Scenario Three

Scenario 3 Contents •

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Hypertension o Physiology – RAA system o Drugs Complications and risk factors for hypertension - hersh Anatomy and histology of pancreas - laura Control of glucose: insulin and glucagon Diabetes pathophysiology Risk factors of diabetes Genetics of diabetes Diabetes sx and signs Diabetes diagnosis and investigations Management of diabetes o Annual review o Drugs Microvascular complications of diabetes Macrovascular complications of diabetes Atherosclerosis Peripheral vascular disease and foot ulcers Diabetic emergencies Psychosocial aspects of diabetes Economics and diabetes Economics of chronic disease o Expert patient programmes Infections in the immunocompromised BMI and obesity o Metabolic syndrome o Control of appetite o Malnutrition and nutrition Anatomy of the glomerulus GFR Chronic kidney disease Glomerulonephritis Nephrotoxic drugs Acute loss of vision Reasons for non-attendance at clinics

Blood Pressure Control of blood pressure The mean arterial pressure is determined by two factors: cardiac output and total peripheral resistance • Cardiac output depends on heart rate and stroke volume  Heart rate increases due to sympathetic nervous system and decreases by the action of parasympathetic nervous system  Stroke volume increases in response to sympathetic activity and it increases as venous return increases. Venous return is increased by sympathetically induced venous vasoconstriction, the skeletal muscle pump, the respiratory pump, cardiac suction and blood volume.  Blood volume depends on magnitude of passive bulk-flow fluid shifts between plasma and interstitial fluid across capillary walls and on the activity of the rennin-angiotensin-aldosterone system. • Total peripheral resistance depends on arteriolar radius and blood viscosity.  Blood viscosity depends mainly on number of red blood cells  Arteriolar radius is influenced by sympathetic activity that causes vasoconstriction and so increases total peripheral resistance and blood pressure. It is also influenced by local metabolic controls and hormones (vasopressin, angiotensin II) Barorecptor reflex is a very important short-term regulator of blood pressure that stimulates or inhibits sympathetic or parasympathetic activity accordingly. • Carotid sinus and aortic arch barorecptors are mechanoreceptors sensitive to changes in mean arterial and pulse pressure that trigger the baroreceptor reflex • Generated action potential are integrated in the cardiovascular control centre in medulla which alters accordingly the balance between sympathetic and parasympathetic activity to effector organs  Sympathetic stimulation increases heart rate and contractile strength of heart = cardiac output increases = blood pressure increases. It also causes arteriolar vasoconstriction and increases total peripheral resistance. It also causes venous vasoconstriction which increases venous return, stroke volume, cardiac output and blood pressure  Parasympathetic stimulation has the opposite effects. Rennin- angiotensin-aldosterone system is long-term regulator of blood pressure Rennin is an enzyme that is secreted by the juxtaglomerular apparatus in the following cases: 1. Low blood pressure leading to low renal perfusion pressure 2. A fall in Na concentration in distal tubule 3. Renal sympathetic nerve activity, β-adrenoreceptor agonist and PGI2 Angiotensin II and atrial natriuretic peptide inhibit rennin release. Rennin acts on angiotensinogen (made in liver) to produce angiotensin I which is converted to angiotensin II by angiotensin converting enzyme when it passes from lung. Angiotensin II has the following actions: 1. Vasoconstriction (direct and via increased noradrenaline release from sympathetic nerves) 2. Salt retention due to secretion of aldosterone and due to increased Na tubular reabsorption. 3. Vascular growth (hyperplasia and hypertrophy in heart and arteries) Hypertension • 95% of cases have essential hypertension with poorly understood mechanism • 5% of cases have secondary hypertension due to chronic renal parenchymal or vascular disease or a catecholamine or aldosterone-secreting adrenal tumour or due to drugs (NSAIDs, steroids, oral contraceptive pill). Pathophysiology • Increased peripheral vascular resistance due to widespread constriction of arterioles and small arteries. Cardiac output and viscosity of blood are normal. • In chronic hypertension structural changes take place that cause further hypertension or complications

 High peripheral resistance = increased work of heart = left ventricular hypertrophy = hypertrophy outstrips coronary blood supply =fibrous tissue deposition= heart failure  Hypertension causes thickening of tunica media = arteries lose compliance = more pronounced pressure wave = mechanical stress and endothelial dysfunction = atherosclerosis  Changes in renal vasculature = reduced renal perfusion = reduced glomerular filtration rate = activation of rennin-angiotensin system = increase in blood pressure Risk factors • Genetic factors: polygenic definite influence of heredity and family history • Fetal factors: low birthweight possibly due to changes in blood vessel structure or hormonal changes • Environment: obesity, sleep disordered breathing, alcohol intake, sodium intake, stress • Diabetes is associated with hypertension. The described metabolic syndrome includes hyperinsulinemia, glucose intolerance, low HDL, hypertriglyceridaemia and central obesity, all of which are associated with insulin resistance. Investigations of hypertension • ECG (check for LV hypertrophy, ischemic heart disease) • Urinalysis for proteinuria if renal disease, vanillyl mandelic acid for malignant hypertension) • U&Es (high urea suggests renal impairment, low potassium without diuretic might suggest Conn’s (mineralocorticoid) or Cushing’s syndrome(corticosteroid) • Lipids (high cholesterol is cardiovascular risk factor) • 24-hour ambulatory blood pressure monitoring • Echocardiography (check for left ventricular hypertrophy) Management of hypertension • Smoking cessation, weight reduction, alcohol intake reduction, salt intake reduction, healthy diet (no saturated fats, more fruits and vegetables), regular physical exercise A= ace and alpha- B= bendroflumethiazide C= calcium channel- D= diuretic Young < 55 & non Black Older > 55 or Black Step 1 ACE inhibitor or B-blockers Calcium channel blockers or Diuretics Step 2 A (or B) + C or D C (or D) + A or B Step 3 A+C+D A+C+D Step 4 + alpha blocker or spironolactone + alpha blocker or spironolactone • •

Statins to reduce cardiovascular risk in elderly with CHD, PVD, CVD or type II diabetes Low dose aspirin or clopidogrel if cardiovascular risk to reduce risk of strokes and MIs

Hypertension Causes of hypertension: BP >120/80mmHg. Essential HTN: No specific medical cause but associated with affecting 95% of hypertensives • Genetics (polygenetic) • Age • Lower birth weight • Obesity • Sleep apnoea • Alcohol • Sodium intake • Stress • Insulin resistance • High renin Secondary HTN: 5% of hypertensive’s where he cause is identified • Renal disease: PCK, chronic GN, diabetic • Endocrine: Conn’s syndrome, adrenal hyperplasia, pheochromocytoma, Cushing’s, acromegaly

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Coarctation of aorta Drugs: OCP, steroids, carbenoxolone, vasopressin, sudden withdrawal of antihypertensive

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PregnancyDamage caused by elevated BP

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Arteriolar thickening and more collagen in large arteries Decreased density of vessels Atheroma Left ventricular hypertrophy due to increased peripheral vascular resistance Secondary renal damage and activation of renin-angiotensin system which exacerbates hypertension

Investigations • CXR – cardiomegaly, pulmonary congestion • ECG/echocardiogram – coronary artery disease, LV hypertrophy • Urinalysis • Blood glucose and lipids (fasting) – DM and hypercholesterolemia • Serum U&Es, creatinine – if deranged indicates testing creatinine clearance, US, renal angiography. Hypokalemia points to an endocrine cause (hyperaldosteronism, glucocorticoid excess). Treatment see drugs table at end • Life-style: weight loss, low fat and low sodium diet, reduces alcohol, increase exercise, fruit and vegetable. • Control underlying diseases: blood sugar control, kidney diseases • Drug treatment: diuretics (reduce risk of stroke), beta-blockers (probably attenuate effects of sympathetic nervous and renin-angiotensin systems), ACE inhibitor or angiotensin II receptor antagonist (prevent vasoconstriction), Ca-channel blocker (cause arteriolar dilatation), alpha-blocker (vasodilation). NICE guidelines on when to refer • Immediately if: accelerated (malignant) hypertension (blood pressure more than 180/110 mmHg with papilloedema, retinal haemorrhage); suspected pheochromocytoma (labile or postural hypotension, headache, palpitations, pallor and diaphoresis). • Consider referral if: unusual signs and symptoms, some suggesting secondary cause; precise BP needed for management; symptoms of postural hypotension, or a fall in systolic blood pressure when standing of 20 mmHg or more. End organ damage Eyes • Hypertensive retinopathy. Changes: vasospastic reaction to an acute pressure rise, arteriosclerotic response to chronic elevation. Features include: • Generalised arteriolar narrowing (arteriosclerosis) through medial hyperplasia and fibrosis; broadening of arteriolar light reflex, venous nipping at AV crossing point. • Focal arteriolar narrowing: vasospastic effect during acute rise • Flame haemorrhages: in nerve fibre layer due to capillary damage. Also: dots and blots • Cotton wool spots: swollen axonal endings due to focal ischaemia • Exudates: intraretinal collections of lipids • Optic disc swelling: local ischaemia • Arteriolar macroaneurysms: HTN, atheroma • Microaneurysms Kidneys • HTN causes changes in intra-renal vasculature (nephrosclerosis) via: • Intimal thickening with reduplication of internal elastic lamina and hyalinisation of wall in small vessels and arterioles. • Concentric reduplication of internal elastic lamina and endothelial proliferation in large vessels • Reduction in size of kidneys in the long term • Increased proportion of sclerotic glomeruli • The result is microscopic haematuria, proteinuria, and progressive uraemia Heart

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Systemic (L sided) hypertensive disease: left ventricular hypertrophy associated with HTN. Changes that are initially adaptive cause cardiac dilatation, CCF, sudden death. Heart adapts with LV hypertrophy. Long term this causes interstitial fibrosis, myocyte atrophyventricular dilatation. • Pulmonary hypertensive disease (cor pulmonale): right ventricular hypertrophy. Can be caused by sudden large PE or lung disease. There is chronic right ventricular pressure load. The RV dilatation my cause tricuspid regurgitation. Vascular • Accelerated atherosclerosis and narrowing of lumen • Arteries: muscular hypertrophy of media, reduplication of external lamina, intimal thickening • Arterioles: hyaline arteriosclerosis (protein deposits in wall) • Vessels in brain: microaneurysms (Charcot-Bouchard aneurysms) • Can be associated with fibrin deposits (necrotising arteriolitis) Management note B is now bendroflumethiazide not beta blocker (2008) Step 1 Step 2 Step 3 Step 4

Young < 55 & non Black ACE inhibitor A or B + C or D A+C+D + alpha blocker or spironolactone

Older > 55 or Black Calcium channel blockers or Diuretics C (or D) + A or B A+C+D + alpha blocker or spironolactone

Antihypertensives DRUG

ACE inhibitors

Beta-Blockers

EXAMPLES Ramipril, Lisinopril

Atenolol, Propanolol

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Hypertension Heart Failure Post MI

Hypertension Angina Arrhythmias Stable heart failure

MECHANISM Block ATIATII by binding to the site on the enzyme that normally accommodates the terminal leucine of ATI. Inhibits vasoconstriction.

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block β-adrenergic receptors inhibiting the • effects of adrenaline and nonadrenaline. β1 (heart) blockage decreases HR and contractility, β2 (bronchial and vascular • • smooth muscle) blockage causes vasodilation.

Hypotension Dry cough (increased bradykinin) Renal failure in pts with bilateral renal stenosis Provocation of asthma, heart failure. Cold hands Bradycardia - fatigue

Calcium Channel Blockers

Thiazide Diuretics

Loop Diuretics

Potassiumsparing diuretics

Dihydropines – Amlodipine, Phenyalkylamin es Verapamil, Benzthiazepines Diltiazem

Bendrofluazide, hydrochlorothiaz ide

Frusemide, Bumetanide

Spironolactone, Amiloride

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Hypertension Angina Supraventricul ar arrhythmia – (Phenylalkyla mines only)

Vasodilation block cellular entry of Ca+ by preventing opening of voltagegated L-type and T-type calcium channels

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Angiotensin II receptor antagonists

Losarten, Valsarten

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Alphaadrenorecepto r antagonists

Doxazosin, Prazosin

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Hypertension Combined with loop for Heart Failure

Hypertension (but less effective than thiazides – used when renal impairment or resistant to multiple drug Tx) Heart Failure Secondary Hypertension Severe heart Failure

Hypertension Alternative to ACE inhibitor in heart failure Hypertension (in addition to other hypertensives)

increase water excretion by decreasing reabsorption of Na+ and Cl- in the distal tubule by binding to the Cl- site of the electroneutral Na+/Cl- co-transport system and inhibiting its action causing a decrease in blood volume, venous return and CO Block Na+ resorption in ascending loop of Henle – diuretic effect.

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Amilioride directly blocks epithelial Na+ channel, spironolactone antagonises action of aldosterone in distal convoluted tubule – diuretic effect

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Vasodilation – by inhibition at the angiotensin II receptor

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Reduces peripheral resistance by inhibiting α1-adrenoreceptormediated vasoconstriction.

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Flushing, headache, P.oedema Phenyalkyla mines – can worsen heart failure Gynaecomas tia Impotence Hypokalaemi a Hyponatrae mia Hypotension Gout Type II DM Hypokalaemi a Hyponatrae mia Hypotension Gout

Hypokalaemi a Hyponatrae mia Abdominal discomfort Usually mild No cough like in ACE inhibitors Postural Hypotension Dizziness

Anatomy and Physiology of the Pancreas Anatomy of the pancreas • Consists of an uncinate process, a head slightly caudal, body and tail both slightly cranial. It is 12-15cm long and 2.5cm thick. • Location: o Lies in the transpyloric plane (L1) o It is retroperitoneal, crossed anteriorly by the mesentery of the transverse colon and lies posterior to the stomach separated by the lesser peritoneal sac o The head an the uncinate process lie anterior to the IVC within the loop of the duodenum on L1-L3 o The body passes obliquely to the left anterior to the aorta, left psoas, splenic artery and vein o The tail lies anterior to the left kidney and extends into the hilum of the spleen • It is connected to the duodenum by 2 ducts (sometimes they join to form a single duct):

The pancreatic duct (or duct of Wirsund) – joins with the common bile duct from the liver and gallbladder and enters the duodenum as a common duct called the hepatopancreatic ampulla (ampulla of Vater). The ampulla opens on an elevation of the duodenal mucosa known as major duodenal papilla which lies about 10cm inferior to the pyloric sphincter of the stomach. 2. The accessory duct (or duct of Santorini) – separate second branch of the pancreatic duct that empties into the duodenum usually in the major duodenal papilla with the pancreatic duct. However, rarely it empties via a separate opening about 2.5cm superior to the hepatopancreatic ampulla. Blood supply and venous drainage: o Pancreatic head receives its supply from the superior and inferior pancreaticoduodenal arteries which come off the common hepatic artery and superior mesenteric artery respectively. o The splenic artery also supplies the pancreas and courses along its upper border. It provides a large branch called the arteria pancreatica magna and numerous smaller branches. o The venous drainage of the pancreas is via pancreatic and pancreaticoduodenal veins  splenic vein  superior mesenteric vein  hepatic portal vein  liver  hepatic veins  IVC Innervation is via the pancreatic plexus, coeliac ganglia and vagus nerve. 1.

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Histology • The pancreas is made up of clusters of glandular epithelial cells. • Endocrine pancreas: 1% of the cells are organised into clusters called pancreatic islets (islets of Langerhans) – these are the endocrine portion of the pancreas and secrete the hormones glucagon, insulin, somatostatin and pancreatic polypeptide. o Beta-cells (70%) – produce insulin o Alpha-cells (17%) – produce glucagon o Delta-cells (7%) – produce somatostatin o Pancreatic Polypeptide (PP) cells o Enterochromaffin cells – produce serotonin • Exocrine pancreas: 99% are arranged in clusters called acini – these constitute the exocrine portion of the organ. They secrete pancreatic juice. • Regulation of pancreatic secretions - under neural and hormonal control: 1. Parasympathetic impulses – transmitted along the vagus nerve (cranial nerve X) during cephalic and gastric phases of gastric digestion causing stimulation of pancreatic enzyme secretion. 2. Fatty acids and amino acids - entering the duodenum (acidic chyme) cause enteroendocrine cells to secrete:  Cholecystokinin (CCK) into the blood which stimulates pancreatic juice rich in digestive enzymes.  Secretin into the blood which stimulates pancreatic juice secretion rich in bicarbonate ions. Exocrine function • Secretes pancreatic juice – clear colourless liquid consisting of water, some salts, sodium bicarbonate, and several enzymes. • Sodium bicarbonate gives the juice a slightly alkaline pH to buffer acidic chyme. This stops pepsin action and provides optimum pH for its own digestive enzymes. • The enzymes:

Enzyme Inactive Form Trypsinogen (activated by enterokinase) Chymotrypsinogen (activated by trypsin) Procarboxypeptidase (activated by trypsin) Proelastase (activated by trypsin)

Enzyme Active Form Pancreatic amylase Trypsin Chymotrypsin

Function Digests carbohydrate Digests protein and activates inactive precursors

Carboxypeptidase Elastase Pancreatic lipase Ribonuclease Deoxyribonuclease

Principle triglyceridedigesting enzyme Nucleic-acid-digestin

enzymes

Endocrine function Insulin • Peptide hormone coded for on chromosome 11. It is made up of two polypeptide chains: A and B which are linked by disulphide bridges. • In beta-cells, DNA transcription produces pre-proinsulin, which is cleaved to proinsulin by the action of protease within the Golgi apparatus. Proinsulin is converted by convertase to insulin and a connecting peptide (c-peptide) which are released together in exocytosis. Secretion of insulin: • Secreted from β-cells into the portal vein in a biphasic pattern: first there is an acute, rapid phase followed by a less intense, more sustained second phase. • Stimulus for secretion: o Nutrients: glucose, amino acids o Hormones: glucagon, gastrin, secretin, cholecystokinin, glucose-dependent insulinotropic peptide (GIP – released by enteroendocrine cells of the small intestine in response to presence of glucose in the GIT), and indirectly ACTH and GH (both raise BGL) o Pancreatic innervation: sympathetic α receptors, parasympathetic (acetylcholine) • Inhibitors of secretion:

Nutrients: fall in glucose Hormones: somatostatin Pancreatic innervation: sympathetic beta-receptors Stress: exercise, hypoxia, hypothermia, surgery, severe burns Process of secretion of insulin: 1. Glucose enters the beta-cell via the GLUT-2 transporter protein (its rate of entry is proportional to its extracellular concentrations) 2. Glucose is phosphorylated to glucose-6-phosphate by the enzyme glucokinase. This enzyme is also the “sensor” of glucose in the beta-cell and stimulates insulin secretion. 3. ATP is released in the cascade (glycolysis) and ATP-sensitive K-channels in the beta-cell close (sulphonylureas binds to a receptor closely apposed to K-channels closing them). There is depolarisation of the cell and an influx of Ca2+ through ion channels. 4. Calcium sensitive proteins are activated and this triggers insulin translocation to the cell surface and exocytosis 5. Glucose is detected by the β-cell, it is taken up and undergoes phosphorylation and metabolism by glycolysis  release of ATP  closure of K-channels  triggers insulin granule o o o o

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Insulin receptor binding: • Insulin binds to insulin receptors which are found on the surface of most body cells (the major insulin-sensitive tissues include: the liver, skeletal muscle and adipose tissue). • The insulin receptor is a glycoprotein (chromosome 19) which consists of 2 α subunits, binding sites for insulin and 2 β subunits which traverse the cell membrane. When insulin binds to the alpha subunits there is a conformational change in the beta subunits  activation of tyrosine kinase and initiation of a cascade response involving intracellular substrate proteins known as insulin responsive substrates (IRS). One consequence of this is migration of the GLUT-2 glucose transporter to the cell surface and increased transport of glucose into the cell. The insulin-receptor complex is then internalized by the cell, insulin is degraded, and the receptor is recycled to the cell surface. Actions of insulin: 1. Glucose metabolism – increases glucose uptake by muscles and adipose tissue, suppresses hepatic glucose uptake, increases glycogen synthesis and inhibits glycogen breakdown. It does this by activating the enzyme glycogen synthase and dephosphorylating glycogen phosphorylase kinase.

2. Lipid metabolism – insulin increases the rate of lipogenesis and suppresses lipolysis in several ways in adipose tissue and liver, and controls the formation and storage of triglyceride.

3. Protein metabolism – insulin stimulates the uptake of amino acids into cells and promotes protein synthesis in a range of tissue. 4. Other:  Regulates growth and development and the expression of certain genes  Vasculature – impaired endothelial function, increased stiffness of arteries and procoagulation  Hyperuricaemia – insulin reduces renal uric acid clearance Glucagon • Polypeptide hormone released from alpha cells when there is a fall in BGL (and by amino acids). • Function - increases glucose levels by binding to glucagon receptors in the liver, and accelerating glyconeogenolysis and initiating gluconeogenesis  release of glucose. • Release is stimulated by: o Low BGL o Exercise + sympathetic division of the ANS o Protein meals and amino acids in the blood • Release is inhibited by: somatostatin and insulin

Diabetes: pathophysiology, diagnosis, symptoms and signs Pathophysiology Type 1 diabetes • Immune-mediated organ-specific disease characterised by an absolute lack of insulin • It is likely that an environmental factor triggers a selective autoimmune destruction of β-cells of the pancreas in a genetically predisposed individual. • Βeta-cells secrete insulin into the blood stream which is essential to the uptake of glucose into body cells therefore glucose builds up in the blood  hyperglycaemia. • The autoimmune nature of type 1 DM is mainly suggested by the presence of T-lymphocytes and macrophages in the islet cells. In addition there are often circulating islet-related autoantibodies such as islet cell autoantibodies, insulin antibodies, glutamic acid decarboxylase autoantibodies. Type 2 diabetes • Relative lack of insulin secondary to two pathophysiological defects: beta-cell dysfunction and impaired glucose tolerance • The combined effect of these is: increased glucose production from the liver owing to inadequate uptake of glucose by skeletal muscle and other peripheral tissues. 1. Impaired insulin action through insulin resistance • Insulin fails to produce its usual biological effects at physiological concentrations. • Causes of insulin resistance:  Absent or ↓insulin receptors – the persistently high insulin levels may suppress the number of receptors present in a process called “down regulation”.  Abnormal insulin receptors – insulin cannot bind, failure of binding to cause activation  Down regulation of postreceptor signalling  Abnormalities of GLUT 4 translocation and function (insulin-responsive transport protein for glucose)  Accumulation of skeletal muscle triglyceride 2. Impaired insulin secretion through a dysfunction of the pancreatic β-cell • Insulin resistance does not account for type 2 DM on its own. • The major beta-cell abnormalities are:  A marked reduction in first-phase insulin secretion  And, in established DM, an attenuated second phase insulin secretion  Usually by diagnosis beta-cell function is <50% with a mean deterioration of 4% per year after diagnosis. • Mechanisms underlying beta-cell dysfunction are likely to be multifactorial:  Early life malnutrition  Hyperglycaemia  Hyperlipidaemia  ??Immunological basis: 10% have islet cell autoantibodies e.g. insulinomas-related antigen (ICA) and GAD (glutamic acid decarboxylase). Risk factors (type 2 diabetes) • Genetics (see genetics section) - unmodifiable • Ethnicity – higher rates in Indians and Africans • Geography – higher in urban populations. Worldwide disease, but highest rates are seen in Pima Indians of Arizona, Europe, N. America. Lowest rates seen in China, Chile. • Obesity - the average BMI of a type 2 diabetic is 30kg/m2 • Fat distribution - ↑visceral fat; “central obesity” • Physical inactivity • Intrauterine environment – low birth weight is a risk factor, babies born to diabetic mothers • Old age - most cases are diagnosed >40y  lifetime risk of 1 in 10. But now type 2 DM is increasingly common in children and young adults. Genetics of diabetes Type 1 diabetes: • Polygenic inheritance

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The greatest contribution to inheritance comes from the histocompatibility (HLA) region on the short arm of chromosome 6, which is important in mounting an immune response to invading organisms. Examples of high risk HLA genotypes for type 1 DM include: HLA DR3/4 and HLA DQB1. There is an increased risk of developing type 1 DM if a 1st degree relative already has it – this seems to be further increased if your father as opposed to your mother has the disease – 6% versus 3% The risk of developing the disease rises to 1 in 2 if you are young and have an affected identical twin

Type 2 diabetes: • Polygenic inheritance • The genes responsible are poorly defined, but they are important – the heritability of type 2 is greater than type 1 – it is estimated to account for 40-80% of disease susceptibility. • Twin studies show a high concordance of 80-90% • Approximately 2-5% of cases are caused by single gene mutations such as maturity onset diabetes of the young (MODY). This is an AD condition caused by a mutation in one of six genes, most commonly Hepatic Nuclear Factor 1α (also glucokinase). Clinical presentation Type 1 diabetes: • Age: peak incidence is puberty (6.5%), but it can present at any age • Rapid onset (1-4 weeks) of symptoms in a young patient • Symptoms relating to the osmotic effect of hyperglycaemia o Increased thirst and polydipsia o Polyuria and nocturia o Blurred vision o Drowsiness and dehydration – as water leaves the cells along the osmotic gradient only to be lost into the urine • Cutaneous candidal infection: o Of the vulva  pruritus vulvae o Of the foreskin  balanitis • Symptoms related to lack of “fuel”: o Extreme fatigue o Muscle wasting through protein breakdown o Weight loss • Diabetic ketoacidosis – some patients will present in this way. Diabetic ketoacidosis occurs when the body metabolises fatty acids because there is no glucose available  nausea, vomiting, acidotic breathing, and ketones on the breath (“pear-drops”) Type 2 diabetes: • Acute presentation Young people often present with a 2-6 week history and report the classic triad of symptoms: 1. Polyuria - due to the osmotic diuresis that results when blood glucose levels exceed the renal threshold 2. Thirst - due to the resulting loss of fluid and electrolytes 3. Weight loss - due to fluid depletion and the accelerated breakdown of fat and muscle secondary to insulin deficiency. • Subacute presentation o Insidious onset over several months or years, particularly in older patients. o Thirst, polyuria and weight loss o Lethargy, visual blurring (owing to glucose-induced changes in refraction), or pruritus vulvae or balanitis that is due to candidal infection. • Asymptomatic diabetes o Glycosuria or a raised BGL may be detected on routine examination (e.g. for insurance purposes) in individuals who have no symptoms of ill-health. o Glycosuria is not diagnostic of diabetes but indicates the need for further investigations. About 1% of the population have renal glycosuria. There is an inherited low renal threshold for glucose, transmitted either as a Mendelian dominant or recessive trait. • Presentation with complications: o Staphylococcal skin infections

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Retinopathy noted during a visit to the optician Polyneuropathy causing tingling and numbness in the feet Erectile dysfunction Arterial disease, resulting in myocardial infarction or peripheral gangrene.

Diagnosis of diabetes 1. Clinical history i.e. polyuria, polydipsia and unexplained weight 2. PLUS a positive result from one of the following tests: • Random venous plasma glucose concentration of more than or equal to 11.1mmol/l • Fasting plasma glucose concentration of more than or equal to 7.0mmol/l • Oral glucose tolerance test: plasma glucose concentration of more than or equal to 11.1mmol/l 2hrs after 75g anhydrous glucose in 300ml water ingested over 5mins  If the patient is asymptomatic, diagnosis should not be based on a single glucose test – a confirmatory plasma venous determination is required on another day.  Impaired glucose tolerance if plasma glucose concentration was 7.8-11.1mmol/L on OGTT or fasting plasma glucose was 6-6.9 Management of diabetes Lifestyle: diet and exercise • Eat a healthy, balanced diet: o Reduce the amount of refined sugar and fat o Increase the proportion of complex carbohydrates and fibre – slower rate of absorption o Moderate alcohol intake • Lose weight if overweight – adopt a diet with a moderate calorie deficit • Exercise - patients should be encouraged to exercise for 30mins at least per day to improve glycaemic control and reduce their cardiovascular risk • Never smoke Specific management type 1 diabetes • Diet as above • Insulin parenterally – usually SC (sometimes IV or IM) • Avoid vascular complications: o Control blood pressure with antihypertensive regimes and aspirin in high risk patients o Control cholesterol with statins o Check feet and legs for cuts or infection Specific management type 2 diabetes: • Patients follow a “stepwise” approach to management: 1. Lifestyle changes only  diet and exercise – continue for 3m, if the patient continues to be symptomatic proceed to 2. 2. 1 + oral hypoglycaemic agent 3. 1 + combination of oral hypoglycaemic agents 4. 3 + insulin 5. 1+ insulin • Insulin is commenced only if the oral hypoglycaemic drugs fail, or there is intercurrent illness, the patient may be put onto an insulin regime such as: o Basal insulin - this is often a suitable first step, using once or twice daily intermediate- or long-acting insulin o Twice daily biphasic insulin o Basal-bolus regimen • Antihypertensives – initiate treatment for hypertension when bp >130/80mm/Hg. Special situations e.g. microalbuminaemia (>135/75) or proteinuria (>125/75). Monitoring of Diabetes Self-monitoring • Blood Glucose

BGL levels are recommended to be in the range:  Pre-prandial levels of 4-6 mmol/l  Post-prandial levels <10 mmol/l 2 hours after meals o Used by patients who need to adjust insulin levels to their blood glucose and especially during ill health Urine o It is possible to monitor diabetes in the urine via glucose and ketones. o Glucose:  Glycosuria occurs when BGLs are too high so urine testing of glucose via a test strip (%) can tell you when you have hyperglycaemia.  This method is easy, cheap and painless, but it must not be used in type 1 diabetics or those on sulphonylureas, because urine glucose testing does not detect hypoglycaemia. This method is also affected by fluid intake. o Ketones can also be detected in the urine, but only when you are in a fasting state i.e. severe hypoglycaemia. Ketonuria is a dangerous sign. How often? o Type 1 diabetic:  If you have good glycaemic control, testing should be carried out once before bed and on one other occasion each day. Vary the timing of the second test so you can build up a profile of your glycaemic control. Some patients prefer to perform frequent tests on 2 or 3 days in the week and then again only if concerned about possible hypos.  Generally test more (qds) if: bad control and recurrent hypos or hypers, ill, using pump/pregnant, nocturnal hypo or resistant hyper (measure also in early morning) o Type 2 diabetic:  Unknown what the ideal number of tests needs to be  If on insulin and oral hypoglycaemic agents – once a day and mix up times of testing so that you can identify trends in your blood sugar  If you control sugars with diet or metformin no need to test because no risk of hypoglycaemia and glycaemic control is adequately monitored by testing glycosylated haemoglobin o

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Measures of long term control • Glycosated Haemoglobin (HbA1c) o Produced by the glycosylation of haemoglobin at a rate proportional to the glucose concentration. It depends on: red cell lifespan and prevailing blood glucose concentration o Providing that the red cell lifespan is normal, HbA1c measures mean blood glucose concentration over the preceding 60 days (half-life of red cell). o Diabetics should aim fro a value of 7.5% or below. • Fructosamine - measure of glycated serum albumin. It is an index of glycaemic control over the previous 2-3 weeks (albumin has a shorter half-life compared to Hb). The Annual Review • All diabetics are reviewed at least once per year by a hospital clinic, a diabetes centre, their GP or a combination of these three. • The purpose of an annual review is: 1. Patient education 2. Optimize targets of therapy e.g. BP 3. Screen for diabetic complications 4. Treat any complications • Lab tests and investigations: o Blood glucose control: check HbA1c o Kidney function: urine/blood tests for protein. Urine protein test - if positive, check microalbuminuria x3. If persists, start ACE inhibitor o Serum creatinine. o Blood fats: lipids, cholesterol and triglycerides. National target ranges are a total cholesterol of below 4.0 mmol/l and a fasting triglyceride of 1.7mmol/l or below. • Physical Examination: o Calculate their BMI o Examine legs and feet – check circulation, skin and nerve supply – if necessary refer to chiropodist.

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o Blood pressure – aim to be 130/80 or below o Fundoscopy to check for retinopathy o If on insulin, check injection sites Lifestyle Issues: o General wellbeing – how the patient is coping with diabetes o Discuss the current treatment – ask about compliance o Discuss the patient’s diabetic control – look at their home monitoring results and discuss their hypos o Discuss smoking, alcohol, stress, sexual problems, physical activity and diet o Discuss any patient concerns Pharmacology and diabetes

Insulin MOA: (see physiology of pancreas) Types of insulin: 1. Short-acting insulins: (actrapid, novorapid, humalog, velosulin) • Rapid-acting insulin analogues – work in about 15 minutes and peak at 1h, and last ~3-4hs. They can be injected shortly before, during or immediately after meals. These are used in those prone to hypos between meals and avoid the need for snacks between meals because of their faster onset and shorter duration of action. • Soluble insulins – work in about 30 minutes, peak at 2-3h and last for 8h. They should be injected 30 minutes before meals. These are usually given SC, but in hospital they can be given IV via a pump. • Inhaled insulin (Exubera) – this is a fast-acting, dry powder preparation of human insulin that is inhaled before meals, using a specially designed inhalation device. However, only 10% of the dose reaches the circulation and this has cost implications. It is not recommended for routine use in patients but it can be used in a few circumstances e.g. poor BG control despite other treatment options or the pt is unable to inject insulin due to: injection phobia or severe + persistent problems with injection sites. 2. Intermediate-acting insulins: onset of action after 2-4h, peak at 6-7h, and last 20h. Examples: Humulin I, Insulatard 3. Long-acting insulin analogues: onset of action at 1-3h, then plateau, and last 20-24h. They are used once or twice daily, and achieve a steady-state to produce a constant level of insulin. They are used in conjunction with short-acting insulins and provide a “background” insulin dose. Examples include: Insulin glargine (Lantus), Insulin detemir (Levemir), Insulin zinc suspension, Protamine zinc insulin 4. Biphasic insulins: mix of rapid or short-acting insulin with intermediate-acting insulins. Examples: NovoMix 30, Humulin M3, Insuman comb, Humalog Mix25 Insulin regimes: 1. Twice-daily regimen • Biphasic insulin (soluble and intermediate insulins) injected twice a day; 20-30 minutes before breakfast and the evening meal. • The patient must eat regularly at predetermined times and there is little flexibility especially with lunch, because the lunchtime insulin is delivered at breakfast. • High risk of hypos 2. Three-times-daily soluble with intermediate- or long-acting insulin given before meals • This is appropriate for most younger pts • Advantages: the food and the insulin go in at roughly the same time so that meal times and size can vary, without greatly disturbing metabolic control. It is also very flexible so useful for pts with busy jobs, shift workers and those who travel regularly. 3. Basal-bolus regimen • Intermediate or long-acting insulin is given at bedtime to cover overnight insulin requirements. • It is combined with rapid or short-acting insulin injections to cover mealtimes. • Offers greater flexibility, and is the most commonly adopted method when intensified insulin therapy is used to provide optimal glycaemic control. 4. Continuous subcut insulin infusion • Indwelling catheter allows an adjustable basal infusion rate of insulin with a small pump strapped around the waist • Indications: useful for those with recurrent hypos, unpredictable lives etc

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Advantages: can activate pre-meal boluses, pumps can be disconnected for short periods e.g. swimming, pre-programmed to compensate for nocturnal/early morning glucose changes, rate of insulin absorption more predictable than with multiple SC injections, Limitations: nuisance of always being attached to a gadget, skin infections, ketoacidosis risk if the flow of insulin is broken and cost.

Complications of insulin • Allergy (local or generalized): circulation insulin antibodies can affect insulin action • Insulin resistance – the most common cause of mild insulin resistance is obesity. Insulin resistance associated with antibodies directed against the insulin receptor has been reported in pts with acanthosis nigricans. • Dose dependent effects: hypoglycaemia and weight gain (insulin also increases appetite) • Dose-independent effects - lipohypertrophy caused by repeated injections at the same site, lipoatrophy (rare) and insulin oedema • Insulin during illness  maintain insulin (or even increase dose) because usually an illness will increase BGL especially if the pt has a fever Oral hypoglycaemic agents 1. Insulin secretagogues  Stimulate insulin release from the pancreas.  Sulphonylureas and Meglitinides 2. Insulin sensitisers  These drugs have no effect on insulin secretion but they can improve the effectiveness of insulin already present in the circulation.  Biguanides (metformin) and glitazones 3. Decrease absorption of glucose from the gut  Acarbose Sulphonylureas • Examples: glibenclamide, glipizide, glicazide, tolbutamide • MOA: increase insulin release from beta-cells. The drug binds to a sulphonylurea receptor leading to closure of the K-ATP channel and thus a ↑ in intracellular calcium and in turn the release of insulin. • S/Es: o Weight gain – patients will put on a lot of weight particularly because previously when their diabetes was poorly controlled, they lost energy through glycosuria. o Hypoglycaemia – 2% of patients suffer this side effect. The drugs interfere with normal glucose homeostasis. o Hyponatraemia – the drug increases the sensitivity of the DCT to ADH. o Worsening of MI (?) – potassium channels also exist in cardiac myocytes o Bone marrow damage is a severe but very rare complication • Pharmacokinetics: taken orally, reach peak plasma concentrations within 2-4hours. Most are secreted in the urine so caution must be taken in anyone with renal impairment particularly the elderly because of the risk of severe hypoglycaemia. They should not be used in pregnancy because they can cross the placenta. • Drug interactions: NSAIDs, coumarins, alcohol, monoamine oxidase inhibitors and some antibacterial drugs (sulfonamides, trimethoprim) – if combined they can produce severe hypoglycaemia Meglitinides • Examples: nateglinide and repaglinide. • MOA: stimulate insulin release by closing the K-ATP channel – they bind to a different receptor to the sulphonylureas. They are designed to restore the early phase post-prandial release of insulin without prolonged stimulation during periods of fasting. • S/Es: hypoglycaemia (less common than with sulphonylureas because of their short duration of action). Metformin • MOA: lowers BGL by complex mechanisms not yet understood o Increases glucose uptake by skeletal muscle and adipocytes o Suppresses hepatic gluconeogenesis o Reduces glucose absorption from the small intestine

May stimulate AMP kinase, an enzyme which activates glucose transporters and facilitates its uptake into cells. May also suppress appetite and thus help achieve weight loss. Clinical use: metformin is the drug of choice in treating type 2 diabetics. Metformin can be combined with sulphonylureas, Glitazones or insulin. Should be taken with or after food. S/Es: GI disturbances including: anorexia, diarrhoea and nausea (these can usually be avoided if the dose is gradually increased). A fatal but rare complication is lactic acidosis because it is associated with an increase in lactate production by inhibiting pyruvate metabolism – therefore when there is impaired clearance of lactate or an increase in anaerobic metabolism such as shock, lactic acidosis can result. Pharmacokinetics: prevents hyperglycaemia but it does not cause hypoglycaemia. It reduces cardiovascular risk by reducing LDL and VLDL cholesterol. It has a half life of 3hrs and is excreted unchanged in the urine. o

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Thiazolidinediones (glitazones) • Examples: Rosiglitazone and Pioglitazone • MOA: bind to a receptor in the cell nucleus called peroxisome proliferator-activated receptor-gamma (PPARγ). This receptor is abundant in adipose tissue and this is the major site of action of these drugs but it is also found in muscle and liver cells. They reduce hepatic glucose output and increase glucose uptake into muscle, which enhances the effectiveness of the insulin produced by the body. This reduces the amount of insulin needed to maintain a given level of blood glucose by about 30%. • S/Es: weight gain on hips and thighs, fluid retention which can precipitate any cardiac failure, dilutional anaemia. An old glitazone called troglitazone was associated with liver toxicity so regular LFTs are recommended. • Pharmacokinetic effects  they can increase sodium reabsorption in the kidney  fluid retention. They may take up to 3 months to reach their maximal effect because their effect on BGL is indirect. Also increase HDL cholesterol  can reduce cardiovascular disease risk. Acarbose • MOA: competitive inhibitor of α-glucosidase in the brush border of the small intestine which hydrolyses disaccharides here  reduces glucose uptake from the gut. The post-prandial peak of blood glucose is reduced and so BGC is much more stable throughout the day. • Indications: type 2 diabetics who cannot control their diabetes with diet alone • S/Es: GI disturbances particularly flatulence, abdominal distension and diarrhoea as unabsorbed carbohydrate is fermented in the bowel. Microvascular complications Pathogenesis • Multifactorial • Hyperglycaemia: o Advanced glycation end-products (AGE) – prolonged exposure of proteins to high glucose levels causes glucose binding and glycation products. Initially this is reversible, but eventually there is irreversible cross-linking and development of AGEs. They accumulate in proportion to hyperglycaemia and time. They promote extracellular matrix formation which impairs the function of tissues. Antioxidants may impair AGE formation. o Reactive oxygen species – are increased leading to reduced nitrous oxide, with loss of its antiinflammatory, antiproliferative and anti-adhesive properties. o Activation of NFκB – this is an intracellular transcription factor that mediates pro-inflammatory responses o Sorbitol pathway – excess glucose is metabolised to sorbitol via the polyol pathway by aldose reductase. This pathway uses NADPH and NAD+ eventually decreasing levels of reduced glutathione which is important in getting rid of reactive oxygen species that are damaging to cells. o Activation of protein kinase Cβ – When glucose is metabolised the expression of PKCβ is increased and this in turn increases the expression of a number of mitogenic cytokines such as transforming growth factor β and vascular endothelial growth factor. o Cytokines – AGE products also increase levels of the afore mentioned cytokines  ↑vascular permeability and angiogenesis – this may be responsible for macular oedema and new vessel formation seen. • Haemodynamic theory of diabetic complications – proposes that microvascular complications result from chronic abnormalities in the blood flow through capillary beds which is thought to be brought on by

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hyperglycaemia. The osmotic effect of hyperglycaemia  high flow rates that are increased further in patients with hypertension  tissue damage due to impaired nutrient and oxygen supply. The growth hormone-insulin-like growth factor axis – there is reduced hepatic production of insulin growth factor in diabetics often in response to artificially administering insulin and hence the body “forgets”. This leads to reduced feedback to the pituitary gland and growth hormone hypersecretion (2-3x). Growth hormone stimulates glucose release and has a diabetogenic effect.

Diabetic retinopathy Pathogenesis: • Hyperglycaemia – as above • Glycosylation of tissue proteins may play a major role • Loss of the blood-retinal barrier - twin processes of small vessel occlusion and increased permeability – there are changes to the vessel wall and loss of supporting pericytes • Ischaemic tendency – caused by an increased red cell and platelet stickiness and reduced oxygen transport. In response to the ischaemia the retina releases vasogenic factors which cause proliferation of new vessels. Natural history: 1. Background of retinopathy  dot haemorrhages (microaneurysms), blot haemorrhages (small intraretinal haemorrhages) or hard exudates (lipid or protein exudates) 2. Pre-proliferative retinopathy  cotton wool spots that result from retinal ischaemia and/or intraretinal microvascular abnormalities (clusters of irregular branched vessels in the retina and may represent early new vessel formation), venous beading/loops. 3. Proliferative retinopathy  new vessel formation due to growth factor release in response to retinal ischaemia/hypoxia. The vessels are weak and have a tendency to bleed, which can lead to blindness because there can be a fibrous tissue reaction. There can be a vitreous haemorrhage, which involves loss of vision in one eye, on waking, or as a floating shadow. It is seen as a featureless, grey haze with ophthalmoscopy. Partial recovery of vision occurs as blood is absorbed but repeated bleeds may occur. 4. Advanced retinopathy  retinal fibrosis, traction retinal detachment, loss of vision, retinal detachment. 5. Maculopathy  retinopathy occurring around the macula  reduction in visual acuity Management: • Screening – annual eye test of visual acuity and fundoscopy with retinal photography and fluorescein angiography. Start screening: type 1 DM within 3-5 years of diagnosis after age 10y; type 2 DM at the time of diagnosis; screen all pregnant women prior to conception and during the 1st trimester if they have DM. • Prevention: good glycaemic control (a 2% reduction in HbA1c can halve the incidence and progression of retinopathy), effective control of hypertension, stop smoking • Treatments:  No drugs are licensed however, protein kinase C inhibitors may have the potential to improve retinopathy  Laser photocoagulation - destroys peripheral parts of the retina thus reducing the ischaemic stimulus for new vessel formation. This sacrifices peripheral vision for central vision but it is effective.  Vitrectomy may be required if an intravitreal haemorrhage fails to clear. Eye disease and prognosis: • Retinopathy develops insidiously and almost always asymptomatic until patient has a catastrophic intraocular sight-threatening haemorrhage • Other eye problems seen in diabetes: cataract (2ndry to osmotic changes in the lens), refractory defects (2ndry to osmotic pressure changes in lens), glaucoma, infections, nerve palsies • Statistics:  Most common cause of new cases of blindness among adults 20-74yrs  12000-24000 people lose their sight due to DM each yr  Affects 1 in 3 diabetics  5% are blind after 30yrs of diabetes Diabetic nephropathy Pathogenesis • Ischaemia - resulting from hypertrophy of afferent and efferent arterioles

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Ascending infection – urinary infections are more common in diabetics. This is because of: urinary stasis due to autonomic neuropathy affecting bladder function, high glucose levels of urine. Glomerular damage and renal failure 1. Functional changes  Increase in GFR – secondary to polyuria (greater urine volumes)  Expansion of tubular tissue and enlargement of kidneys – secondary to ↑renal filtration. This leads to glomerular hypertrophy and oxidant stress. The result is premature glomerulosclerosis. 2. Structural changes  AGE products cause irreversible protein cross-linking in the glomerulus and basement membrane  Disruption of protein cross links and basement membrane thickening occur  There is also dilation of the afferent arteriole more than the efferent arteriole leading to a rise in intraglomerular filtration pressure, further damaging the glomerular capillaries. 3. Microalbuminuria  Disruption of protein cross-links alters the glomerular filter allowing progressive leak of large molecules into the urine  There is microalbuminuria and in 20% progression to proteinuria and nephrotic syndrome  The GFR decreases and serum creatinine rises 4. Overt clinical nephropathy - as glomerular filtration fails so the blood pressure and plasma creatinine rise and proteinuria increases. 5. End-stage renal failure – anaemia, altered calcium metabolism (↓Ca and ↑phosphate), dyslipidaemia, and hypertension.

Prevention of nephropathy • Essential as diabetes is the main cause of renal failure in Europe. Clinical nephropathy appears between 15-25y after diagnosis. • Prevention: o Optimise glycaemic control (HbA1c <7%) – metformin should not be used with a raised creatinine, insulin therapy should be initiated when it goes >200. o Normalisation of bp (<130/80mm/Hg) + correction of CV risk factors – treatment with ACE inhibitors (e.g. –pril) is the optimal drug even in normotensive patients if they have microalbuminuria. Other antihypertensives used include angiotensin receptor blockers (ARBs) such as candesartan (which should be used if there is an intolerance to ACEs), or B-blockers. o Other therapy: restrict dietary protein to RDA of 0.8 g/kg body weight per day; stop smoking; reduce lipids. • Screening – via urine dipstick for proteinuria, 24-hr urine sampling or albumin:creatinine ratio. For confirmation of microalbuminuria, 3 urine tests should be positive and other causes of proteinuria excluded. • When to refer - when to refer microalbuminuria is determined by a locally defined protocol – referral to a nephrologist should be considered with increasing proteinuria, ↓GFR <60mL/min and ↑serum creatinine to 200-250umol/L. Diabetic neuropathy Pathophysiology • Occlusion of vasa nervorum (blood vessels supplying nerves) secondary to atherosclerosis • Hyperglycaemia – slows nerve conduction and causes uncomfortable sensory symptoms. It also causes an increase in the formation of sorbitol and fructose in schwann cells – so that an accumulation of these can disrupt function and structure  segmental demyelination Patterns of diabetic neuropathy: 1. Acute sensory neuropathies • Usually asymmetrical mononeuropathies which are transient. • Diffuse and painful – burning or crawling pains especially at night. This neuropathy usually resolves after 3 months • Focal mononeuritis and mononeuritis multiplex – any nerve can be affected causing radiculopathies, isolated cranial nerve palsies, carpel tunnel etc. Onset is rapid but there is always a full spontaneous recovery. 2. Chronic, symmetrical, sensory polyneuropathy • Very common

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There is loss of vibration sense, pain sensation, and temperature sensation in the feet and hands mainly – glove and stocking distribution • At later stages there can be balance problems and impaired proprioception (“walking on cotton wool”). • Complications include: trauma at pressure points, blistering, clawed toes, callus formation, ulcers, and eventually neuropathic arthropathy i.e. Charcot’s joints. 3. Acute motor neuropathies • This is rare and can lead to amyotrophy or muscle wasting. • Quite prevalent in old men with diabetes whereby they have weight loss and painful, asymmetrical muscle wasting, usually of the quads. The wasting may be so marked that there is no knee reflex and the area affected becomes quite tender. • Amyotrophy is usually associated with poor glycaemic control and will resolve if control is improved. 4. Autonomic neuropathy • Affect the sympathetic and/or parasympathetic nervous systems • CV system  vagal neuropathy  tachycardia at rest and loss of sinus rhythm; postural hypotension; peripheral vasodilatation. • GIT  gastroparesis due to vagal damage (can cause vomiting); diarrhoea • Bladder  loss of tone  incomplete emptying  stasis  ↑infections • Erectile dysfunction Management • Control blood pressure • Introduce insulin • Pain-killers such as amitriptyline, carbamazepine, gabapentin etc • Where there is sensory loss in feet: immobilisation, custom-made footwear, reconstruction, IV bisphosphonates. Macrovascular complications Pathogenesis - atherosclerosis 1. Chronic endothelial injury: • Due to physical forces e.g. turbulent flow at points of bifurcation • Due to toxins e.g. cigarette smoke, hyperlipidaemia, hyperglycaemia, viruses, immune reaction 2. Endothelial dysfunction: • Increased permeability • Increased expression of cell surface adhesion molecules that recruit leukocytes • Altered release of vasoactive substances • Release of inflammatory cytokines • Impaired production of antithrombotic agents (nitrous oxide or antioxidants) which are promoted by a laminar flow 3. Lipoprotein entry and modification: • The Dysfunctioning endothelium allows circulating lipoproteins to pass through and into the internal elastic intima particularly in areas of haemodynamic strain • LDL cholesterol accumulates in the subendothelial space and binds to proteoglycans  fatty streak • The lipids can be oxidised and altered by enzymatic change or even glycated (in diabetics) to form inflammatory lipids that attract inflammatory cells 4. Leukocyte recruitment: • Inflammatory, antigenic lipids and the release of inflammatory mediators by the Dysfunctioning endothelium, encourage monocytes and T-lymphocyte entry • Monocytes:  Mature into macrophages on entry  Produce: IL-1, TNF-alpha and MCP-1 increasing adhesion and recruitment of leukocytes to plaque  Engulf oxidised LDL to form foam cells and present the oxidised LDL as an antigen to T-lymphocytes causing their activation • T-lymphocytes:  Produce inflammatory cytokines, INF-gamma, lymphotoxin, IL-1, TNF-alpha setting up the chronic inflammatory state  Stimulate macrophages via oxidised LDL as well

 Try to heal the blood vessel by producing ground substance (collagen) and fibrous tissue, but this only thickens the vessel and helps in plaque formation 5. Plaque formation: • Macrophages, T-lymphocytes and platelets release growth factors (PDGF, FGF, TGF-a) which cause smooth muscle cell migration from the arterial media to the intima • Subsequent smooth muscle proliferation, extracellular matrix formation, fibrous tissue release and foam cells modified with inflammatory mediators form an atheromatous plaque. • The plaque has a thrombogenic lipid core (tissue factor-concentrated) and a protective fibrous cap 6. Plaque instability and rupture: • The continuous cycle of matrix synthesis and degradation by inflammatory cytokines with cell necrosis and release of contents, the lipid core grows • The plaque may fissure and release its thrombogenic core  STEMI or NSTEMI The diabetic foot Pathophysiology – combination of neuropathy, ischaemia and infection Charcot’s arthropathy 1. Acute onset – acutely swollen, hot foot. Only a 1/3 have pain. The initiating event is often a trivial injury. Differential: gout, cellulitis, DVT. At this point, the foot should be immobilised in a non-weight-bearing cast. 2. Bony destruction – if treatment of the acute stage is delayed then the foot can become deformed as bone is destroyed. These changes can happen very quickly, in just a matter of weeks. Any deformity predisposes the foot to ulceration, particularly on the plantar surface. Immobilisation is essential. 3. Radiological consolidation and stabilisation – the destructive process stabilises after 6-12m. Arterial leg ulcers • Painful, small, punctuate ulcers that are usually well circumscribed and usually on the dorsum of the foot • Pulselessness, pallor, cool skin • Delayed capillary return time • Atrophic appearing skin (shiny, thin, dry) with loss of digital and pedal hair Acute ischaemia • Pain - sudden onset, continuous, variable intensity; often at the junction of perfused and ischaemic tissue, usually in one periphery. • Paraesthesia - sudden onset, usually in one periphery; may be an altered or a complete absence of sensation. • Pallor - periphery is white and may become blue with onset of necrosis. There is poor peripheral capillary return on pressure blanching and the skin may blister. Buerger's test is positive. • Perishing cold • Pulselessness - foot pulses are absent, and may be undetectable by Doppler ultrasound. Popliteal and femoral pulses may be absent depending on the level of occlusion. • Paralysis - indicates extreme ischaemia. The movements of flexion and extension of the ankle and toes are eventually lost. Chronic ischaemia • Mild ischaemia presents with intermittent claudication • Critical ischaemia: rest pain, poor healing, ulcers and pressure sores Investigations of the diabetic foot: ischaemia • Listen for arterial bruits with a stethoscope of the artery (you might hear a whooshing sound) • Decreased or absent pulse in the extremities • Decreased blood pressure in affected limb • High cholesterol • Claudication distance inquiry and exercise testing – normally foot pressure should increase with exercise but it drops in the case of occlusive arterial disease (the size of the drop gives you an indication of severity). • Ankle/Brachial Index (ABI) <1; severe ischaemia if <0.4 • Doppler ultrasound examination of an extremity – this examines blood flow in the major arteries and veins of the arms and legs. You can use a Doppler machine to amplify the korotoff sounds when measuring blood pressure in the ankle. • Angiography of the arteries in the legs • Distinguish between an ischaemic and a neuropathic foot:

Symptoms

Ischaemia Claudication Rest pain

Inspection

Dependent rubor Trophic changes

Palpation

Cold Pulseless Painful heals and toes

ulceration

Neuropathy Usually painless Sometimes painful neuropathy High arch Clawing of toes No trophic changes Warm Bounding pulse Painless Plantar

Treatment of the diabetic foot Foot ulcers: • Prevention: carefully measured footwear, wash feet daily + dry well, cut nails carefully + regularly, inspect feet daily, use moisturising creams for callus or fissures. • Treatment: o Relief of pressure by bed rest or contact casting o Radical debridement o Treat any infection with appropriate antibiotics – common infectious agents are strep pyogenes and staph aureus. Antibiotics should be broad-based and given for 1m. Antibiotics used: penicillin-cloxacillin combination, metronidazole (anaerobes), cephalosporin, vancomycin (for resistant bacteria). For severe infection, consider osteomyelitis. o It may be necessary to perform revascularisation of ischaemic limbs. o Amputation – last resort because it can result in w/c use, and can ↑risk of ulceration. Peripheral artery disease: • Self care is essential – it is good to walk to the point of pain alternated with rest periods because it allows new, smaller blood vessels to develop. Stop smoking! Good foot care! Low fat diet! • Medication: analgesics, anticoagulants, antiplatelets such as aspirin 75mg od, vasodilators (Naftidrofuryl 100200mg tds daily or Cilostazol 100mg bd) and a statin • Surgery – this is usually only performed in the most severe cases. Examples of surgery includes: removing the lining of the artery (endarterectomy), repair/replacement of a vessel (grafting), bypass using a vein or synthetic graft. • Alternatives to surgery are treatments such as balloon angioplasty, stent implantation

Surgery: • Angioplasty – a catheter is introduced percutaneously into an artery and a balloon is inflated inside an artery to attempt to widen a narrowing. Patency is about 95% for 2 years for lesions above the inguinal ligament or 80% below. Complications include: rupture of the vessel, embolism, or damage at the entry site for angioplasty. • Stenting –a cage-like stainless steel support device is inserted collapsed into the right place in the blood vessel and then expanded into the open position by inflating a high pressure balloon in its interior. The stent will act as a scaffold for the artery and maintains blood flow. The stent is thrombogenic however, and so a combination of oral antiplatelet agents e.g. aspirin + clopidogrel, is crucial after stent implantation. Stenosis rates are much lower with stents, but there is still a problem due to migration of smooth muscle cells. Drug-eluting stents have been devised to reduce re-stenosis. These stents are fabricated with a polymer coat that incorporates an antiproliferative medication. • Thrombectomy – excision of a thrombus • Thrombolysis – use of thrombolytic drugs to dissolve a thrombus • Endarterectomy – surgical removal of an atherosclerotic plaque. • Bypass grafting – a good vein is attached to the area of atherosclerosis and acts as a bypass. Usually this is the greater saphenous vein. The vein must be inverted so that the valves do not close and block off the blood flow or the valves can be stripped off; depends on the technique preferred. If there are no suitable veins, then a

synthetic tube can be used – this always has a higher complication rate. Any sort of bypass can be performed e.g. iliofemoral, fem-fem, femoropopliteal, femorodistal/femorotibial etc. Erectile dysfunction • Prevalence increases with age – 60% of men with DM >60y are affected. Women may also suffer sexual dysfunction - there is an increased risk of vaginal dryness and impaired sexual arousal and genitourinary infections, in particular candidiasis, are common in diabetic women. • Pathophysiology - penile erection occurs following the flow of blood into the erectile tissue. Nitrous oxidemediated vascular smooth muscle relaxation of the corpus cavernosum produces expansion of the cavernosal space and compression of the outflow venules. This allows blood to flow into, but not out of the penis. Erectile dysfunction in DM mainly results from autonomic neuropathy and endothelial dysfunction. Other factors can also contribute: drugs, psychological, neurological, endocrine, and metabolic disorders (hypothyroidism). • Treatment: o Phosphodiesterase type-5 inhibitors – e.g. sildenafil, tadalafil, vardenafil. These inhibit the breakdown of cyclic GMP, which is a second messenger of NO. So they enhance the effects of NO on smooth muscle and increase penile flow. These drugs should be taken before intended sexual activity because they enhance erections under conditions of sexual stimulation. They are effective in ~50-60%. Patients must take care not to use these drugs with nitrates because they may cause severe, acute hypotension. o Prostaglandin E (alprostadil) - Administered by injection into the corpus cavernosum or transurethrally o Apomorphine - 2 or 3 mg sublingually 20 minutes before sexual activity. It is a dopamine agonist. o Vacuum devices - draw blood into the penis while a constriction band around the base of the penis prevents blood leaving the penis and thereby maintains the erection. o Surgery - is a last resort. It involves the insertion of a plastic rod in to the penis so that penetration can be achieved. Prevention of macrovascular complications Lifestyle measures: • Quit smoking – reduces risk of progression to CVD by up to 70% in the non-diabetic population • Increase physical activity • Loss weight • Balanced, healthy diet • Clean and check feet regularly - ? chiropodist Control BGL • For every 1% fall in HbA1c there is a reduction in microvascular risk by about 25% irrespective of whether the patient has type 1 or type 2 DM. • Glitazones/Thiazolidinediones are effective in controlling multiple risk factors AND BGL Control blood pressure • When bp >130/80mm/Hg, the risk of complications increases, so current proposals aims for these levels. • ACE inhibitors are particularly good because of their role in renal protection - lowers the risk of a heart attack, stroke, overt nephropathy or CV death by 25-35%. Control of blood cholesterol • Lipid-lowering therapy: o Statins – simvastatin produced a 55% reduction in the incidence of major CHD. Pravastatin also good. o Fibrates or nicotinic acid are helpful in patients with low HDL cholesterol despite statin therapy Use of aspirin • Patients with a risk of CV events of >20% in the next 10y have a reduced mortality with aspirin • If intolerant, clopidogrel is a good alternative • The benefits outweigh the bleeding risk when: o Age 45 with 3 strong CV risk factors o Age 45-54 with 3 strong CV risk factors o >65 with 1 CV risk factor Psychosocial and Economics of Diabetes Social implications 1. Work • Risk of hypoglycaemia from insulin therapy may put others at risk

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Can apply for registration as a disabled person, which can help in finding a job Shift work, long working days, international travel can all impact insulin regimens. Meals can be early or late, sometimes meals are missed, and sometimes there are frequent business lunches. • Generally excluded from: o Vocational driving: LGVs, PCVs, taxi drivers, chauffeurs, underground trains o Civil aviation: commercial pilots, flight engineers, aircrew, air-traffic controllers o National and emergency services: armed forces, police force, fire brigade or rescue services, prison and security services o Dangerous areas for work: offshore oil-rig work, moving machinery etc o Work at heights: crane driving, scaffolding etc Finance • Life and car insurance need to be informed if diabetic and on insulin. Premiums are often dependent on the risk of hypos and the presence of complications. • In UK they are exempt from prescription charges (GP signs a SP92 form) • Small, supplementary pensions are available to help diabetics with the increased cost of food for their diets Sport • Can play most sports • Wary in: scuba diving, motor rally, boxing • Should avoid dangerous situations e.g. swimming alone • Intense exercise warrants better control: measure BGL before exercise, take 20g carbohydrate every 45mins, keep fast-acting glucose preparations in pocket. Holidays and travel • Can be very difficult; extra precautions need to be taken (medic Alert bracelet, letter to confirm they can carry syringes on aeroplanes) • Time differences make insulin dosing difficult: ?supplementary injections • On day of travel, aim for higher BGL + take regular BGL checks • Sea sickness – vomiting – continue insulin • Looking after insulin: topical climates may require refrigeration, do not leave it in luggage hold as it may freeze • Soluble insulin is usually available in most countries Driving • All diabetic otherwise fit and well can hold ordinary driving licence but the law demands that all patients whether type I or II should inform the DVLA of their condition. o If on insulin licenses are restricted to 1,2 or 3 years only o Patients are only refused a license if erratic control, hypoglycaemia or poor eye sight • Visual acuity and fields must be assessed to determine suitability for driving. • The DVLA require patients to sign a declaration allowing their doctor to disclose medical information about them if they are treated with insulin. • Patients must plan their journey, not drive for >2h, always take glucose. If they experience warning symptoms of hypoglycaemia they should stop, switch off the engine and leave the car, since otherwise they may be charge of driving under the influence of drugs. Surgery • ↑risk of post-operative death • Metabolic control should be optimised before the operation • Generally stop all tablets before surgery and consider insulin treatment (if tablet-controlled) • If insulin-controlled  Substitute short-acting insulin the day before surgery and perioperatively, use IV 10% dextrose with potassium chloride. Post-op, maintain this infusion, until the patient can eat.

Psychological implications • Low self image, loss of self-esteem, denial • Social isolation - adolescents can feel isolated and they don’t want to be different from their peers, therefore often going out and drinking large quantities of alcohol, despite knowing the risks as a diabetic. • Much anxiety about future: driving, fertility • Eating disorders are more common in diabetics – 30-40% of young women will have a significant eating disorder • Serious psychological distress is 90% higher in adults with DM - many experience episodes of not coping, of helplessness.

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Psychiatric problems are 3x more common in adolescents: the difficulty to cope is magnified and there is often a period of poor metabolic control and then later re-emerging with complications. Diabetics often do not get much sympathy or concessions as it is a the presence of the disease is hidden Treatment is complex and demanding. Diabetics may feel uncomfortable/embarrassed/different having to inject insulin in public places. The use of insulin pens and meters mirroring the shape of a pen or MP3 players might help to reduce embarrassment and to cope with the alteration of image. Embarrassing loss of control over personal behaviour Risk taking behaviour is effected e.g. alcohol consumption, unplanned pregnancies, tobacco

Economic impact of diabetes on NHS • 10% of the total UK health budget • Costs the US nearly $132 billion a year – 92 billion in direct medical costs and 40 billion in indirect costs due to lost productivity. • The first Wanless report (2002) estimated the total annual cost of diabetes to the NHS to be £1.3 billion. • Average yearly health cost for a person with diabetes was $13,243 in 2002, compared with $2,560 for someone without diabetes • Life expectancy is decreased by 5-10 years Patient education and diabetes • NICE states 3 goals of patient education: 1. Control of vascular factors e.g. blood glucose, blood lipids, blood pressure 2. Management of diabetes associated complications, if and when they develop 3. Maintaining good quality of life • NICE guidelines on how to educate: o Delivered by an appropriately trained and skilled MDT (at least a Specialist Diabetes Nurse + Dietician) o Group work is less costly and a more efficient use of health professionals’ time, as well as allowing patients to support one another. o Accessible to all  hold meetings in a local community centre? o Use a range of educational methods to “promote active learning” • Special patient education projects: 1. DAFNE (Dose Adjustment For Normal Eating) o Designed for Diabetes Type I patients so that there insulin dose is adjusted according to carbohydrate and activity levels. o ↑Freedom with meals, independence o Patients have a small booklet which lists every food type and its carb count so that they can adjust the insulin dose respectively. o It is an outpatient scheme, delivered over 5 days to groups of between 6 and 8 patients. It costs £545 to educate a patient via DAFNE. 2. DESMOND (Diabetes Education and Self Management for Ongoing and Newly Diagnosed) o Designed for Diabetes Type II patients o It aims to help patients identify their risk factors and possible diabetic complications. o Still quite new Economics of Chronic Disease Economics of chronic disease • What is chronic disease? – a non-communicable life-long or long-term disease such as asthma, RA, cancer, COPD, diabetes and heart failure, that can be controlled but not cured. • The prevalence of chronic disease is increasing – approx 17.5 million adults (1/4 of the UK population) suffer from a chronic condition, an average of 6 in 10 adults. By 2030 it is estimated that the incidence of chronic disease in the over-65s will more than double. • Reasons for the increasing prevalence:  Reduction in mortality at younger ages

 Demographic Transition – longer life-expectancy (proportion elderly aged 80+ increased from 17% to 24%), therefore more people and more chronic disease; but also with old age comes degenerative and acquired chronic diseases  Health transition – great lifestyle risks – diet, exercise, smoking, alcohol trends The costs of chronic disease: • The World Health Organisation has identified that chronic conditions will be the leading cause of disability by 2020 and that, if not successfully managed, will become the most expensive problem for health care systems. • Direct costs o Medical: drugs prescribed, staff time  80% of GP consultations, 60% of hospital beds, 60% of emergency admissions have exacerbation of chronic condition, Pts with >1 chronic disease cost 6x as much, Pts with >1 chronic disease make higher use of health care (eg. >3 diseases; use 30% bed days) o Patient: transport; out-of pocket expenses. • Indirect costs: production losses; there are often problems with staying in work • Intangible costs: pain, suffering, adverse effects, lifetime costs (dialysis) What is the solution to the rising costs of chronic disease? 1. Prevention of the disease 2. Self-care and self-management  Support people to take an active role in managing their own care  Help people to manage their specific conditions and to adopt approaches that prevent these conditions from getting worse and reduce the risk of getting further conditions  E.g. expert patient programmes (see below) 3. Disease management and treatment – multidisciplinary teams providing high-quality, evidence-based care, including the use of pathways and protocols 4. Case management – active management of high-risk people with complex needs 5. Knowledge management – identify at-risk groups within the population, carry out needs assessments, understand resource and activity levels and identify trends. Expert patient programmes • Piloted between 2002 and 2004; now part of the NHS Improvement Plan • Lay-led, group-based support for people with chronic diseases to help them in the self-management of their long-term condition. Helps patients take control over their disease and lives. • The programme is delivered locally by a network of trainers and volunteer tutors with long-term conditions. • Relies on the fact that patients know their condition best and know how to manage it, but they need support in this • The programme focuses on five core self-management skills: 1. Problem solving 2. Decision making 3. Resource utilisation 4. Developing effective partnerships with healthcare providers 5. Taking action – develops confidence and motivation, plans for the future • Benefits of self-management include: o Reduced severity of symptoms o Significant decrease in pain o Improved life control and activity o Improved resourcefulness and life satisfaction  Overall improved QoL and reduced incapacity! • Reduced burden on NHS as aim of these programs is to cease involvement with healthcare systems and they also improve outcomes: o 50% reduction in unplanned admissions o 50% reduction in bed-days o Significant education in medications compliance o However: moderate increases in clinic visits, test ordering and consultations