Pathophysiology of diabetes complications Flashcards
List the micro and macrovascular complications of diabetes
Microvascular
- Diabetic retinopathy
- Diabetic nephropathy
- Diabetic neuropathy
Macrovascular
- Coronary artery disease - this is a major cause of death in diabetics
- Peripheral vascular disease
- Cerebrovascular disease
depending on location of atherosclerosis.
Broadly describe the cause of macrovascular complications
- Diabetes is a risk factor of atherosclerosis as chronic hyperglycemia creates a dysfunctional epithelium = impaired vasodilation, oxidative stress, pro-coagulative state and pro-inflammatory state
- Major determinants are other metabolic risk factors i.e. obesity, dyslipidemia and arterial hypertension
- Diabetics often have 1 or more of these risk factors
- Coronary artery disease - this is a major cause of death in diabetics
- Peripheral vascular disease
- Cerebrovascular disease
depending on location of atherosclerosis.
List and briefly describe other diabetes complications
- Hypoglycemia-related: seizures, death, accidents…
- Hyperglycemic crises: DKA, HHS
- Infections, including candidiasis (because high glucose affect WBC function)
- Oral, gingivitis: can lead to systemic inflammation indicated by high CRP and WCC
- Musculoskeletal and connective tissue e.g. joint stiffness, inflammation of joints, tendinitis
- Impotence: poor erectile dysfunction as consequence of neuropathy and microvascular disease (poor blood flow and autonomic function)
- Depression: daily challenge of managing condition = diabetes stress
List the factors contributing to diabetes complications
- Hyperglycemia
- Dyslipidemia
- Hypertension
- Overweight/obesity
- Smoking
Describe some of the evidence behind treating hyperglycaemia
Hyperglycaemia is associated with diabetic tissue damage in both type 1 and 2 diabetes.
DCCT and EDIC
* T1D: starting intensive treatment early results in long-term positive effects
* Diabetic retinopathy (3-step development) - 60–80% reduction in diabetic retinopathy progression when HbA1c kept high
* Microalbuminuria (first sign of renal injuries from diabetes) → macroalbuminuria (established diabetic nephropathy)
* Microvascular complications prevented when sugars maintained are low
* * *Microvascular complications prevented when sugars maintained are low (~60%)
- CVD events and reduction of GFR each reduced by about 50%**
UKPDS (UK Prospective Diabetes Study)
- Intensive blood glucose with sulphonylureas or insulin compared with conventional treatment
- Average plasma fasting glucose and HbA1c lower in therapy group
- Initial improvement, then loss of that same level of control - reflects how T2D gets harder to control as years progress
- Microvascular disease reduction in treated group remained (legacy effect)
- Myocardial infarction was significantly reduced after 10 years
- All-cause mortality was reduced - long-term control was better at preventing all cause mortality
- Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for MI and death from any cause were observed during 10 years of post-trial follow-up
Describe the mechanism of hyperglycaemia-induced tissue injury
- Genetics important in developing diabetes
- Cumulative long-term changes in stable macromolecules
(e.g. glycosylation of proteins, lipoproteins) in response to
↑ glucose →tissue damage- Not just average glucose control, but also how much it waxes and wanes is important
- Independent accelerating factors also play a role e.g.
hypertension, hyperlipidemia- Once patient has early stage nephropathy, HTN will speed up process of renal decline
- Synergistic effect of hyperglycaemia and HTN
- Lipid lowering medications can slow retinopathy and neuropathy and T2D
Pathways/Processes Involved
- Reactive oxygen species (ROS) production
- Polyol pathway, sorbitol
- Hexosamine pathway
- Advanced glycosylation end-products (AGEs)
- Glucolipotoxicity
- Activation of inflammation
- Activation of fibrosis
Describe the pathways involved in hyperglycaemia-induced tissue injury
- Reactive oxygen species (ROS) production (e.g. with GL, G6P –> sorbitol pathways, hexosamine pathway, pkc pathwa and AGE pathway)
- Polyol pathway, sorbitol – cataract formation and neuropathy associations
- Hexosamine pathway
- Advanced glycosylation end-products (AGEs) - glycosylation, oxidation, making macromolecules toxic to cells
- Glucolipotoxicity
- Activation of inflammation e.g. by AGEs
- Activation of fibrosis
Describe glucolipotoxicity
- Elevated fatty acids become toxic to cells in the context of hyperglycemia: elevated glucose and fatty acids are synergistic in causing damage
- Glucose via glycolysis into TCA builds up malonyl-CoA, which inhibits FA oxidation
- Glucose provides glycerol-3-phosphate and free fatty acids e..g glycerolipids e.g. phospholipid, diacylglycerol, triglycerides
- Involves toxic lipids such as ceramide
Describe diabetic nephropathy
Nephropathy overview:
Pathology:
- Glomerulosclerosis and nodular sclerosis occurs - drop out of glomeruli
- Mesangial thickening
- Gloumerular capillaries lost
- Tubules in kidneys also diseased with ↑ BM
- Some epithelial cellular changes to tubules
- Interstitial lesions and fibrosis → tubular atrophy
- Early on, hyperglycaemia causes hyperfiltration ∴ eGFR ↑ and creatinine ↓ (changes in haemodynamics of kidney tissue)
- As cellular damage occurs, eGFR ↓ → can then progress quickly to end-stage renal disease
- Microalbuminuria arises → inspirent diabetic nephropathy
- A smaller group of patients may not have albuminuria nephropathy - instead, often have hypertension → renal artery stenosis
- Contributing factors:
- Advanced glycosylation end-products (AGEs)
- Protein Kinase C activates growth factors that lead to fibrosis, inflammation and albuminuria
- High BP can contribute → ACEi and ARB antihypertensives may help
Detect with urinalysis (proteinuria, microalbuminuria in early stage and macroalbuminuria in late stage).
- Diabetic nephropathy progression:
- Stage 1 = Hyperfiltration = increase in GFR and normal albuminuria
- Stage 2 = Silent stage = Normal GFR and normal albuminuria
- Stage 3 = Incipient stage = Normal GFR and microalbuminuria
- Stage 4 = Overt stage = GFR decline and macroalbuminuria (additionally results in hypertension)
- Stage 5 = End stage renal disease = GFR <15 and macroalbuminuria (hypertension)
- Exploration of the various factors that contribute to the development of diabetic nephropathy: high glucose, blood pressure, grwoth factors present leading to fibrosis, inflammatoion and albuminuria
- Many points to intervene: ACEis and ARBs, glucose lowering medications, GLP-1 and DPP4 agonists/inhibitors
- Several potential treatments: anti-VEGF/TGFb, PKCis
Describe diabetic retinopathy
Summary of retinopathy:
- Tends to occur in parallel to nephropathy
- Same pathways affected, particularly affecting microvasculature at back of eye
- Retinal ischaemia
- Vascular permeability (leaky vessels causing macular oedema)
- Hypertension may contribute
Proliferative diabetic retinopathy (PDR)
- Ischaemic retina releases VEGF, growth hormone, IGFR → all drive proliferative diabetic retinopathy
- New vessels (in response to VEGF) and abnormal capillaries
- Weak vessels prone to haemorrhage and fibrosis → retinal detachment → loss of vision
- Retinal flurocene angiogram shows blushes - abnormal vessel formation due to ischaemic retina
- Erythropoietin excreted in ischaemic retinopathy → retinal neovascularisation
- Treatment:
- laser to burn ischaemic parts → VEGF not produced
- Anti-VEGF injections
Non-proliferative diabetic retinopathy (NPDR)
- Cholesterol-like material (hard exudates aka dots and blots) build up on retina → leaky vessels
- Soft tissue oedema can affect central vision
- Capillary weakness → micro-aneurysms or haemorrhages from breaks in capillaries
- Important to have check ups every 2 years to exclude diabetic retinopathy - includes:
- Visual acuity test
- Retinal exam
- Better results if picked up early
Describe diabetic neuropathy
Summary of neuropathy:
- Peripheral neuropathy: painful feet that burn at night (doesn’t improve with diabetes control). “Gloves and socks” distribution
- Longer the nerve, the more likely it will get damaged by diabetes
- Mononeuropathy: one nerve damaged → can cause mononeuritis, multiplex or plexopathy (e.g. lumbosacral plexus affecting thigh)
- Autonomic neuropathy: issues with vital organs: postural hypotension, nocturnal diarrhoea, trouble with bladder, etc.
- Pathophysiology:
- Hyperglycaemia and glycosylation involved
- Oxidation of LDL - intracellular inflammation activated
- Increased glucose causes ROS production
- Interruption of microcirculation to single nerve e.g. diabetic CN3 palsy causing diplopia (eye goes down and out)
- Pupil sparing occurs in diabetic
- Principal treatment is to optimise glycemic control and pain management if applicable
- Also key to assess feet: sensory, motor and any deformities/calluses/ulcers/infections
- Additionally look for Charcot’s foot deformity = swollen flattened foot due to microfractures and collapse
- Lipid lowering drugs shown to help decrease all microvascular complications especially diabetic neuropathy
Describe diabetes and vascular disease
- Diabetes and vascular disease is multi-factorial
- Lipoprotein glycosylation makes them more atherogenic
- Dysfunctional endothelium
- Impaired vasodilation (↓ NO, PGI2)
- ↑ oxidative stress
- Pro-coagulants
- Pro-inflammatory
- ↓ repair and ↑ damage
- Insulin effects on endothelium
- Excess nutrient supply (e.g T2D where glucose and FAs ↑) inhibits PI3K signalling
- PI3K signalling activates NO production, vasodilatation, etc.
- Excess nutrient supply (e.g T2D where glucose and FAs ↑) inhibits PI3K signalling
- Excess nutrient supply has no effect on MAPK signalling →ET-1 production → vasoconstriction and pro-thrombosis
- ∴ Inhibition of PI3K signalling and activation of MAPK signalling cause endothelial dysfunction
- Treatment:
- Insulin therapy improves nutrient supply (glycemic control) ∴ relieve inhibitory effect and improve endothelial function
- Improved PI3K signalling → NO production increased → vasodilation and vasoconstriction balance appropriate
- Inhibition of adhesion molecule expression
- Inhibition of smooth muscle cell proliferation
- Insulin therapy improves nutrient supply (glycemic control) ∴ relieve inhibitory effect and improve endothelial function
- In insulin-resistant T2 patients, insulin treatment can make things worse
- High insulin and persistent hyperglycaemia
- PI3K signalling impaired
- Increased MAPK signalling unopposed - increased endothelin 1 (ET-1) production
- ∴ vasoconstriction effects of insulin predominate
- Smooth muscle cell proliferation
- Insulin treatment worsens endothelial dysfunction
Describe treatment of macrovascular disease in diabetes
- Treatment:
- Insulin therapy improves nutrient supply (glycemic control) ∴ relieve inhibitory effect and improve endothelial function
- Improved PI3K signalling → NO production increased → vasodilation and vasoconstriction balance appropriate
- Inhibition of adhesion molecule expression
- Inhibition of smooth muscle cell proliferation
- Insulin therapy improves nutrient supply (glycemic control) ∴ relieve inhibitory effect and improve endothelial function
- In insulin-resistant T2 patients, insulin treatment can make things worse
- High insulin and persistent hyperglycaemia
- PI3K signalling impaired
- Increased MAPK signalling unopposed - increased endothelin 1 (ET-1) production
- ∴ vasoconstriction effects of insulin predominate
- Smooth muscle cell proliferation
- Insulin treatment worsens endothelial dysfunction
