Endocrine 1 (Type 1 Diabetes) Flashcards
What is Type 1 Diabetes
Insulin deficiency due to beta cell destruction
Pharmacology Insulin Action (Beta Cells)
Beta Cells are always producing Insulin (Basal Release)
When Beta Cells produce more insulin glucose spikes (Intermittent Release)
Pharmacology Insulin Action (Ketogeneisis)
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
What happens when you have not enough insulin?
Can not move glucose into muscles
- Hyperglycemia
Blood pH drops from too many ketone bodies
- Diabetic Ketoacidosis
How is insulin stored endogenously
Insulin self-associates to form dimers which then form hexamers
- These insulin hexamers are then stored within granules in beta cells of pancreas
Insulin Absorption (Injection)
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
Regular Insulin
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
Neutral Protamine Hagedorn
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
Short Acting Insulin Formulation
- Examples
Aspart
Glulisine
Lispro
Short Acting Insulin Formulation
- Absorption
Modified so that they do not associate into dimers
- Can not be stored = Rapid acting
Long Acting Insulin Formulation
- Examples
Glargine
Detemir
Degludec
Long Acting Insulin Formulation
- Absorption
Modified so that they stay as hexamers
- Can be stored = Slow Acting
Acylation of Insulin
By adding a fatty acid insulin can bind to serum albumin
- Creates a reservoirs of insulin that is slowly released
Insulin
- MOA
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
Insulin
- Glucose Uptake
- Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
- Activates Akt
- Translocation of GLUT4 to plasma membrane (Muscle, Fat)
Result: Muscle and Fat can now uptake glucose using Glucose Transporter 4
Insulin
- Glycogen Synthesis
- Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
- Activates Akt
- Inhibits GSK3
- Prevents GSK3 mediated inhibition of GS
Result: Glycogen Synthase can now synthesize Glycogen
Insulin
- Gluconeogenesis
- Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
- Activates Akt
- Inhibits FoxO1
- Reduces the transcription of genes of gluconeogenesis
Result: Liver does not produce glucose
Insulin
- Protein Synthesis
- Insulin activates Insulin Receptor (Tyrosine Kinase Receptor)
- Activates Akt
- Activates mTOR
- Modifies signaling molecules which turn on protein synthesis (Muscle)
Result: Muscles synthesize proteins
Insulin
- Lipolysis/Ketogenesis
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
Insulin
- Adverse Effects
- Hypoglycemia (Low blood sugar levels as it has all been mobilized into muscle and fat)
- Weight Gain (Anabolic Hormone)
Glucagon
- MOA
- Glucagon activates Glucagon Receptor (GPCR | Gs)
- Increased Adenylate Cyclase
- Increased CAMP
- 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
