Pathology of Diabetes Mellitus Flashcards
What is the major insulin-responsive site for prostprandial glucose utilization?
skeletal muscle - it is critical for preventing hyperglycaemia and maintaining glucose homeostasis
What tissues have insulin receptors?
adipose tissue, striated muscle, and liver
Adipose tissue responds to insulin by
increasing glucose uptake and lipogenesis; decreasing lipolysis
Striated muscle responds to insulin by
increasing glucose uptake, glycogen synthesis, and protein synthesis
Liver responds to insulin by
decreasing gluconeogenesis; increasing glycogen synthesis and lipogenesis
What are the other cellular effects of insulin binding its receptor?
changes interior environment - cell growth and proliferation
Tissue complications in diabetes are related to
severity and duration of hyperglycaemia, NOT the type of DM
Major changes in DM involve
blood vessels
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
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)
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
What are the microvascular effects of DM?
nephropathy, retinopathy, and delayed wound healing
Microvascular complications in DM are related to
long-term effects of hyperglycaemia on cells and ECM, particularly glycosylation of protiens
What are Advanced Glycation End-products (AGEs)?
stable glycosylation of proteins that is irreversible
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
The commonest pathology associated with heavy proteinuria is
diabetic nephropathy
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
What is the macroscopic appearance of diabetic nephropathy (decades)?
bilaterally shrunken, scarred, pitted external surface due to microvascular and macrovascular injury
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
What are the typical histological lesions of diabetic nephropathy on SEM?
glomerular basement membrane thickening of capillary loops and KW nodules
Proteinuria is due to what complication of the basement membrane?
the loss of charge on the constituent proteins, NOT the thickening of the BM
Diabetic retinopathy occurs in what percentage of DM patients?
80% who have had it for +20yrs
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
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)
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
AGEs bind to
RAGE receptor on inflammatory cells: macros, T cells, endothelial cells, and vascular smooth muscle
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)
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)
Protein Kinase C is activated by
intracellular hyperglycaemia
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
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
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)
What are the effects of DM on the liver?
NASH/NAFLD
What are the characteristics of NASH?
fat accumulation in cells, infiltrate of neutrophils and lymphocytes that cause hepatocyte damage and fibrosis
Commonest causes of death in DM are
macrovascular: MI, stroke, renal failure
Major morbidity/chronic illness in DM is related to
microvascular: renal, retinal, neuropathy, impaired healing/foot care, liver disease
Type 1 DM is classified by
beta cell destruction leading to absolute insulin deficiency; can be immune-mediated or idiopathic
Type 2 DM is classified by
insulin resistance with relative insulin deficiency
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
Clinical features of T1DM present when what percent of beta cells are destroyed?
70-80%
Non-proliferative retinopathy
microangiopathy with pericyte loss leads to leaky weakened vessels with impaired blood flow –> exudates, haemorrhages, microaneurysms, ischaemia
Proliferative retinopathy
ischaemia from microangiopathy leads to proliferation of small vessels into the vitreous, causing haemorrhages, fibrosis, and retinal detatchment
Peripheral nephropathy
symmetric, motor and sensory
Autonomic nephropathy
impotence, bowel and bladder dysfunction
Diabetic polyradiculopathy
severe disabling pain in the distribution of one or more nerve roots +/- motor weakness
Mononeuropathy
affects larger nerves
