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Flashcards in Chronic Complications of Diabetes Mellitus Deck (55):
1

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

T2D

2

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

DKA

3

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

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

4

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

atherosclerotic vascular disease

5

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

renal failure

6

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

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

7

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

F- BEFORE

8

What are the major enviornmental factors in T2D?

development of obesity and reduced exercise

9

What is the significance of visceral fat in metabolic syndrome?

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

10

Excessive oxidation generates ROS that activates _______ and damages ______.

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

11

SO can be generated via coenzyme _____.

Q10

12

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

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.

13

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

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

14

SO ______ the synthesis of NO.

inhibits

15

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

NO

16

What does deficiency of NO cause?

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

17

What is auto-oxidation?

method by which excess glucose generates additional SO

18

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

Ceramide

19

T or F NO induces apoptosis.

T

20

When is apoptosis good and when is it bad?

Plaque: good--> shrinkage
Islets: bad

21

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

Arachidonate

22

What is beta-oxidation?

oxidation of FFA

23

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

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

24

T or F SO is a potent activator of PKC

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

25

3 additional ways SO is generated

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

26

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

sorbitol and then fructose

27

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

False- Fructose is

28

What happens to sorbitol that causes osmotic swelling of cells?

accumulates in cytoplasm

29

What does hyperosmolarity activate?

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

30

Sorbitol is structurally similar to _____.

myo-inositol (ringed)

31

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

phosphatidylinositol

32

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

PI turn over is very fast

33

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

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

34

How does the PI pathway normally function?

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

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?

both

36

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

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

37

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

formation of schiff base; Amadori product

38

How is non-enzymatic glycosylation measured?

hemoglobin A1C

39

The degree of non-enzymatic glycoyslation is determined by ____

simple mass action

40

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

true

41

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

AGE-products

42

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

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

43

Are AGE-products reveresible?

negative ghost rider

44

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

glycosylators

45

_________ express RAGE. When bound, they activate ______.

macs and enothelial cells; PKC

46

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

TGF B- increased thanks to PKC
NO- reduced

47

Heparan sulfate binding is inhibited by ______

glycosylation

48

Hall mark of diabetic tissue annddd GO!

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

49

How is glomerular perfusion pressure affected?

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

50

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

All increase

51

What happens if nephropathy progresses?

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

52

How does nephropathy lead to secondary hypoparathyroidism

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

53

Retinopathy affects ___% of diabetics.

80

54

2 types of clinical presentations of retinopathy

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

55

The accumulation of fluorescein in vitreous is due primarily to _____

dysfunctional pigment epithelial cells