCREASE Glycolysis and Carbohydrate Oxidation
- Increase Hexokinase (1), Phosphofructokinase (2), and Pyruvate Dehydrogenase 3)

2) DECREASE Glucogenesis (4)
3) INCREASE Protein Synthesis (5) and DECREASE Protein Breakdown (6)

Question 13

Effects of Insulin on Nutrient Flow and Resulting Effects on Blood Levels of Nutrients

Answer 13

GLUCOSE:
- Decreased

FATTY ACIDS:
- Decreased

KETOACIDS:
- Decreased

AMINO ACIDS:
- Decreased

Question 14

Summary of Insulin actions in the Liver

Answer 14

1) GLUT 2 Transporter
- INCREASE Glucokinase

2) INCREASE Glycogen Synthesis

3) DECREASE Glucose Release (Decrease Gluconeogenesis)
- Decrease Glucose - 6 - Phosphate

4) INCREASE Glycolysis
- Increase Acetyl CoA, and Increase FA Synthesis

5) INCREASED Triglycerides Storage and Export (Very Low Density Lipoproteins- VLDLs)
6) INCREASED Protein Synthesis, DECREASE Protein Degradation

Question 15

Summary fo Insulin Actions in Adipose Tissue

Answer 15

1) INCREASE GLUT4 Transporters

2) INCREASE Glycolysis
- Increased Alpha Glycerol Phosphate
- Increased Acetyl CoA, Increased FA Synthesis

3) INCREASED Triglycerides
- Decreased hormone Sensitive Lipase (HPL) (Decreased Lipolysis)
- INCREASED Lipoprotein lipase (LPL) (Increased Uptake)

Question 16

Summary of Insulin actions in the Muscle

Answer 16

1) INCREASE GLUT 4 Transporters
2) INCREASED Glycogen Synthesis
3) INCREASED Glycolysis
4) INCREASED Protein Synthesis, DECREASED Protein Degradation
5) INCREASED Triglycerides (FA’s form Circulation)

Question 17

Summary of Insulin Actions and Effect on Blood Levels

Answer 17

Actions of Insulin:

1) INCR Glucose Uptake into Cells
2) Incr Glycogen Formation
3) Decr GLycogenolysis
4) Decr Glucogenesis
5) Incr Protein Synthesis
6) Incr Fat Deposition
7) Decr Lipolysis
8) Incr K+ Uptake into Cells

Effect on Blood Level:

1) Decr Glucose
5) Decr A.A
6) Decr F.A
7) Decr Ketoacid
8) Decr K+

Question 18

Factors affecting Insulin Secretion

Answer 18

STIMULATORY FACTORS:

1) Incr [Glucose]
2) Incr [A.A]
3) Incr [F.A] and [Ketoacid]
4) Glucagon
5) Cortisol
6) Glucose-Dependent Insulinotropic Peptide (GIP)
7) Vagal Stimualtion; ACh
8) K+
9) Sulfonylurea Drugs
10) Obesity

INHIBITORY FACTORS:

1) Decr Blood Glucose
2) Fasting
3) Exercise
4) Somatostatin
5) Alpha Adrenergic Agonist
6) Diazoxide

Question 19

Diabetes Mellitus Type I

Answer 19

DIABETES MELLITUS Type I: Inadequate Insulin Secretion
- Destruction of Beta Cells, often as the Result of Autoimmune Disease

• Symptoms do not become evident until about 80% of the Beta Cells are Destroyed

Question 20

Diabetes Mellitus Type I Cont

Answer 20

DB Type I: Inadequate Insulin Secretion

1) INCR Blood [Glucose]
- Decr Uptake of Glucose

• Decr Glucose Utilization
• Incr Gluconeogenesis

2) INCR Blood [F.A] and [Ketoacid]
- Decr F.A Synthesis

• Decr Triglyceride Synthesis
• Incr Triglyceride Breakdown
• Incr level of Circulation free F.A
• Incr Conversion of F.A to ketoacids and Decr Ketoacid Utilization by Tissues (Results in DIABETIC KETOACIDOSIS (DKA): Metabolic Acidosis

3) INCR [A.A]
- Incr Protein Breakdown

• Decr Protein Synthesis
• Incr Catabolism of A.A
  ( Loss of Lean Body Mass, Ex: Catabolic State)
• Incr Ureagenesis

Question 21

Diabetic Mellitus Type I: Osmotic and Hyperkalemia

Answer 21

1) OSMOTIC DIURESIS
- INCR Blood [Glucose] results in INCR Filtered Load of Glucose, Exceeding Reabsorptive Capacity of the PROXIMAL TUBULE

• Water and Electrolyte Reabsorption is also prevented
• POLYURIA: Incr Excretion of Na+ and K+ even though Urine Concentration of Electrolytes is LOW
• Thirst

2) HYPERKALEMIA: Shift of K+ out of the Cell
- Intracellular Concentration is LOW

• Lack of Insulin effect on Na+/ K+ ATP Pump
• Even though Plasma Levels may be Above Normal, Total Body K+ is usually below Normal due to the Polyuria and Dehydration

Question 22

Diabetes Mellitus Type I: Treatment

Answer 22

1) INSULIN REPALCEMENT

- Objective is to recreate Normal Physiology (Basal and Bolus Insulin)

Question 23

Diabetes Mellitus Type I

Answer 23

Drawbacks of Insulin Replacement Therapy
1) Painful and Time Consuming

2) Lag between Glucose Measurement and Insulin dosing
3) Delayed Absorption of Insulin following Subcutaneous Injection
4) Poor Blood Glucose Control (Period of Hyperglycemia)

Question 24

Diabetes Mellitus Type II

Answer 24

*** INSULIN RESISTANCE!!!

1) Vast Majority of Diabetes is Type II Diabetes (About 95%)
2) Patents are able to make Insulin, but not enough to Overcome Insulin Resistance
3) Normal or Elevated [insulin] initially; Relative Insulin Deficiency

Question 25

Diabetes Mellitus Type II: Often Associated with Obesity

Answer 25

Associated with OBESITY!!!*

1) Reactive Hyperinsulinemia followed by Relative Hypoinsulinemia

2) 3 Causes of Obesity-Induced Insulin Resistance
a) DECREASED GLUT4 Uptake fo Glucose in response to insulin to Repress

b) DECREASED ability of Insulin to Repress Hormone-Sensitive Lipase (HSL) or Increase Lipoprotein Lipase (LPL) in Adipose Tissue

Question 26

Diabetes Mellitus Type II: Insulin Resistance

Answer 26

1) PREVALENCE: Middle-aged or Older
2) Insuline Resistance mechanisms not well understood
3) Increase Hepatic Glucose Production
4) Hyperglucagonemia

5) Not as prone to KETOACIDOSIS as Type I
- Presence of some Insulin Secretion appears to protect from the Development of Ketoacidosis

6) In Non-Obese patients, Diabetes Tpye II can occur due to a DECREASE in Insulin release by the Pancreas; varying degrees of Insulin Resistance can also occur

Question 27

Diabetes Mellitus Type II: Treatment

Answer 27

1) Caloric Restriction and Weight Reduction

2) Insulin Secretagogues:
- Sulfonylurea Drugs
- INCRETIN analog of GLP-1 (Eventide); Injection Needed

3) Slow absorption of Carbohydrates
- Alpha- Glucoside Inhibitors (Acarbose, Miglitol)
- Amylin Analogs (PAMLINTIDE)

4) Insulin Sensitizers:
- Biguanide Drugs (Ex: Metformin): Upregulate Insulin Receptors on Target Tissues

Question 28

Type I vs Type II Diabetes

Answer 28

TYPE I:

1) Age of Onset:
- Peak in Early Childhood and Adolescence

2) Ketosis at Onset:
- Common

3) Family History:
- 10 to 20%

4) Pathophysiology:
- Autoimmune Disease

TYPE II:

1) Age of Onset:
- Post-Pubertal

2) Ketosis at Onset:
- Uncommon but Possible

3) Family History:
- Greater than 50%

4) Pathophysiology:
- Insulin Resistance

Question 29

Plasma [Glucose]

Answer 29

• Reflects the Balance between the Hypoglycemic action of Insulin and the Hyperglycemic action of the Anti-Insulin Hormones

**To Obtain [Glucose] in mg/dL, multiple the value in mmol/L by 18

Question 30

Glucagon

Answer 30

• Single Straight-Chain Polypeptide with 29 Amino Acids
• Members of a family of peptide that includes the GI Hormones Secretin and GIP
• Synthesized as PREPROGLUCAGON
• Stored in Dense Granules until Alpha Cells are Stimulated

Question 31

Major Stimulatory Factors of Glucagon Secretion is DECREASE in Blood [Glucose]

Answer 31

• INCREASE a.a (Arginine and Alanine) also stimulate Glucagon Secretion

Other Stimulatory Factors:

• Fasting
• Cholecystokinin (CCK)
• Beta-Adrenergic Agonists
• ACh

Question 32

Plasma [Glucose] reflects the Balance between the Hypoglycemic action of Insulin and the Hyperglycemic action of the Anti-Insulin Hormones

Answer 32

• Insulin inhibits the Synthesis and Secretion of Glucagon

Other Inhibitory Factors:

• Somatostatin
• INCREASE Fatty Acids and Ketoacid Concentration

Question 33

Major Actions of Glucagon are on the Liver

Answer 33

Glucagon INCREASES Blood [Glucose]

• Increased GLUCOGENOLYSIS and Inhibits Glycogen formation from Glucose
• Increased GLUCONEOGENESIS by DECREASING the Production of FRUCTOSE 2,6, BISPHOSPHATE
• Substrate are direct towards Glucose formation

Question 34

Effect of Glucagon on Nutrient Flow in Liver and Adipose Tissue, and resulting effects on Blood Levels of Nutrients

Answer 34

• Glucagon INCREASES Lipolysis and Inhibits Fatty Acid Synthesis, which shunts substrates toward GLUCONEOGENESIS
• Ketoacids are produced from Fatty Acids

Question 35

Diabetes Mellitus Type II: Insulin Resistance Effects

Answer 35

DIRECT EFFECTS OF INSULIN:

• Decrease Glycogenolysis
• Decrease Gluconeogenesis

INDIRECT EFFECTS OF INSULIN:

• Decreased free Fatty Acid flux to Liver
• Decreased Glucagon Secretion

** In Insulin Resistance, the ability of Insulin to SUPPRESS lipolysis in Adipose Tissue and Glucagon Secretion by ALPHA Cells in the ISLET results in INCREASED Gluconeogenesis

Question 36

Incretin Hormones

Answer 36

1) Intestine Derived Hormones
- GLP-1, GIP
- Short T1/2
- Secreted in response to GI Glucose and Fat

2) Stimulate INSULIN Secretion (Glucose Dependent)
3) Inhibit Glucagon Secretion
4) Slow Gastric Emptying

**Type 2 Diabetes have a REDUCED INCRETIN EFFECT!!!!!

• The incretin effect is defined as the increased stimulation of insulin secretion elicited by oral as compared with intravenous administration of glucose under similar plasma glucose levels.