Complications of Diabetes mellitus Dr Bill Young 16 March 2015
Complications of diabetes Multi-organ involvement 2
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). 3
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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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 Feet problems - are they neuropathy or micro-vascular or macro-vascular? Other complications of diabetes Skin disorders Sexual dysfunction Pregnancy related Depression
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 8
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
Framingham Study: DM and CHD Mortality 20-Year Follow-up Annual CHD Deaths per 1000 Persons 17 8 17 4 DM Non-DM Men Women Kannel WB, McGee DL. JAMA 1979;241:2035-2038.
Diabetes and CV disease Diabetic cardiovascular disease is mainly due to accelerated atherosclerosis Causes morbidity and mortality obesity type 2 insulin hypertension diabetes type 1 diabetes resistance 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 underproduction 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 adipokinesis 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, monocytes move into the sub-endothelium. Increased LDL leads to penetration of LDL into the arterial wall. Monocytesform into macrophages. Macrophages release free radicals that oxidise LDL Oxidised LDL is toxic to the endothelium
Atherosclerosis Macrophages take up oxidisedldl 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 unstable plaque Picture courtesy of Dr Angus Shaw, GC
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)
BP Lipids Treating macrovascular disease 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 -21 P=ns -34 P=0.019-35 P=0.023-37 P=0.0092-44 P=0.013-56 P=0.019 MI Microvascular endpoint Heart failure Stroke All macrovascular endpoints Retinal photocoagulation Any diabetes related endpoint -24 P=0.0046 0-10 -20-30 -40-50 % Reduction in Risk UK Prospective Diabetes Study (UKPDS) Group (38). British Medical Journal 1998;317:703 713.
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