Pathology of Diabetes Mellitus Flashcards Preview

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Flashcards in Pathology of Diabetes Mellitus Deck (46):
1

What is the major insulin-responsive site for prostprandial glucose utilization?

skeletal muscle - it is critical for preventing hyperglycaemia and maintaining glucose homeostasis

2

What tissues have insulin receptors?

adipose tissue, striated muscle, and liver

3

Adipose tissue responds to insulin by

increasing glucose uptake and lipogenesis; decreasing lipolysis

4

Striated muscle responds to insulin by

increasing glucose uptake, glycogen synthesis, and protein synthesis

5

Liver responds to insulin by

decreasing gluconeogenesis; increasing glycogen synthesis and lipogenesis

6

What are the other cellular effects of insulin binding its receptor?

changes interior environment - cell growth and proliferation

7

Tissue complications in diabetes are related to

severity and duration of hyperglycaemia, NOT the type of DM

8

Major changes in DM involve

blood vessels

9

Organ pathology and resulting morbidity and mortality is due to

changes in the macrovascular (larger muscular and elastic arteries) and microvascular (capillaries and arterioles) circulation

10

What are the macrovascular effects of DM?

accelerated and more severe atheroma but in same areas - coronaries, carotids, aorta, iliacs, cerebral - 10x higher risk for CVD events (MI, stroke, angina)

11

What are the reasons for accelerated and severe atheroma in DM?

chronic hyperglycemia leads to changes in the liver - metabolism of proteins (increased production of atherogenic proteins) and lipids; suppression of uptake of lipids in peripheral tissues; changes in macrophage function; changes in endothelial function (pro-coagulant); hyperlipidaemia and hypertension

12

What are the microvascular effects of DM?

nephropathy, retinopathy, and delayed wound healing

13

Microvascular complications in DM are related to

long-term effects of hyperglycaemia on cells and ECM, particularly glycosylation of protiens

14

What are Advanced Glycation End-products (AGEs)?

stable glycosylation of proteins that is irreversible

15

What are the cellular/extravascular effects of DM?

different cell types are affected by chronic hyperglycaemia in different ways - neutrophils, macrophages, Schwann cells, neurons, astrocytes - their biochemistry changes

16

The commonest pathology associated with heavy proteinuria is

diabetic nephropathy

17

What are the 4 different adverse effects of DM on the kidney?

diabetic glomerulosclerosis/arteriolosclerosis; bacterial infection due to impaired neutrophil-mediated immune function (pyelonephritis); papillary necrosis - deep medullary pyramids die; accelerated atherosclerosis in larger arteries increasing susceptibility to renal infarct and ischaemic injury

18

What is the macroscopic appearance of diabetic nephropathy (decades)?

bilaterally shrunken, scarred, pitted external surface due to microvascular and macrovascular injury

19

What are the typical histological lesions of diabetic nephropathy?

Kimmelsteil-Wilson nodules - acelluar spheres of collagen in the mesangium of the glomerulus; hyaline arterioscelrosis - thickening of media of arteriolar walls with bright thick acellular proteinaceous material

20

What are the typical histological lesions of diabetic nephropathy on SEM?

glomerular basement membrane thickening of capillary loops and KW nodules

21

Proteinuria is due to what complication of the basement membrane?

the loss of charge on the constituent proteins, NOT the thickening of the BM

22

Diabetic retinopathy occurs in what percentage of DM patients?

80% who have had it for +20yrs

23

What is the primary process of diabetic retinopathy?

ischaemia due to microvascular injury (thickening, glycosylation) and reduced perfusion of retinal circulation; vascular proliferation (attempts to regrow ischaemic areas) is a response to the ischaemia

24

Why do DM patients have impaired wound healing?

impaired perfusion due to microvascular injury; also macrovascular disease/atheroma leading to infarction eg in toes (gangrene); healing is slow, granulation tissue grows more slowly, microvasculature impaired; increased susceptibility to infections (neutrophil dysfunction) +/- neuropathy (prone to injury)

25

Advance Glycation End-products (AGEs) are the result of

interactions between glucose or molecules derived from glucose and amino groups of various proteins inside and outside cells

26

AGEs bind to

RAGE receptor on inflammatory cells: macros, T cells, endothelial cells, and vascular smooth muscle

27

Receptor-mediated effects of AGEs include

release of pro-inflam cytokines and GFs from macrophages; ROS generation and pro-coag activity in endothelial cells; proliferation and matrix production by vascular smooth muscle cells (remodelling)

28

What are the non-receptor mediated effects of AGEs?

cross-linking of ECM proteins altering dynamics of vessels: type I collagen in vessel walls, type IV collagen in BM (alters endothelial attachment and permeability, thickening); proteins are resistant to degradation and can trap other proteins and LDL (+atheroma in DM)

29

Protein Kinase C is activated by

intracellular hyperglycaemia

30

Activation of PKC results in

pro-angiogenic GF (VEGF), elevated endothelin-1 and reduced NO (pro-constriction); pro--fibrogenic GFs like TGFB increasing production of BM and matrix; pro-inflam cytokines from endothelium; overall becomes a pro-coag environment

31

What are the 3 metabolic pathways of tissue damage due to chronic hyperglycaemia?

Advanced Glycation End-products (AGEs)
Activation of Protein Kinase C
Intracellular hyperglycaemia and abnormal Polyol pathways

32

Diabetic neuropathy is caused by

combination of microvascular damage, biochemical abnormalities that affect Schwann cells and axons caused by AGEs, Polyols, and neuronal ischaemia (damage to arterioles)

33

What are the effects of DM on the liver?

NASH/NAFLD

34

What are the characteristics of NASH?

fat accumulation in cells, infiltrate of neutrophils and lymphocytes that cause hepatocyte damage and fibrosis

35

Commonest causes of death in DM are

macrovascular: MI, stroke, renal failure

36

Major morbidity/chronic illness in DM is related to

microvascular: renal, retinal, neuropathy, impaired healing/foot care, liver disease

37

Type 1 DM is classified by

beta cell destruction leading to absolute insulin deficiency; can be immune-mediated or idiopathic

38

Type 2 DM is classified by

insulin resistance with relative insulin deficiency

39

What are the classifications of DM?

Type 1
Type 2
Gestational
Drug and chemical induced
Specific genetic defects affecting beta cell function or insulin action
Diseases of the pancreas
Endocrinopathies e.g. acromegaly, Cushing’s syndrome
Other

40

Clinical features of T1DM present when what percent of beta cells are destroyed?

70-80%

41

Non-proliferative retinopathy

microangiopathy with pericyte loss leads to leaky weakened vessels with impaired blood flow --> exudates, haemorrhages, microaneurysms, ischaemia

42

Proliferative retinopathy

ischaemia from microangiopathy leads to proliferation of small vessels into the vitreous, causing haemorrhages, fibrosis, and retinal detatchment

43

Peripheral nephropathy

symmetric, motor and sensory

44

Autonomic nephropathy

impotence, bowel and bladder dysfunction

45

Diabetic polyradiculopathy

severe disabling pain in the distribution of one or more nerve roots +/- motor weakness

46

Mononeuropathy

affects larger nerves