Chronic Complications of Diabetes Mellitus

Question 1

Pt with _____ usually have significant insulin resistance and are USUALLY older.

Answer 1

T2D

Question 2

Pt with ___ are prone to have episodes of DKA which may have long tern effects on a variety of organs.

Answer 2

DKA

Question 3

What are the 3 organs most commonly and dramatically affected by diabetes?

Answer 3

eyes (retinopathy), nerves (neuropathy), kidneys (nephropathy)

Question 4

What is the most common cause of death in a diabetic pt?

Answer 4

atherosclerotic vascular disease

Question 5

What is the most common cause of death in T1D before 40 years old?

Answer 5

renal failure

Question 6

What are 6 metabolic abnormalities contributing to chronic complications of diabetes?

Answer 6

1. Increased metabolism–> increased ROS
2. Def in myo-inositol–> abnormal phosphoinositide metabolism
3. Increased metabolism of glucose through sorbitol pthwy
4. Non-enzymatic glycosylation of proteins, RNA, DNA
5. Abnormal ECM, increase in collagen and fibronectin, decrease in heparan sulfate
6. Metabolic syndrome has added impact of adipose derived tissue components: leptin, TNFa, Ang II, PAI-1, FFA

Question 7

T or F The development of complications in pt with insulin resistance begins after hyperglycemia develops.

Answer 7

F- BEFORE

Question 8

What are the major enviornmental factors in T2D?

Answer 8

development of obesity and reduced exercise

Question 9

What is the significance of visceral fat in metabolic syndrome?

Answer 9

Secretes excessive amounts of FFA, leptin, TNF-a, ATII, PAI-1, decrease secretion of adiponectin

Question 10

Excessive oxidation generates ROS that activates _______ and damages ______.

Answer 10

Serine-threonine kinase such as PKC; many cellular mechanisms including proteins, FA, DNA, RNA

Question 11

SO can be generated via coenzyme _____.

Answer 11

Q10

Question 12

How does excess oxidation of glucose or FFA cause generation of SO from CoQ10?

Answer 12

Excessive H is pumped into mitochondria by ETC. High [H] inhibits cytochrome from accepting electron from CoQ10. CoQ10 diverts these electrons to oxygen and generates excess amounts of SO.

Question 13

ROS, kinases, and gene products (cytokines, chemokines, etc.) produce _________ that lead to diabetic complications

Answer 13

ischemia, cellular proliferation, matrix accumulation and dysfunction, cellular necrosis, apoptosis

Question 14

SO ______ the synthesis of NO.

Answer 14

inhibits

Question 15

_____ is the primary endogenous inhibitor of Nfkb and platelet aggregation.

Answer 15

NO

Question 16

What does deficiency of NO cause?

Answer 16

allows inflammation to proceed unchecked. It is an important vasodilator and its deficiency contributes to vasoconstriction and ischemia.

Question 17

What is auto-oxidation?

Answer 17

method by which excess glucose generates additional SO

Question 18

____ is a fatty acid that is a direct inducer of NO.

Answer 18

Ceramide

Question 19

T or F NO induces apoptosis.

Answer 19

T

Question 20

When is apoptosis good and when is it bad?

Answer 20

Plaque: good–> shrinkage
Islets: bad

Question 21

_____ is a substrate for the pro-inflammatory prostaglandins that contribute to the destruction of islets.

Answer 21

Arachidonate

Question 22

What is beta-oxidation?

Answer 22

oxidation of FFA

Question 23

Excessive oxidation and ROS changes the redox state. What are detrimental effects of this?

Answer 23

1. Inhibits further glucose and fatty acid oxidation–> partially degraded FA bound to carnitine –>
2. inhibiting transfer of more FA into mitochondria and toxic accumulation in cytoplasma.
3. Increased glyceraldehyde 3P–> major intracellular glycosylator of proteins
4. GAP–> DAG–> PKC
5. Equilibrium shifted to lactate (from pyruvate)–> acidosis

Question 24

T or F SO is a potent activator of PKC

Answer 24

TRUE (this is bolded and underlined in the document so its probably not important….)

Question 25

3 additional ways SO is generated

Answer 25

1. NADPH oxidase stimulated by oxidized LDL, TNFa, ATII 2. auto-oxidation 3. Neutrophils and macrophages

Question 26

In cells that have aldose reductase, glucose is converted to ____.

Answer 26

sorbitol and then fructose

Question 27

T or F Glucose is a more potent glycosylating agent than fructose

Answer 27

False- Fructose is

Question 28

What happens to sorbitol that causes osmotic swelling of cells?

Answer 28

accumulates in cytoplasm

Question 29

What does hyperosmolarity activate?

Answer 29

AMP kinase--> DAG synthase--> DAG --> PKC (inflammation) and JNK and MAPK which induce apoptosis

Question 30

Sorbitol is structurally similar to _____.

Answer 30

myo-inositol (ringed)

Question 31

Myo-inositol is a 2nd msger in the _____ pathway.

Answer 31

phosphatidylinositol

Question 32

Why is an abundant supply of intracellular myo-inositol required?

Answer 32

PI turn over is very fast

Question 33

What does sorbitol and probably glucose do to the transport pathway of myo-inositol?

Answer 33

Blocks- When sorbitol/glucose levels are high, PI pathway is starved- nerves are susceptible

Question 34

How does the PI pathway normally function?

Answer 34

PI--> PIP-2--> activation of PKC--> IP3 and DAG IP3--> stimulates release of Ca--> Na/K ATPase and calcium chanels DAG--> activates PKC, metabolized to PG like PGE1 that is pro-inflammatory

Question 35

In order for NaK ATPase to function normally and play its role in normal nerve impulse propagation, is one or both arms of the PI pathway required?

Answer 35

both

Question 36

What happens when glucose comes in contact with protein or DNA molecule?

Answer 36

covalently linked via aldehyde group on glucose and terminal amino groups on arginine, lysine, and nucleic acids

Question 37

What is the initial step in non-enzymatic glycosylation reactions? What is the slow rearrangement step?

Answer 37

formation of schiff base; Amadori product

Question 38

How is non-enzymatic glycosylation measured?

Answer 38

hemoglobin A1C

Question 39

The degree of non-enzymatic glycoyslation is determined by ____

Answer 39

simple mass action

Question 40

T or F glycosylation can create novel binding sites to create new binding sites

Answer 40

true

Question 41

Glycosylated proteins can undergo an extensive series of oxidation-dehydration reactions and rearrangements to form _________

Answer 41

AGE-products

Question 42

What is the most important reaction in formation of AGE products?

Answer 42

cross links between proteins and/or DNA- prevent normal degradation

Question 43

Are AGE-products reveresible?

Answer 43

negative ghost rider

Question 44

GAP, other glyolytic intermediates, and fructose are all potent ______

Answer 44

glycosylators

Question 45

_________ express RAGE. When bound, they activate ______.

Answer 45

macs and enothelial cells; PKC

Question 46

Collagen synthesis is stimulated by _____ and inhibited by _____. What happens to these in diabetes?

Answer 46

TGF B- increased thanks to PKC | NO- reduced

Question 47

Heparan sulfate binding is inhibited by ______

Answer 47

glycosylation

Question 48

Hall mark of diabetic tissue annddd GO!

Answer 48

massive increase in ECM that is unable to provide a physiological barrier

Question 49

How is glomerular perfusion pressure affected?

Answer 49

WITHIN DAYS, control of arterioles becomes dysfunctional and pressure INCREASES accompanied by an increase in GFR

Question 50

What happens to GFR, perfusion pressure, and kidney size at the beginning of diabetes?

Answer 50

All increase

Question 51

What happens if nephropathy progresses?

Answer 51

micro-albuminuria--> proteinuria Matrix material dysfunction--> crowding--> fall in GFR Toxic filtered protein--> tubular cells die HTN, loss of EPO, anemia,

Question 52

How does nephropathy lead to secondary hypoparathyroidism

Answer 52

loss of VD, decreased Ca absorption, increase PTH (pro-inflammatory)

Question 53

Retinopathy affects ___% of diabetics.

Answer 53

80

Question 54

2 types of clinical presentations of retinopathy

Answer 54

macular edema and/or neo-vascularization.....This is bolded and underlined soooo yea

Question 55

The accumulation of fluorescein in vitreous is due primarily to _____

Answer 55

dysfunctional pigment epithelial cells