Diabetes Complications -Grimm

Question 1

Diabetec complications fall into these 2 major categories

Answer 1

1. Microvascular: retinopathy, neuropathy, nephropathy
2. Macrovascular: Atherosclerosis, cardiac disease, stroke

**also cataracts, which doesnt fit into either

Question 2

5 mechanisms that contribute to micro and macrovascular complications:

Answer 2

1. Increased movement of glucose through the aldose reductase pathway
2. Inappropriate activation of Protein Kinase C isozymes
3. Increased formation of advance glycation products (intracelular and extracellular)
4. Increased flow of glucose through the hexosamine pathway
5. Increased ROS formation

Question 3

What is the first clinically observable evidence (in vivo via opthalmoscopic exam) of microvascular disease in the retina?

Answer 3

Formation of capillary aneurisms (step 2)

Question 4

List the 6 steps leading to malfunction of the capillaries due to diabetes

Answer 4

1. increased capillary blood flow with venule distension
2. Formation of capillary anuerisms (associated with severe loss of capillary pericytes
3. Capillaryes become leaky, exudates are leaked out into the ISF –> macular edema
4. Arteriolar occlusion - affects blood supply to multiple capillaries and involves a greater territory than the initial events
5. Proliferation of new blood vessels in affected area due to VGF stimulation
6. The new capillaries are dysfunctional and have a tendency to hemorrhage, retinal hemorrhages. Scarring leads to vitreous humor detachment and blindness

Question 5

What is also associated with stage 2 formation of capillary aneurisms?

Answer 5

Transient closure of capillaries – interrupted blood flow and thickening of the basement membrane and capillary ghosts (channels devoid of live endothelial cells)

Question 6

What is the polyol pathway? What is the key enzyme? What is the culprit?

Answer 6

The polyol pathway is normally used to inactivate reducing aldehydes. The enzyme **aldose reductase **is responsible for the inactivation step.

Excessive amounts of intracellular glucose enter pathway, glucose is first converted to sorbitol. Sorbitol can exert osmotic effect and cause swelling.

Question 7

Sorbitol can be metabolized further (in polyol pathway) and can cause the following: 4 words

Answer 7

1. Fructose
2. oxidized state
3. Diacylglycerol
4. ROS

Question 8

What is the fate of fructose produced in the polyol pathway?

Answer 8

Fructose must go into fat:

Fructose must enter the glycolytic pathway. It can’t enter the TCA cycle, so if cell doesn’t need ATP, the resulting acetyl-CoA is used for FFA synthesis

Question 9

Why does the polyol pathway produce an oxidized state?

Answer 9

the pathway consumes NADPH, hence decreases the availability of GSH

Question 10

What are the consequences of the polyol pathway stimulating DAG?

Answer 10

DAG activates DAG dependent protein kinases C –> contribute to various microvascular complications (especially in the kidney)

Question 11

What are advanced glycation end products (AGE)?

What problems do they cause?

Answer 11

A series of reactions (glucose form Schiff’s bases with amino groups, rearrange to form Amadori products, further interact with proteins and lipids) that ultimately form x-linked molecules. Extracellular AGE products aren’t turned over properly.

Might lead to basement membrane thickening (nephropathy, retinopathy, neuropathy)

Question 12

What other players interact with advanced glycation end products (AGE)? How? What is the result?

Answer 12

• Macrophages and endothelial cells via receptor (RAGE)
• macrophages engulf AGE: release pro-inflammatory cytokines (may contribute to macrovascular disease)
• endothelial cells secrete angiogenic factor (might explain capillary proliferation in retinopathy)

Question 13

What is the hexosamine Flux pathway?

Answer 13

An increase in hexosamine (N-acetylglucosamine) due to increased intracellular glucose. This can over-glycosylate proteins in the ER and TR resulting in dysregulated protein synthesis and altered half life and function of glycoproteins.

Question 14

What are 3 important molecules affected by the hexosamine flux pathway? What is the consequence?

Answer 14

• PAI - thrombosis
• TGF-B - proliferation of blood vessels
• ECM - decreased turnover and basement membrane thickening

Question 15

4 proposed mechanisms for how hyperglycemia causes disorders of the capillaries

Answer 15

1. polyol pathway
2. AGE products
3. Hexosamine Flux pathway
4. Oxidative damage

Question 16

Retinopathy is a progressive disease. Eye exam shows the following (4)

Answer 16

1. aneurisms of retinal blood vessels
2. increased permeability of capillaries-exudates
3. angiogenesis
4. retinal hemorrhages

Question 17

Two important components of diabetic neuropathy

Answer 17

1. vascular disease (note basement membrane thickening)
2. direct nerve damage (narrowing of artery in nerve sheath)
   - altered GF and cytokine profile causes metabolic changes in neurons and Schwann cells

Question 18

What is the definition of Cataract? What causes it? What are two secondary causes?

Answer 18

• Cloudiness of the lens - to decrease its transparency
• due to alterations of crystalline proteins in the lens fiber cells
• secondary to ostmotic imbalance secondary to sorbitol accumulation
• secondary to same mechanisms that lead to microvascular (capillary disease)

Question 19

4 macrovascular complications of Diabetes

Answer 19

• dyslipidemia
• atherosclerosis
• stroke
• heart attack

Question 20

what death occurs in the capillaries of retina and glomerulues due to diabetes

Answer 20

death of:

pericytes (retina)

podocytes (glomerulus)

Question 21

Inhibitors of aldose reductase

Answer 21

It is not specific for glucose, and catalyze the reduction of many important substrates, therefore, inhibiting this enzyme causes too many severe side effects