9 - Biochemistry of Diabetes

Question 1

Alpha

Cell Types of the Pancreatic Islets of Langerhans

Answer 1

Glucagon

pro-glucagon

GLP 1/2

20% of cells

Question 2

Beta

Cell Types of the Pancreatic Islets of Langerhans

Answer 2

Insulin

C- Peptide (biomarker)

proinsulin

Amylin

75 % of cells

Question 3

Delta

Cell Types of the Pancreatic Islets of Langerhans

Answer 3

Somatostatin

3-5% of cells

Question 4

G / F (PP)

Cell Types of the Pancreatic Islets of Langerhans

Answer 4

Gastrin

Pancreatic Peptide (F)

~1% of cells

Question 5

Somatostatin

Answer 5

from Delta cells, UCN3

Inhibits secretion of BOTH

Insulin

Glucagon

Question 6

Amylin

Answer 6

From Beta cells

Co-secreted W/ Insulin

• Slows Gastric Emptying*
• Inhibits gastric secretions*
• Inhibits GLUCAGON secretion*

Smooths out abrupt rises in BG after meal

Question 7

Gastrin

Answer 7

From G cells

Stimulates secretion of

Gastric Acid + Pepsin

Gastric motility

Question 8

GLP-1

Answer 8

from Alpha cells

weak secretagogue for -> Insulin

~promotes its release

Glucose Uptake consequentally

Question 9

GLUT

Answer 9

• Specialized Transmembrane proteins
  
  • similar to enzymes (characterized by Km / Vmax)
  • but NO Chemical Action on glucose
    
    • ​= Passive (but some active)
• ​Glucose uptake = Rate limiting Step
  
  • in glucose utilization & Storage
    
    • = GLUT are KEY transporters in metabolism
• Some are found on _kidney_

Question 10

GLUT1

Answer 10

Ubiquitous (everywhere)

1.5mM

basal glucose uptake

Question 11

GLUT2

Answer 11

15-20mM = low affinity

Intestine

Liver = remove excess glucose

Pancreas = regulate insulin release

Question 12

GLUT3

Answer 12

Brain

1mM = highest affinity / most sensitive

glucose uptake

Question 13

GLUT4

Answer 13

Muscle / Fat / heart

5mM

Activity INCREASED by INSULIN

more glucose brought into by insulin binding

Question 14

GLUT5

Answer 14

Intestine / Testis / KIDNEY / Sperm

Mainly Fructose transport

Question 15

Causes of T2DM

Answer 15

• Defects in 1+ pathways including:
  
  • Signaling / Metabolic pathways
• ​​​~10 genes implicated
  
  • Genetic & Environmental
• Correlated w/ exogenous stimuli (environmental factors)
  
  • IRON overload
  • Glucocorticoid treatment

Question 16

How is OBESITY linked with DM?

Answer 16

• Obesity -> Visceral Fat -> Insulin resistance in peripheral tissues
  
  • Upsets in lipid metabolism
    
    • Close connection of lipid & glucose metabolism
• Sedentary life / High calorie diet
  
  • Strong correlation between DM & Obesity

Question 17

How do “Thrifty Genes” contribute to DM/Obesity

Answer 17

• Early times, starvation was an issue:
  
  • When food was abundant:
    
    • calories were stored as FAT (TG’s)
      
      • Fat was Denser energy source than glycogen

Question 18

Randle Diet / Hypothesis

Answer 18

Possible cause for Insulin Resistance & Obesity

• Increase in Carb (Sugar) & FA (Fats) metabolism
  
  • ​more Acetyl CoA + Citrate
  • Citrate inhibits PFK
  • Acetyl CoA inhibits Pyruvate Dehydrogenase (PDH)
    
    • ​-> reduction in the rate of Glycolysis
      
      • ​INTRACELLULAR GLUCOSE + G6P RISES
        
        • ​GLUT4 slows, hexokinase inhibited
          
          • less glucose uptake

Question 19

Randle Hypothesis: Fatty Acid Side

Answer 19

• LCFA undergoes Beta Oxidation in Mito
  
  • -> Acetyl-CoA buildup
    
    • negative feedback, inhibits PDH
      
      • ​pyruvate -/-> acetyl-CoA
  • ​​Acetyl-CoA -> CITRATE -> Cyto
    
    • ​inhibits PFK-1 & GLUT4
      
      • ​**less glucose intake & G6K conversion

Question 20

Randle Hypothesis: Glucose Side

Answer 20

• Glucose metabolism -> Pyruvate ->
  
  • Acetyl-CoA buildup in Mito->Cyto
    
    • -> buildup of MALONYL-CoA
      
      • ​inhibits CPT-1
        
        • less FA transport to MITO
          
          • ​buildup of Fatty Acids in cytosol
• ​​​​​Cytosolic FA (DAG / Ceramide) stress ER:
  
  • Release Cytokines
  • FA stores as TGs in fat droplets -> OBESITY

Question 21

Malonyl CoA

Answer 21

• Buildup of Malonyl-CoA (is from Acetyl-CoA)
  
  • ​which then blocks CPT-1
    
    • reduces FATTY ACID TRANSPORT into the MITO
      
      • buildup of Cytosolic FA’s
        
        • ​converted to -> DAG / Ceramide

Question 22

DAG & Ceramide

Answer 22

• Malonyl CoA Buildup inhibits CPT-1
  
  • which results in a buildup of Cytosolic FA’s (convert to DAG / Ceramide)
    
    • Bind to Stress Induced Ser-Kinases
      
      • ​-> competitively inhibit INSULIN RECEPTORS
        
        • -> less GLUT4 to take in glucose
• Insulin receptors are also Ser-Kinases
  
  • DAG & Ceramide binding to these interferes with the signal transduction pathway of insulin

Question 23

Insulin Resistance in Muscle

similar to randle hypothesis

Answer 23

• Increase in DAG / Ceramides / Fatty Acyl coA
  
  • bind to SER / THR Kinases -> Cascade
    
    • instead of Tyr-kinases
    • ​​​​Insulin normally binds to Tyr Kinase Receptor
      
      • ​but there is less of it phosporylated due to the Ser/Thr Kinase cascade
        
        • -> Less GLUT4 Activity
          
          • ​Insulin Resistance

Question 24

How Insulin Resistance leads to T2DM

Answer 24

• Insulin Resistance -> Beta cell compensation
  
  • ​-> more INSULIN secreted but no effect
    
    • increase in Gluconeogenesis (more GLUCOSE)
    • increase in Lipolysis in visceral fat
      
      • normally insulin would supress these
• ​​​Beta Cells DEcompensated (stressed, not working)
  
  • -> decrease in INSULIN Synthesis / Secretion
    
    • ​​​Glucose buildup & impaired glucose tolerance

Question 25

**Causes of Type 1 DM**

Answer 25

* ***Loss of Beta-Cells*** due to: * **viral infection / environmental triggers** * **​**-\> immune system attacks the cells * Chemical Triggers: * **Zinc Chelators** * **Nitrates** * **Rodenticides**

Question 26

**Type 3 DM**

Answer 26

**Elevated Blood Glucose *_not caused by insulin resistance_*** * **Genetic Defects** on: * **beta cell fxn** * **insulin action** * Diseases of the **exocrine pancreas** * **Drugs / Chemicals** (rat poison) * **_Endocrine Disorders_**

Question 27

**Rare Causes of DM: Endocinopathies**

Answer 27

* Some **_Increase Insulin Resistance:_** * **Acromegaly / POS** * **HYPERthyroidism** * **​Cushing's Syndrome** * hypercortisolism * Some ***DECREASE Insulin Secretion:*** * ***​*****somatostatinoma** * **aldosteronoma** * **pheochromocytoma**

Question 28

**Gestational DM**

Answer 28

* **~4x increase in INSULIN** secretion demand for pregnancy * Mother *does not secrete **enough insulin*** * can not compensate for **higher metabolic demands & glucose output** * **4% of all pregnancies** * H/O **diabetes** increase risk * Increase risk of **stillbirth**

Question 29

**Diabetes Insipidus**

Answer 29

* Urine W/o taste; no glucose * Defect in **Aquaporin-2 (AQP-2)** * becomes ***insensitive to vasopressin*** * ​-\> *little water is reclaimed in kidney* * *​***MORE "dilute = insipid" URINE is passed**

Question 30

**Aquaporin-2** **AQP-2**

Answer 30

* Epithelial Protein in _Kidney_ * **Vasopressin** stimulates its action of: * **Increases in water re-absorption in kidney** * *when vasopressin falls -\> there is more water in the urine excreted* * *​​***_DEFECT in AQP-2_** * ​-\> **Diabetes Insipidus**

Question 31

**How does T2DM affect Hypertension**

Answer 31

* T2DM -\> High **Blood Glucose Concentration** * **​**increase in **Osmotic Pressure** * -\> **Increase BP** * **Polyuria** from filtering out glucose * -\> leads to **Polydipsia** * -\> increased rate of filtration of PROTEINS * -\> damage to kidney * pore size increase * glycosylation

Question 32

**Polyuria**

Answer 32

**Large Amounts of URINE** --\> **Polydipsia** (thirst) * Can be caused by **T2DM** * due to kidney's need to filter out GLUCOSE * Polyuria effects: * -\> Increased rate of **filtration of Proteins** * **​**Increase in **Pore Size / Urinary Space** * **​-\> Kidney Damage** * **Glycosylation** of enzymes/transporters * caused by HIGH BG

Question 33

**How does T2DM cause Glycosylation & Tissue Damage?**

Answer 33

* High **Blood Glucose** * **​-\>** **Glycosylation of proteins** * -\> produce **_AGE's_** * **_​​_**AGE's damage cell by **altering enzymatic/binding activity of cellular proteins** * -\> abnormal interactions in matrix * -\> ***Tissue Adhesion*** * ***-\> Recognition Systems*** * *​of* **_Blood Vessels / Nerves / Organs_**

Question 34

**AGE's**

Answer 34

**Advanced Glycosylation End Products** * Can be made due to HIGH Blood GLUCOSE * -\> increase in glycosylation of proteins * -\> AGE's * **Affect Tissue Adhesion & Recognition Systems** * of _BV's / Nerves / internal organs_ * ​by ***altering enzymatic / binding activity of proteins***

Question 35

**Trauma's effect on Diabetes**

Answer 35

* Trauma -\> release of stress hormones: * **Catecholamines + Cortisol** * **​**raise level of CATABOLISM * -\> ***Supress Insulin Release*** * -\> more **Glucose** * -\> more lipolysis -\> **more FFA** * --\> **_HYPERGLYCEMIA & KETOSIS_** * _​_esp important consideration for DM patients

Question 36

**Why do DM patients require special consideration for surgery?**

Answer 36

* **TRAUMA** -\> stress hormones + ***Supression of Insulin release*** * Catacholamines + Cortisol * -\> increase in **Catabolism** * --\> **_HYPERGLYCEMIA_** * **_​​KETOSIS_**