Complications of
Diabetes mellitus
Dr Bill Young
16 March 2015
2
Complications of diabetes
Multi-organ involvement
3
The extent of diabetes complications
• At diagnosis as many as 50% of patients may have complications.
• Diabetes is the major cause of blindness in people of working age.
• Diabetes is the major cause of amputation
(after accidents).
The extent of diabetes complications
(continued)
• Largest group of patients requiring dialysis is people with diabetes.
• 60% of men with diabetes experience erectile dysfunction.
• Increased risk of cardiovascular problems and strokes.
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partnership with Tesco!
Acute metabolic complications
of diabetes
1. Hypoglycaemia
2. Diabetic ketoacidosis
3. Hyperosmolar Non-Ketotic coma (HONK)
4. Lactic acidosis
Chronic complications of diabetes
Microvascular
• Retinopathy
• Nephropathy
• Neuropathy
Macrovascular
• Cardio-vascular
• Cerebro-vascular
• Peripheral vascular
Other complications of diabetesSkin disorders
Sexual dysfunction
Pregnancy related
Depression
Feet problems - are they neuropathy or micro-vascular or macro-vascular?
8
More than half a million
people with diabetes in
England are at increased
risk of blindness
because they have not
received retinal
screening, an essential
annual check which
tests for eye disease
(diabetic retinopathy).
Diabetes UK 08.09.11
One in four people
with diabetes in
Scotland are at
increased risk of
amputation
because they have
not had their feet
checked
• Diabetes UK 08.09.11
9
Topics
1. Macro-vascular complications
2. Treating macro-vascular disease
3. Diabetic nephropathy
4. Skin disorders
5. Depression
6. Pregnancy related complications
7. Erectile Dysfunction
1. Macro-vascular complications
Annual CHD Deaths per
1000 Persons
Kannel WB, McGee DL. JAMA 1979;241:2035-2038.
Framingham Study: DM and CHD Mortality
20-Year Follow-up
1717
88
1717
44
MenMen WomenWomen
DMDM
NonNon--DMDM
Diabetes and CV
disease
• Diabetic cardiovascular
disease is mainly due to
accelerated atherosclerosis
• Causes morbidity and
mortality
obesity type 2
diabetes
hypertension
insulininsulin
resistanceresistance
type 1
diabetes
atherosclerosis
Link between obesity and
atherosclerosis
• Fat is NOT a simple storage chemical
• Adipose tissue secretes chemicals called
adipokines
• Abdominal fat is particularly active
• Excess adipose tissue causes over-production
of pro-inflammatory adipokines
• Excess adipose tissue causes under-
production of anti-inflammatory adipokines
Link between obesity and
atherosclerosis (continued)
• Over-production of Pro-inflammatory
adipokines leads to endothelial damage
• Under-production of Anti-inflammatory
adipokines is linked to insulin resistance
Atherosclerosis – the process
• Starts with endothelial injury
• This damage allows adhesion and aggregation of
platelets leading to formation of thrombi
• Endothelial damage also brought about by Low
Density Lipoproteins (LDL)
Picture courtesy of Professor Ann Graham GCU
Atherosclerosis
• In response to endothelial damage, monocytesmove into the sub-endothelium.
• Increased LDL leads to penetration of LDL into the arterial wall.
• Monocytes form into macrophages.
• Macrophages release free radicals that oxidise LDL
• Oxidised LDL is toxic to the endothelium
Atherosclerosis
� Macrophages take up oxidised LDL but cannot
degrade it and so become foam cells (the oxidized
LDL stored in granules in the macrophage looks like
foam under the microscope).
� After 4 to 5 days, foam cells die and release oxidised
LDL with its cholesterol into the plaque to form a
lipid core.
Lipid Pool:
Foam cells, cholesterol crystals,
necrotic cells,
Picture courtesy of Dr Angus Shaw, GCU
Atherosclerosis
• Surviving macrophages release factors that lead to
migration and increased number of smooth muscle
cells in the plaque.
• This leads to formation of new connective tissue and
a fibrous plaque.
Picture courtesy of Dr Angus Shaw, GCU
Atherosclerosis
• Smooth muscle cells multiply and also synthesise
collagen, forming a fibrous cap over the lesion.
• This makes the lesion bigger.
• This stabilises the plaque.
Fibrous cap (stable
plaque)
Picture courtesy of Dr Angus Shaw, GCU
Atherosclerosis
• In unstable plaques, enzymes degrade the cap
allowing the platelets access to underlying tissue
and therefore clot formation.
• Clots break off and block blood vessels, leading to
MI, stroke etc.
Platelet/fibrin
thrombus
Picture courtesy of Dr Angus Shaw, GCU
unstable plaque
Peripheral Vascular
disease
�Caused by atherosclerosis
�Affects the upper and lower limbs
�produces narrowing of arterial lumen in large
conduit arteries (iliac, femoral, brachial)
• Blood stasis encourages increased risk of infection
• Adds to hypoxia and decreases white blood cell
function - they can’t reach the site of infection
Peripheral
Vascular
Disease
�Progresses from intermittent discomfort during
exercise (claudication) to severe pain during rest
�Skin lesions (ulceration and gangrene)
�Leads to critical limb ischaemia (CLI) and
amputation
Treating macrovascular disease
• BP
• Lipids
• Hyperglycaemia
• Smoking (men with diabetes who stop smoking live ≈
3yr more than those who continue)
• Weight management
• Exercise
• Alcohol “In patients with no evidence of CHD , light to
moderate alcohol consumption may be protective
against coronary events” SIGN 97
Tight Control of BP Reduces Risk
of Complications
UK Prospective Diabetes Study (UKPDS) Group (38). British Medical Journal 1998;317:703–713.
0 -10 -20 -30 -40 -50
% Reduction in Risk
MI
Microvascular endpoint
Heart failure
Stroke
All macrovascular endpoints
Retinal photocoagulation
Any diabetes related endpoint
--24 24 PP=0.0046=0.0046
--34 34 PP=0.019=0.019
--21 21 PP=ns=ns
--44 44 PP=0.013=0.013
--56 56 PP=0.019=0.019
--37 37 PP=0.0092=0.0092
--35 35 PP=0.023=0.023
BP
• In diabetes with complications treat at threshold of
systolic >130 mm Hg and /or diastolic >80 mm Hg.
• Each 10 mm Hg reduction in systolic pressure gives a
15% reduction in the risk of CVD death over 10 years.
SIGN 116
BP
• Thiazide diuretics, angiotensin-converting enzyme
(ACE) inhibitors, angiotensin II receptor antagonists,
calcium channel blockers and beta-blockers lower BP
• Patients often need polypharmacy to control BP
• ACE inhibitors first line in microalbuminuria
(additional benefit on renal function)
• See SIGN 116 for use of ACE inhibitors, aspirin
SIGN 116
Lipids
• Patients with T2DM >40yrs should be considered for
statin therapy
• Each 1 mmol/l reduction of LDL cholesterol
represents a 36% reduction in risk of CVD disease
• Total cholesterol >5.0 mmol/l - institute statins.
Titrate as necessary to reduce total cholesterol to
<5.0 mmol/l
SIGN 116 2010
Lipids
• Patients with T1DM or T2DM with nephropathy
should be considered for statins at a lower level of
cholesterol
• In CHD if cholesterol is <5mmol/l but HDL is
<1.0mmol/l and not on a statin, consider
gemfibrozil (fibrate)
SIGN 116 2010
Conclusions for Macro-vascular
complications
• Diabetic macro-vascular disease is due to
accelerated atherosclerosis, causes morbidity and
mortality, and is associated with insulin resistance
and hyperglycaemia
• Lifestyle modification and treatment modalities can
modify CV risk