Endocrine 1 (Type 1 Diabetes)

Question 1

What is Type 1 Diabetes

Answer 1

Insulin deficiency due to beta cell destruction

Question 2

Pharmacology Insulin Action (Beta Cells)

Answer 2

Beta Cells are always producing Insulin (Basal Release)

When Beta Cells produce more insulin glucose spikes (Intermittent Release)

Question 3

Pharmacology Insulin Action (Ketogeneisis)

Answer 3

Insulin prevents ketogenesis

When body is starving/fasting insulin levels drop, body starts to mobilize fat instead of glucose
- Mobilize fat goes to liver where it is then oxidized into ketone bodies
- Too many ketones causes a decline in blood pH

Question 4

What happens when you have not enough insulin?

Answer 4

Can not move glucose into muscles
- Hyperglycemia

Blood pH drops from too many ketone bodies
- Diabetic Ketoacidosis

Question 5

How is insulin stored endogenously

Answer 5

Insulin self-associates to form dimers which then form hexamers
- These insulin hexamers are then stored within granules in beta cells of pancreas

Question 6

Insulin Absorption (Injection)

Answer 6

Hexamer Insulin can not pass through membrane as they are too large
- Causes issues in storing it

Inject 30 minutes before meal to allow insulin to be properly absorbed

Question 7

Regular Insulin

Answer 7

Recombinant DNA from Human Proinsulin Gene
- Short acting insulin that must be administered 30 mins before having a meal
- Mimics meal insulin

Intermittent (Bolus) Release

Question 8

Neutral Protamine Hagedorn

Answer 8

Protamine + Regular Insulin
- Intermediate duration of action by reducing absorption rate from injection site
- Very unpredictable rate of absorption, very high variability (25-50%)

Continuous (Basal) Release

Question 9

Short Acting Insulin Formulation
- Examples

Answer 9

Aspart
Glulisine
Lispro

Question 10

Short Acting Insulin Formulation
- Absorption

Answer 10

Modified so that they do not associate into dimers
- Can not be stored = Rapid acting

Question 11

Long Acting Insulin Formulation
- Examples

Answer 11

Glargine
Detemir
Degludec

Question 12

Long Acting Insulin Formulation
- Absorption

Answer 12

Modified so that they stay as hexamers
- Can be stored = Slow Acting

Question 13

Acylation of Insulin

Answer 13

By adding a fatty acid insulin can bind to serum albumin
- Creates a reservoirs of insulin that is slowly released

Question 14

Insulin
- MOA

Answer 14

Intrinsic Receptor Tyrosine Kinase Activity
- Anabolic Hormone

Facilitates:
- Glycogen storage in liver / Reduces glucose production by liver
- Fat storage in adipose tissue
- Protein synthesis in muscle

Question 15

Insulin
- Glucose Uptake

Answer 15

1. Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
2. Activates Akt
3. Translocation of GLUT4 to plasma membrane (Muscle, Fat)

Result: Muscle and Fat can now uptake glucose using Glucose Transporter 4

Question 16

Insulin
- Glycogen Synthesis

Answer 16

1. Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
2. Activates Akt
3. Inhibits GSK3
4. Prevents GSK3 mediated inhibition of GS

Result: Glycogen Synthase can now synthesize Glycogen

Question 17

Insulin
- Gluconeogenesis

Answer 17

1. Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
2. Activates Akt
3. Inhibits FoxO1
4. Reduces the transcription of genes of gluconeogenesis

Result: Liver does not produce glucose

Question 18

Insulin
- Protein Synthesis

Answer 18

1. Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
2. Activates Akt
3. Activates mTOR
4. Modifies signaling molecules which turn on protein synthesis (Muscle)

Result: Muscles synthesize proteins

Question 19

Insulin
- Lipolysis/Ketogenesis

Answer 19

Akt Activates
3. Increased Phosphodiesterase 3B activity
4. Decrease of cAMP
5. Reduces lipolysis (Adipose Tissue)

Reduction in Lipolysis
1. Free Fatty Acid delivery to liver is reduced
2. Reduction Ketone Body Production

Insulin Activates
1. Acetyl CoA Carboxylase (ACC) in the liver
2. Produces Malonyl CoA
3a. Inhibits Fatty Acid Oxidation
3b. Promotes Fatty Acid Biosynthesis
4. Inhibition of Ketogenesis

Result: Lipolysis is reduced | Ketogenesis is inhibited

Question 20

Insulin
- Adverse Effects

Answer 20

• Hypoglycemia (Low blood sugar levels as it has all been mobilized into muscle and fat)
• Weight Gain (Anabolic Hormone)

Question 21

Glucagon
- MOA

Answer 21

1. Glucagon activates Glucagon Receptor (GPCR | Gs)
2. Increased Adenylate Cyclase
3. Increased CAMP
4. Activation of PKA

PKA activates
1. Glycogen Phosphorylase
2. Mobilizes liver glycogen stores
3. Increases hepatic glucose output
4. Maintain normoglycemia

Result: Increase Blood Glucose Levels