B2.050 Prework 1 Chronic Complications of Diabetes

Question 1

what is the difference between micro and macrovascular disease?

Answer 1

macro includes damage induced in large and medium sized muscular arteries
micro includes damage in small vessels

Question 2

what is responsible for the long term complications of diabetes?

Answer 2

persistent hyperglycemia

glucotoxicity

Question 3

how is glycemic control primarily assessed?

Answer 3

percentage of glycated hemoglobin

HbA1c

Question 4

what is the recommended HbA1c level in diabetic patients?

Answer 4

maintenance below 7%

Question 5

what are AGEs?

Answer 5

advanced glycation end products
formed as a result of noenzymatic reactions between intracellular glucose derived dicarbonyl precursors with amino groups of proteins

Question 6

what is the AGE-RAGE signaling axis?

Answer 6

AGEs bind to RAGE receptors expressed on inflammatory cells, endothelium, and vascular smooth muscle

Question 7

what are the 4 primary negative effects of the AGE-RAGE signaling axis?

Answer 7

1. release of cytokines and growth factors
   TGFB- leads to deposition of excess basement membrane material
   VEGF- implicated in retinopathy
2. generation of ROS in endothelial cells
3. increased procoagulant activity
4. enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix

Question 8

what other effect can AGEs have outside of receptor mediated effects?

Answer 8

can cross link extracellular matrix proteins

Question 9

what are some of the negative effects of AGE mediated cross linking?

Answer 9

collagen type 1-decreases elasticity, predisposing vessels to injury
collagen type 4- decreases endothelial cell adhesion and increases extravasation of fluid
protein- resists digestion

Question 10

what is protein kinase C?

Answer 10

intracellular protein activated by calcium and DAG

Question 11

what are effects of excessive PKC activation by hyperglycemia?

Answer 11

VEGF, TGFB, and procoagulant protein plasminogen activator inhibitor-1

Question 12

how does hyperglycemia disturb the polyol pathway?

Answer 12

excess glucose is metabolized by aldolase reductase to sorbitol
sorbitol metabolized to fructose using NADPH
decrease of NADPH availability for reduction of glutathione
less GSH for antioxidant mechanisms

Question 13

what is an effect of sorbitol accumulation?

Answer 13

cataracts

Question 14

what is the effects of hyperglycemia induced flux through the hexosamine pathway?

Answer 14

increased intracellular levels of fructose-6-phosphate (substrate for glycosylation)
generation of excess proteoglycans

Question 15

what pancreas alterations are commonly found in type 1 diabetes?

Answer 15

reduction in number and size of islets

leukocytic infiltrates in islets

Question 16

what pancreas alterations are commonly found in type 2 diabetes?

Answer 16

subtle reduction in islet cell mass

amyloid deposition within islets

Question 17

what is the hallmark of diabetic macrovascular disease?

Answer 17

accelerated atherosclerosis

Question 18

what is the most common cause of death in diabetes?

Answer 18

MI caused by atherosclerosis of the coronary arteries

Question 19

what is 100x more common in diabetics than in the general population?

Answer 19

gangrene of the lower extremities

Question 20

what is hyaline arteriolosclerosis?

Answer 20

hyaline thickening of the wall of the arterioles which causes the narrowing of the lumen

Question 21

what is one of the most consistent morphologic features of diabetes?

Answer 21

diffuse thickening of the basement membrane

Question 22

what is the result of thickening of the basement membranes?

Answer 22

diabetic capillaries are more leaky than normal to plasma proteins
underlies development of diabetic nephropathy, retinopathy, and some neuropathy forms

Question 23

what is the second leading cause of death in diabetics?

Answer 23

renal failure

Question 24

what are 3 renal lesions encountered in diabetic nephropathy?

Answer 24

1. glomerular lesions
2. renal vascular lesions (arteriolosclerosis)
3. pyelonephritis

Question 25

what are the most important glomerular lesions?

Answer 25

capillary basement membrane thickening
diffuse mesangial sclerosis
nodular glomerulosclerosis

Question 26

what percentage of cases of diabetic nephropathy show widespread thickening of the glomerular capillary basement membrane?

Answer 26

virtually all of them

Question 27

when does GBM thickening begin?

Answer 27

2 years after onset of diabetes

amounts to 30% by 5 years

Question 28

what is mesangial increase typically associated with?

Answer 28

overall thickening of the GBM

Question 29

what does the progressive expansion of the mesangium correlate with?

Answer 29

measures of deteriorating renal function such as increasing proteinuria

Question 30

what are other names for nodular glomerulosclerosis?

Answer 30

intercapillary glomerulosclerosis

Kimmelstiel-Wilson disease

Question 31

where are KW nodules located?

Answer 31

periphery of the glomerulus
within mesangial core of the glomerular lobules and can be surrounded by peripheral capillary loops or loops that are markedly dilated

Question 32

what frequently accompanies nodular lesions?

Answer 32

prominent accumulations of hyaline material in capillary loops (fibrin caps) or adherent to bowmans capsule (capsular drops)

Question 33

what are some consequences of glomerular and arteriolar lesions?

Answer 33

kidney ischemia
tubular atrophy
interstitial fibrosis
overall contraction in size

Question 34

is efferent arteriolosclerosis found in nondiabetics?

Answer 34

no

changes in other arteries and arterioles are similar in other tissues tho

Question 35

what is pyelonephritis?

Answer 35

inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules

Question 36

discuss some ocular pathologies of diabetics

Answer 36

cataract
glaucoma (increased intraocular pressure)
retinal changes (preproliferative or proliferative)

Question 37

what percentage of diabetics have peripheral neuropathy?

Answer 37

50% overall

80% of those who have had the disease for 15 years

Question 38

what types of effects are responsible for the overwhelming majority of morbidity and mortality of diabetes?

Answer 38

long term effects more than acute complications

Question 39

what are some cardiovascular risk factors that often accompany diabetes?

Answer 39

hypertension
dyslipidemia
elevated levels of procoagulant PAI-1

Question 40

how does insulin resistance contribute to diabetic dyslipidemia?

Answer 40

favors hepatic production of atherogenic lipoproteins and by suppressing uptake of circulating lipids in peripheral tissues

Question 41

what populations are at higher risk of developing end stage renal disease with diabetes

Answer 41

Native Americans
Hispanics
African Americans

Question 42

what is the earliest manifestation of diabetic nephropathy?

Answer 42

albumin in urine

Question 43

what is microalbuminuria?

Answer 43

30-300 mg/day albumin in urine

Question 44

what is overt nephropathy with macroalbuminuria?

Answer 44

> 300 mg/day albumin in urine

developed by 80% of DM1 and 20-40% DM2 patient without interventions

Question 45

characterize the progression of overt nephropathy to end stage renal disease

Answer 45

highly variable

by 20 years, 75% of DM1 and 20% of DM2 patients with overt nephropathy will develop end stage renal disease

Question 46

what percentage of patients develop diabetic retinopathy 15-20 years after diagnosis?

Answer 46

60-80%

Question 47

what is the most frequent pattern of diabetic neuropathy?

Answer 47

distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function

Question 48

why are diabetics plagued by enhanced susceptibility to infections?

Answer 48

neuropathy (cant feel infections beginning)
decreased neutrophil function
impaired cytokine production
vascular compromise

Question 49

what is the relationship between obesity and insulin resistance?

Answer 49

excess FFAs
cytokines released from adipose
inflammation