Pathology of Diabetes Mellitus

Question 1

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

Answer 1

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

Question 2

What tissues have insulin receptors?

Answer 2

adipose tissue, striated muscle, and liver

Question 3

Adipose tissue responds to insulin by

Answer 3

increasing glucose uptake and lipogenesis; decreasing lipolysis

Question 4

Striated muscle responds to insulin by

Answer 4

increasing glucose uptake, glycogen synthesis, and protein synthesis

Question 5

Liver responds to insulin by

Answer 5

decreasing gluconeogenesis; increasing glycogen synthesis and lipogenesis

Question 6

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

Answer 6

changes interior environment - cell growth and proliferation

Question 7

Tissue complications in diabetes are related to

Answer 7

severity and duration of hyperglycaemia, NOT the type of DM

Question 8

Major changes in DM involve

Answer 8

blood vessels

Question 9

Organ pathology and resulting morbidity and mortality is due to

Answer 9

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

Question 10

What are the macrovascular effects of DM?

Answer 10

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

Question 11

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

Answer 11

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

Question 12

What are the microvascular effects of DM?

Answer 12

nephropathy, retinopathy, and delayed wound healing

Question 13

Microvascular complications in DM are related to

Answer 13

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

Question 14

What are Advanced Glycation End-products (AGEs)?

Answer 14

stable glycosylation of proteins that is irreversible

Question 15

What are the cellular/extravascular effects of DM?

Answer 15

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

Question 16

The commonest pathology associated with heavy proteinuria is

Answer 16

diabetic nephropathy

Question 17

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

Answer 17

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

Question 18

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

Answer 18

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

Question 19

What are the typical histological lesions of diabetic nephropathy?

Answer 19

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

Question 20

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

Answer 20

glomerular basement membrane thickening of capillary loops and KW nodules

Question 21

Proteinuria is due to what complication of the basement membrane?

Answer 21

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

Question 22

Diabetic retinopathy occurs in what percentage of DM patients?

Answer 22

80% who have had it for +20yrs

Question 23

What is the primary process of diabetic retinopathy?

Answer 23

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

Question 24

Why do DM patients have impaired wound healing?

Answer 24

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)

Question 25

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

Answer 25

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

Question 26

AGEs bind to

Answer 26

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

Question 27

Receptor-mediated effects of AGEs include

Answer 27

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)

Question 28

What are the non-receptor mediated effects of AGEs?

Answer 28

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)

Question 29

Protein Kinase C is activated by

Answer 29

intracellular hyperglycaemia

Question 30

Activation of PKC results in

Answer 30

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

Question 31

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

Answer 31

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

Question 32

Diabetic neuropathy is caused by

Answer 32

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

Question 33

What are the effects of DM on the liver?

Answer 33

NASH/NAFLD

Question 34

What are the characteristics of NASH?

Answer 34

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

Question 35

Commonest causes of death in DM are

Answer 35

macrovascular: MI, stroke, renal failure

Question 36

Major morbidity/chronic illness in DM is related to

Answer 36

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

Question 37

Type 1 DM is classified by

Answer 37

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

Question 38

Type 2 DM is classified by

Answer 38

insulin resistance with relative insulin deficiency

Question 39

What are the classifications of DM?

Answer 39

``` 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 ```

Question 40

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

Answer 40

70-80%

Question 41

Non-proliferative retinopathy

Answer 41

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

Question 42

Proliferative retinopathy

Answer 42

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

Question 43

Peripheral nephropathy

Answer 43

symmetric, motor and sensory

Question 44

Autonomic nephropathy

Answer 44

impotence, bowel and bladder dysfunction

Question 45

Diabetic polyradiculopathy

Answer 45

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

Question 46

Mononeuropathy

Answer 46

affects larger nerves