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Metabolism > Pathology of Diabetes Mellitus > Flashcards

Pathology of Diabetes Mellitus Flashcards

1
Q

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

A

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

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2
Q

What tissues have insulin receptors?

A

adipose tissue, striated muscle, and liver

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3
Q

Adipose tissue responds to insulin by

A

increasing glucose uptake and lipogenesis; decreasing lipolysis

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4
Q

Striated muscle responds to insulin by

A

increasing glucose uptake, glycogen synthesis, and protein synthesis

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5
Q

Liver responds to insulin by

A

decreasing gluconeogenesis; increasing glycogen synthesis and lipogenesis

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6
Q

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

A

changes interior environment - cell growth and proliferation

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7
Q

Tissue complications in diabetes are related to

A

severity and duration of hyperglycaemia, NOT the type of DM

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8
Q

Major changes in DM involve

A

blood vessels

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9
Q

Organ pathology and resulting morbidity and mortality is due to

A

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

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10
Q

What are the macrovascular effects of DM?

A

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

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11
Q

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

A

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

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12
Q

What are the microvascular effects of DM?

A

nephropathy, retinopathy, and delayed wound healing

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13
Q

Microvascular complications in DM are related to

A

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

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14
Q

What are Advanced Glycation End-products (AGEs)?

A

stable glycosylation of proteins that is irreversible

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15
Q

What are the cellular/extravascular effects of DM?

A

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

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16
Q

The commonest pathology associated with heavy proteinuria is

A

diabetic nephropathy

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17
Q

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

A

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

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18
Q

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

A

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

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19
Q

What are the typical histological lesions of diabetic nephropathy?

A

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
Q

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

A

glomerular basement membrane thickening of capillary loops and KW nodules

21
Q

Proteinuria is due to what complication of the basement membrane?

A

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

22
Q

Diabetic retinopathy occurs in what percentage of DM patients?

A

80% who have had it for +20yrs

23
Q

What is the primary process of diabetic retinopathy?

A

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
Q

Why do DM patients have impaired wound healing?

A

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
Q

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

A

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

26
Q

AGEs bind to

A

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

27
Q

Receptor-mediated effects of AGEs include

A

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
Q

What are the non-receptor mediated effects of AGEs?

A

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
Q

Protein Kinase C is activated by

A

intracellular hyperglycaemia

30
Q

Activation of PKC results in

A

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
Q

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

A

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

32
Q

Diabetic neuropathy is caused by

A

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

33
Q

What are the effects of DM on the liver?

A

NASH/NAFLD

34
Q

What are the characteristics of NASH?

A

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

35
Q

Commonest causes of death in DM are

A

macrovascular: MI, stroke, renal failure

36
Q

Major morbidity/chronic illness in DM is related to

A

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

37
Q

Type 1 DM is classified by

A

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

38
Q

Type 2 DM is classified by

A

insulin resistance with relative insulin deficiency

39
Q

What are the classifications of DM?

A 
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
Q

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

A

70-80%

41
Q

Non-proliferative retinopathy

A

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

42
Q

Proliferative retinopathy

A

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

43
Q

Peripheral nephropathy

A

symmetric, motor and sensory

44
Q

Autonomic nephropathy

A

impotence, bowel and bladder dysfunction

45
Q

Diabetic polyradiculopathy

A

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

46
Q

Mononeuropathy

A

affects larger nerves

Metabolism (16 decks)

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