Diabetes Mellitus

Diabetes mellitus: (DM): ‘‘ Definition Diabetes mellitus results from a lake of, or diminished effectiveness of endogen insulin and is characterized by hyperglycaemia.

Presentation: Patients may be a symptomatic. Acute : Ketoacidosis unwell hyper ventilation, ketones on breath, weight loss, polyuria and polydipsia., fatigue

Subacute : History as above but longer and in addition lethargy , infection (pruritus vulvae, boils).

Complications : may be the presenting feature: infections, neuropathy, retinopathy arterial disease e.g. myocardial infarction or claudication).

Type I ( insulin-dependent DM- IDDM) Usually juvenile onset but may occur at any age. characterized by insulin deficiency. Patients always need insulin, and are prone to ketoacidosis and weight loss. Associated with other autoimmune diseases (HLA DR3 & DR4; +ve islet cell antibodies around time of diagnosis). Concordance is >30% in identical twins. 4 genes are important one determines islet sensitivity to damage (eg from viruses or cross-reactivity from cows’ milk antibodies).

Type II : (non insuline dependent DM,. NIDDM, maturity onset DM) Older age group, often obese, NB: NIDDMs may eventually need insulin: this does not mean that IDDM has developed. Insulin is likely to be needed in those with ketoanuria, glucose >25mmol/L, sudden onset weight dehydration If Ketoacidosis then lDDM exists. — 100% concordance in identical twins. Due to impaired insulin secretion and/or insulin resistance.

Causes of secondary diabetes Drugs (steroids and thiazides) Pancreatic disease (pancreatitis, surgery in which >90% pancreas is removed, haemochromatosis cystic fibrosis, pancreatic cancer). Endocrine (Cushing’s disease, acromegaly, phaeochromocytoma, throtoxicosis) Others (acanthosis nigricant. congenital lipodystrophy with insulin receptor antibodies. and glycogen storage diseases).

* Fasting venous plasma glucose > 7mmol/L a glucose of 6-7 mmol/L implies impaired fasting glucose. * If the patient has no diabetic symptoms. diagnosis should not be based on a single glucose value. * If there is any doubt the 2-hour value in an OGTT should be used (look for a level >l1.1mmol/L Method for performing a 2-hour oral glucose tolerance test: • Fast overnight and give 75g of glucose in 300 ml water to drink • Venous plasma gIucose before and 2h after drink. Diagnosis: (WH0 criteria adopted by UK in June 2000)

* Urine tests for glycosuria and random blood glucose tests are unreliable (but if 11.1 mmol/l and symptoms are present, this is diagnostic of DM). * Severs hyperglycaem’a in acute infection, trauma, or circulatory or other stress may be transitory delay formal o (but not management). Plasma HbA1c values: If >7%. DM is likely (specificity 99.6% sensitivity 99%) and risk of microvascular complication occurs. Screening for glycosuria : This is easy but 1% of the population have low renal threshold for glucose; the sensitivity is only 32% (specificity: 99%).

Causes of insulin resistance : * Obesity * Pregnancy * Asian origin * Acute and chronic renal failure *Acromegaly * Isolaiazzid * Rifampicin * Sympathetic tone ↑ * Werner’s syndrome * Polycystic ovaries * Ataxia * Teiangiectasia * Cystic fibrosis

Mechanism of insulin resistance: Obesity probably causes insulin resistance by the associated ↑ rate of release of non-esterified fatty acids causing post-receptor defects in insulin’s action. Other mechanisms . Mutation of the gene encoding receptor . Circulating autoantibodies to the extracellular domain of the insulin receptor

Management: Advise weight loss and exercise mange hyperglycaemia, with drugs or insulin. Vitamin E improves insulin sensitivity and delays oxidation of LDL (The postulated common factor in development of atheroma, hypertension, hypercholesterolaemia, and diabetes: this LL down-regulates nitric oxide production). We don’t know if vitamin E saves lives.

Thiazolidinediones (PPAR-gamma againsts) ↑ insulin sensitivity eg rosiglitazone 4mg/24h. LFT ↑ check LFTs They have complex metabolic effects, including ↓ leptin expression , and ↑ p85alpha K gene expression ( a gene that allows insulin to work ) They also augment insulin’s down regulation of angiotensinogen gene expression; this may explain why thiazilsiniones decrease blood pressure.

NICE : (recommends their use as an alternative to insulin only if metformin with a sulfanyurea is not working, or tolerated. They are better combined with metfarmin than with sulfanyureas.

Impaired glucose regulation that does not amount to diabetes This metabolic state lies between normal glucose homeostasis and diabetes. Impaired glucose tolerance (IGT): Fasting plasma glucose <7mmol/l and OGTT 2-hour glucose > 7.8mmol/L but <11.l mmol/L

Impaired fasting glycaemia/glucase (IFG): Fasting glucose levels above the normal range, but below the diagnostic level for DM, a fasting plasma glucose > 6.l mmol/L but <7mmol/L. Diabetes UK (formerly BDA) recommends all those with IFG should have an OGTT to exclude diabetes. 1FG and IGT are not interchangeable and represent different abnormalities of glucose regulation fasting and post-prandial). Both have the risk of progress to diabetes and rnacrovsscular disease. Although prospective data are sparse, there may be lower risk o progression in IFG than in IGT. Both should be managed with lifestyle advice (ag exercise and diet).

Gestational diabetes: This term now intrudes both gestational impaired glucose tolerance (GIGT) and gestations) diabetes mellitus (GDM). Use the same diagnostic values as IGT and diabetes above. As glucose tolerance changes during pregnancy, the gestation at ‘which use diagnosis was made needs to be stated . > 6 weeks postpartum, So a further 75g GGTT whether she still has diabetes or IGT/IFG. Regardless of the 6-week post-pregnancy result these women are at risk of later diabetes.

Diabetes management Principales: Patient motivation and education are the keys to success. Aim to avoid complications, which include hypoglycaemia as well as the long-term con— sequences of hyperglycaemia. Strict plasma glucose control does reduce renal, CNS and retinal damage. However, a balance is required for each patient between lower blood glucose readings and the risk of hypo ‘glycaemia.

Interestingly, tight blood pressure control is as effective in reducing microvascular disease, but also reduces macrovascular disease, and mortality. This emphasizes the importance of a global assessment of a individuals risk—glucose, blood pressure, cholesterol, and smoking history. Don’t treat DM in isolation.

Basic investigations Blood : Glucose, U&Es, lipids, HbA1c , cholesterol. Urine: Urine analysis, urinary protein excretion.

Fundoscopy and feet exam: Assess feet and check for signs of neuropathy. initial treatment If there is ketonuria, dehydration, or the patient is ill, hospital admission is required. Children are liable to become ketotic rapidly, so prompt psediatric referral is a must. If pregnant. share care with an interested obstetrician. Stress the need for special pre-conception counselling.

Education/negotiation: is crucial on drugs, diet, and the issues below: • Monitoring blood or urine glucose and adopting treatment accordingly. Explain that when ill more, not less, insulin is needed. Recognition and treatment of hypoglycaemia (eg sweets/sugars) is essential. • Introduce to a specialist nurse/dietician, chiropodist. and diabetic association. • Regular follow-up and regular exercise ( ↓ insulin resistance & ↓ risk of MI). • Patients must inform their driving licence authority .

Healthy eating: (saturated fats ↓ , sugar ↓ starch-carbohydrates ↑ , moderate protein). Ensure that some starchy carbohydrate (bread, potato pasta) is taken at each meal. If renal impairment or micro albuminuria , restrict protein, and consider ACE.

Insulin Strength: l00u/mL Formulations of different durations: soluble insulin is short-acting (peak 2-4h, fasting - 8h). Longer-acting suspensions have onest of action of 1- 2 h, peck 4 - 12h and duration 16 – 35 h.

Oral hypoglycaemics: Sulfonylureas : These ↑ insulin secretion. tolbutamide is short-acting; useful in elderly as hypogiycaemia unlikely (0.5—1 g in 2 - 3 doses) Clilazide is medium-acting (40 - 160mg po as a single daily dose, or up to 320mg in divided doses). Less frequently used is glibenclomiae - medium-acting l2.5-l5mg/24h P0 at breakfast).

Metformin (a biguonide) Action: insulin sensitivity ↑ ; hepatic glucorieogenesis ↓ Se: anorexia; D& V; B12 absorption ↓; not hypoglycaemia. It has been shown to decrease mortality in obese subjects. Avoid in hepatic and renal impairment. Dose: 500—1000mg/8h P0 after food. May be used as first-line therapy: unlike sulfonylureas, weight gain is not a problem.

Acarbose (an α -glucosidase inhibitor) It decreases breakdown of starch to sugar. An adjust to oral hypoglycaemics (50mg chewed at start of each meal, start with a once-daily dose; max 200mg/8h). SE: wind (can be terrible; less if slow dose build-up), abdominal distension/pain, diarrhoea.

Thiazolidinediones: Rosiglitazone e.g 4mg po. CL;: hepatic impairment, SE; headache, diarrhoea, dyspepsis, fatigue, anaemia, fluid retention (caution in CCF). Do LETs every 2 months for the 1 year. Stop if AIT up >3-fold. This new drug ↓ insulin resistance

Other considerations: ACE (many beneficial affects, not just BP ↓ ); aspirin and statins to ↓ overall risk. Exercise also helps.

Some commonly used insulin regiments I- A single dose of medium-acting insulin with 3 doses of short- acting insulin (15 – 30 mins before each meal). This tends to be favoured by younger subjects (it offers greater flexibility in lifestyle), 2-A mixture of short- and longer insulin (eg saluble and Lente) at 7 AM and 6 PM (ie ½ h before meal). Give 2/3 of total insulin in the morning and ,2/3 as Lente (or medium-acting). To Improve control before breakfast, adjust evening Lente; before lunch - morning soluble; before supper - morning Lente; before bed evening soluble.

3- ‘Pen’ devices are popular because of their ease of use (e.g. during parties), Short-acting insulin is given 15 - 30 mins before each meal, with basal insulin requirement being provided by a conventional evening dose of long-acting insulin; mixed soluble (short) and isophane preparations (medium) are also available (e.g. PenMix 10/90, 20/80, 30/70, 40/60, 50/50). Other biphasic human insulin’s; Insuman Comb SO® for the Optipen®, 20 – 30 mins before a meal. The 50 refers to % of soluble insulin (the rest is isophane); 15%, 25%, and 50% are the options. Onset is at >30min, duration 12 -19hrs Pre-filled and reusable pens are prescribable in the UK, e.g. Autopen®, BD Pen®, Novopen; their accompanying needles are also prescribable (eg Microfine+® and Novofi

4- If mealtimes are random, or pastprandial glucose ↑ very rapidly absorbed, genetically engineered human insulin lispro (Humalog) can be injected just be eating. It helps iron-out glucose variability and can ‘tendency to pre-lunch hypoglycaemia ↑. It can be mixed with Ultralente (needed at night if lispro injections separated by > 5 h). Encourage regular home blood glucose monitoring in all patients (esp. those with hypoglycaemic unawareness consider ‘allowing ‘ laxer glycaemic control here). Discuss the pros and cons with your patient, Begin with at least 6u of soluble insulin before meals, monitoring blood glucose; transfer to one of the above when control is achieved

Assessment of the established diabetic Continuing assessment of the diabetic patient has 3 main aims: I- To educate. 2- To find out what problems the patient is e (glycaemic control and morale). 3- To find, or pre-empt, complications.

Assess glycaemic control from: I Glycated (glycosylated) haemoglobin (= HbA1c – levels relate to mean glucose level over previous 8 weeks (i.e RBC half-life). The target HbAIc must be set individually. Tight control is desirable in pregnancy or those with microvascular complications.

The elderly may opt for less tight control. Complications increase in frequency with increasing HbA1c Note that fructosomine (glycated plasma protein) levels relate to control over previous 1-3 weeks. May be useful in pregnancy to assess shorter-term control, also if there is a condition interfering with HbA1c measurement (eg some haemoglobinopathies). 1. History of hypoglycaemic attacks (and whether symptomatic). 2. 3 Home fingerstick glucose records may be useful

Assessment of complications Check injection sites for infection, lipoatrophy, or lipohypertrophy.

• Vasculor disease: Commonest cause of death. Look for evidence of cere brovascular, cardiovascular, and peripheral vascular disease. MI is 3-5 times more common in DM and is more likely to be ‘silent’ (i.e without classic symptoms). Stroke is twice as common. Women are at particular relative risk—DM removes The cardiovascular advantage conferred by female gender. Reduce other risk factors NB: ACE.

Also slow progression or renal disease. Treat lipid disorders: good glycaemic control helps. HMG CoA reductase inhibitors (eg simvastatin) are first-line. Fibrates may be useful for ↑ triglycerides and ↓ HDL. An aspirin a day may ↓ risk of MI in diabetics as in non-diabetics (no significant risk to the eye).

• Kidneys ( Check urine regularly. If dipstick is +ve for protein, collect 24h urine for creatinine clearance and for quantifying albuminuria. Measuring rnicroalbuminuria ( helps detect early renal disease. Control BP with ACE- inhibitor if tolerated (cautions and CL),

• Diabetic reonopatrty: (Dilate pupils with 0.5% tropicamide.) Blindness is common but preventable. Arrange regular fundoscopy for all patients, including retinal photography, if ossib1e Refer if maculopathy or pre-proliferative changes. Pre-symptomatic screening enables laser photocoagulation to be used.

Background: Microaneurysms (dots), microhaemorrhages (blots) and hard exudates. Refer to specialist if near the macula. pre-proliferotive retinopathy: Cotton-wool spots (small retinal infarcts) and extensive microhaomorrhages. Proliferative retinapathy: New vessels form. Needs urgent referral. Maculopathy: More common in NIDDM. Suspect f visual acuity.

Pathogenesis: Capillary endotheliai change —>. vascular leakage—>. microa neurysms. Capillary occlusion—> hypoxia + ‘schaemia —> new vessel formation. High retinal blood flow caused by hyperglycaemia (and BP ↑ and pregnancy) triggers these events, and causes capillary oericyte damage. Microvascular occlusion causes cotton wool spots; there may blot haemorrhoges at interfaces with perfused retina. New vessels form on disc or schaemic areas, profferace, bleed. fibrosis. and can detach the retina.

• Cataracts: These occur earlier in DM (senile and juvenile ‘snowflake’ cataracts). The osmotic changes in the lens induced in acute hyperglycaemias reverse after normoglycaemia (so wait before buying glasses). • Rubeosis Irides: New vessels on the iris: occurs late and may lead to glaucoma.

Metabolic complications: Diabetic feet. Neuropathy Amputation is preventable: good care saves legs feet regularly . Distinguish between ischaemia (eg critical toes) and peripheral neuropathy (injury/infection over pressure points, eg the metatarsal heads). Symptoms: Numbness, tingling, and burning, often worse at night .

Signs: Sensation ↓ (especially vibration) in ‘stocking’ distribution; absent ankle jerks; deformity (pea cavus, claw toes, loss of transverse arch, rocker-bottom sole). Neuropathy is patchy, so examine all areas. If the foot pulses cannot be felt, consider Doppler pressure measurement. Any evidence of neuropathy or vascular disease puts the patient at high risk of foot ulceration. Educate (daily foot inspection, comfortable shoes—ie very soft leather, increased depth, cushioning insoles, weight- distributing cradles, extra cushioning - no barefoot walking, no corn- plasters). Regular chiropody. Treat fungal infections .

Foot ulceration: Usually painless, punched-out ulcer in an area of thick callous ± superadded infection, pus, oederna, erythema, crepitus, odour. Assess degree of: 1- Neuropathy (clinical). 2- lschiaemia (clinical and Doppler’s; consider angiography - even elderly patients may benefit from angioplasty). 3- Bony deformity, eg Charcot joint (clinical, x-ray). 4- Infection (do swabs, blood culture, x-ray: probe ulcer to assess depth).

Management: Regular chiropody to debride lesions (remove dead tissue). Relieve high-pressure areas with bed rest ± therapeutic shoes (Pressure Relief Walkers and similar shoes may be as good as total contact casts); metatarsal head surgery may be needed. ischemia, shoes must be wide- fitting with deep toe boxes to protect vulnerable forefoot margins and toes. If there is cellulitis, admission is mandatory for iv antibiotics: start with benzyipenicillin 600 mg/6h iv and flucloxacillin 500 mg/6h iv ± metrondazole 500mg/8h iv, refined when microbiology results are known. Get surgical help early: normoglycaemia helps.

Absolute indications for surgery • Abscess or deep infection • Spreading anaerobic infection • Severe ischaemia –gangrene/rest pan • Suppurative arthritis The degree of peripheral vascular disease, patient’s general health, and patient request will determine whether local excision and drainage, vascular reconstruction, and/or amputation (and how much) is appropriate.

Types of neuropathy in diabetes Motor and sensory neuropathy I- Symmetric sensory polyneuropathy – distal numbness, tingling, and visceral pain, e.g. worse at night Consider aspirin, paracetamol, or a tricyclic drug (± a low-dose phenorthiazine or caroamazepine,) Capsaicin cream can relieve pain: it acts as a counter-irritant. 2- Mononeuritis multiplex - especially III and VI cranial nerves. 3- Amyotrophy - painful wasting of quadriceps; reversible.

Autonomic neuropathy: Postural BP ↓ urine retention; impotence; diarrhoea s: night. The latter may respond to 3 doses of tetracycline 250mg P0 or long-term codeine phosphate (the lowest dose which controls symptoms. e.g. l5 mg/8h po). Vomiting associated with gastraparesis may respond to anticmetica. Postural hypotension may respond to fludrocortisone 0.lmg - 0.3mg/24h P0 (SE aedema), Consider hydrochloride 30 - 6Omg/8h P0 for neuropathic oedema.

Diabetic patients with intercurrent illness: The stress of illness often increases basal insulin requirement If calorie Intake ↓ (if voniting) then increase long-acting insulin (by -‘-20%); reducing short-acting in proportion to meal size. Check blood sugar often. I- Insulin-treated; mild illness (eg gastroenteritis). Maintain calorie Intake with oral fluids (lemonade etc.). Continue normal insulin. Test blood glucose and urine ketones regularly (eg twice daily). Increase insulin if blood glucose consistently >l0mmol/L

2- Insulin-treated; moderate illness (eg pneumonia). Normal insulin and supplementary sliding scale of rapid-acting. insulin four times daily (before meats and bedtime snack); 3- Insulin-treated; severe illness (eg Ml, severe trauma). IV soluble insulin by pump and iv dextrose . 4- Diet arid tablet treated moderate/severe illness If on metformin, stop. If on sulfonytureas and illness likely to be self-limiting. keep on tablets, supplement with SC insulin, and sliding scale or iv infusion . Tail off insulin as patient recovers.

Hypoglycaemia : This is the commonest endocrine emergency. Prompt diagnosis and treatment is essential. Definition: Plasma glucose <2.5mmol/L Threshold for symptoms varies. Symptoms Autonomic—Sweating; hunger, tremor, Neuroglycopenic - Drowsine personality change; fits; rarely focal symptoms, eg transient hemiplegia, loss of consciousness, Two types:

Fasting hypoglycaemia : (requires full investigation if documented). Causes: By far the commonest cause is insulin or sulfonylurea treatment in a known diabetic in the non-diabetic subject with fasting hypoglycaemia the following mnemonic is useful: EXPLAIN. Exogenous drugs, eg insulin or oral hypoglycaemics . Does he have access to these? Is there a diabetic in the family? Alcohol, eg alcoholic on a binge with no food. Also: aminoglutethimide; 4- quinolones; pen tomidine: quinine sulfate, Pituitary insufficiency.

Liver failure plus some rare inherited enzyme defects. Addison’s disease. Islet cell tumours (insulinorna) and immune hypoglycaemia (eg anti- insulin receptor antibodies in Hodgkin’s disease). Non-pancreatic neoplasms (especially retropentoneal fibrosarcomas and haemangiopericytomas).

Diagnosis and investigations: I- Document hypoglycaemia by taking finger-prick (on filter-paper at home for later analysis) during attack, or lab glucose if in hospital. 2- Exclude liver failure and malaria. 3- Admit for 72h fast. Do glucose, insulin & C-peptide if symptomatic.

Interpretation of results 1- Hypogtycaemia with high or normal insulin and no elevated ketones. Causes: insulinoma; sulfonylurea administration; insulin administration (no detectable C-peptide); insulin autoantibodies. 2- Insulin low or undetectable, no excess ketones. Causes: Non-pancreatic neoplasm; anti-insulin receptor antibodies. 3- Insulin low or undetectable, ketones high. Causes: Alcohol: pituitary or adrenal failure.

NB if insulinonia suspected, confirm with a suppressive test: eg infuse iv insulin and measure C-peptide. Normally exogenous insulin suppresses C-peptide, but this suppression does not occur in patients with insulinomas. Localize the insulinoma using CT. If none is visible, sophisticated techniques (eg utra-operative pancreatic ultra sound) may be needed.

Post-prandial hypoglycaemia: This occurs particularly after gastric surgery, and in those with mild Type II Diabetes. Investigation: Prolonged OGTT.

Treatment : Treat with oral sugar, and a long-acting starch (eg toast); if coma, glucose 25 – 50g iv or glucagon 0.5-lmg SC (± a repeat after 20 mins; follow with carbohydrate). If episodes frequent, advise many- small meals high in starch, If post-prandial glucose ↓ . slowly absorbed carbohydrate (high fibre, complex carbohydrates). Insulinomas: surgical removal if possible: diazoxide and a thiazide diuretic.

Diabetes Mellitus

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Diabetes Mellitus