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.

£2m campaign funded in

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

2. Treatment of Macro-vascular

complications

(With thanks to Dr Jane Nally,

J.E.Nally@gcu.ac.uk)

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