Diabetes

Back to medical school: beginners guide to type 1 DM SG Gilbey 24/5/07 1) What is type 1 diabetes mellitus? 2) How does it present? What are its consequences? 1. general health: staying alive 2. diabetic complications 3. special situations eg adolescence, pregnancy 4. Living: work, driving, travel 3) How is it treated? Kinds and choice of insulin Different methods of administration Aims of treatment Complications of treatment: eg hypoglycaemia 4) Practical skills of diabetes management Hypers and hypos Dose adjustment Recognizing disaster: when to admit/refer Patient advice eg travel, driving, pregnancy The Pancreatic beta cells Make insulin in response to food intake and rising glucose levels. The purpose of insulin is to instantaneously store energy in the liver, muscle, fat As a consequence 1) glucose levels are remarkably stable 2) we do not starve between meals Glucose & insulin fluctuations compared 800 700 Glucose (mg/dl) 600 500 400 300 200 100 0 4 160 140 800 120 700 NORMAL OBESE 0800 8 1200 12 1600 16 2000 20 2400 24 0400 28 Clock time (hours) Glucose (mg/dl) Insulin ( U/ml) NORMAL 600 100 500 80 400 60 300 40 200 20 100 OBESE NORMAL OBESE 0 4 0800 8 8 1200 1200 12 12 1600 1600 16 16 2000 2000 20 20 2400 2400 24 24 0400 0400 28 28 Clock time (hours) Type 1 Diabetes The beta cell is destroyed by lymphocytes as part of an autoimmune phenomenon Glucose levels rise but the body thinks it is starving – glucose is released from its stores, high blood glucose levels cause overflow into the urine Thinking it is starving: the body switches on ketone metabolism giving rise to high levels of ketone bodies acidosis, and metabolic instability Islet cell: lymphocytic infiltration What do patients present with? Thirst Polyuria Weight loss Susceptibility to infection Visual disturbance Typically below 25 years: may be any age May present over a period of weeks or months Making the diagnosis: Clinical history Family history Hyperglycaemia Ketonuria Recheck if not certain Other tests autoantibodies: GAD, Islet Cell Can we get the diagnosis wrong? 1. Missing the diagnosis 2. Misdiagnosing type 1 diabetes as type 2 diabetes (LADA) 3. Misdiagnosing type 2 DM as type 1 DM – not such a worry 4. Take a family history: rare cases of MODY – strong FH and may present very young (eg under 6 months) 5. Underlying pancreatic disease (eg CF, cancer, pancreatitis: usually obvious) Diseases associated with type 1 DM Thyroid disease Addison‘s disease Coeliac disease Implications: 1) may complicate clinical picture and management 2) is it worth screening diabetic patients regularly? Progressive shortfall of insulin Normal insulin Balanced metabolism Insulin supply  Moderately reduced Raised glucose Severely reduced Protein (muscle) breakdown Absent Breakdown of fats Ketosis Insulin fatty acids Fat stores Liver Energy Adrenaline/ noradrenaline Ketosis fatty acids Fat stores Liver Energy Ketone bodies = acids Excreted via kidneys Buffer by overbreathing Why do patients get Type 1 diabetes? Inherited predisposition to immune damage (HLA DR3) ―Two hit hypothesis‖ (viz risk in identical twins) Increasing prevalence ?why (but numerically swamped by type 2 diabetes) North-South divide: now closing Which age groups are affected? Two peaks: a) infancy (1-4y) b) early adolescence (8-12y) May present at any time in life (if ~ type 2: LADA) Problems with differential diagnosis Age 0 20 40 60 80 years Type 1 Type 1 BMI 15 20 25 Type 2 Type 2 30 35 kg.m-2 Differentiation Profound insulin deficiency (keto-acidosis) Type 1 autoimmunity: islet cell antibodies anti-GAD antibodies (Family history) (‘Metabolic syndrome’) Incidence of diabetes rapidly increasing Diabetes prevalence (thousands)  3000 2500 Type 1 Type 2 2000 1500 1000 500 0 1995 2000 2010 Amos AF et al. Diabet Med 1997;14(Suppl 5);S1–S85 Life for a type 1 diabetic Condition for life Condition affecting – every day – every meal – every physical activity – every social relationship – Parent-child relationship Life for a type 1 diabetic Burden of ‗control‘: loss of autonomy Threat of hypoglycaemia Threat of early death, blindness, gangrene & amputation, kidney failure Jobs, driving, life insurance, marriage Risk of type 1 diabetes in offspring (what is it?) Aims of treatment 1) Stay alive and well 2) Maintain quality of life 3) Avoid complications Microvascular Macrovascular 4) Avoid premature death: diabetics diagnosed between 25 and 35 years lose 15 years of life expectancy Capillary damage Microaneurysms Hard exudates Haemorrhages Neuropathic heel ulcer DiabeticIschaemic ulcer and gangrene feet Toe deformity and ulcer Charcot foot + ‘rocker’ ulcer Maintaining good blood glucose control DCCT (Type 1 diabetes) – intensive therapy delayed the onset and slowed the progression of microvascular disease by 35–70% compared with conventional therapy Threshold for retinopathy FPG 7.0 mmol/l 2hPG 11.1 mmol/l Prevalence of retinopathy in a population survey by deciles of glycaemia Glucose molecules HbA1c value Not diagnostic Any Diabetes Related Endpoint 5 p<0.0001 Hazard ratio 1 12% decrease per 10 mm Hg decrement in BP 0.5 110 120 130 140 150 160 170 Updated mean systolic blood pressure UKPDS 36. BMJ 2000; 321: 412-19 Any diabetes endpoint Risk factors and complications Macrovascular disease Microvascular disease Ischaemic heart disease Eyes Feet Strokes Kidneys Peripheral vascular Nerves disease Hyperglycaemia Hypertension Coagulopathy Dyslipidaemia Smoking Treatment Insulin: the perfect treatment for blood glucose in diabetes Are there any alternatives? immunosuppression pancreas or islet cell transplantation Patients will do anything to avoid insulin The aim of treatment Stay alive Avoid hypos Maintain day to day living Achieve optimal control – a glucose as near to normal as possible for most of the time BLOOD GLUCOSE MONITORING IS ESSENTIAL (how often?) Choices of insulin Fast acting: cover a meal Intermediate: 6-12 hours Long acting: up to 24 hours Beef—Pork—Human—Analogue 24-hour plasma glucose and insulin profiles in healthy individuals 1.10 ©Elsevier Science. Reproduced with permission from Elsevier Science (The Lancet, 2001, Vol 358, pages 739–746). Owens DR et al. Lancet 2001;358:739–746 Analogue Insulins: Short acting: Novorapid, Humalog, Glulisine Pre-mixed (30/70): Mix 25, Novomix 30 Very long acting: Glargine, Levemir Very few differences between insulins, some differences between insulin delivery systems (pens) Short-acting Insulin • • • • • Soluble Clear Onset Peak 30 minutes 1 - 3 hours Time Action Duration of action up to 8 hours Note: The graphical representation above is for educational and illustrative purposes only Slide no 9 • MEDINFO/AIRE/182 Date of Preparation November 2004 • Rapid-acting Analogues • Soluble Action • Clear • Onset 10 - 20 minutes • Peak 1 - 3 hours Time • Duration of action up to 5 hours Note: The graphical representation above is for educational and illustrative purposes only Slide no 15 • MEDINFO/AIRE/182 Date of Preparation November 2004 • Lispro insulin (Humalog) Intermediate-acting Insulin • • • • • • Crystals in suspension (need to re-suspend prior to injection) Cloudy NPH or Isophane (NPH = Neutral Protamine Hagedorn) Onset 1 1/2 hours Peak 4 - 12 hours Duration of action up to 24 hours Action Time Note: The graphical representation above is for educational and illustrative purposes only Slide no 10 • MEDINFO/AIRE/182 Date of Preparation November 2004 • Long-acting Analogues • • • • • Clear - no need for re-suspension Delayed and prolonged absorption from injection site Flatter profile than NPH (peak reduced) Longer duration of action than NPH Duration of action up to 24hrs depending on dose Action Time Note: The graphical representation above is for educational and illustrative purposes only Slide no 17 • MEDINFO/AIRE/182 Date of Preparation November 2004 • Primary structure of insulin glargine A-chain A21[Gly] COOH COOH S S S S S NH2 B-chain NH2 S B31[Arg] B32[Arg] Premixed Analogue Combinations • Premixed combinations of short and intermediate acting • • • • • analogues Cloudy (needs re-suspending) 3 different combinations (25, 30, 50) Onset 10-20 minutes Peak 1-4 hours Durations of action up to 24 hours Action Time Note: The graphical representation above is for educational and illustrative purposes only Slide no 16 • MEDINFO/AIRE/182 Date of Preparation November 2004 • Ideal Basal/Bolus Insulin Absorption Pattern Breakfast Plasma insulin Lunch Dinner 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Novopen (rechargeable) Flexpen (disposable) Storage of Insulin • Before use • store in fridge (2-8oC) • store out of fridge to max 25oC • • In-use vials (analogues 30°C – check SPC) use within 4-6 weeks (depending on insulin) • In-use pens and cartridges • store out of fridge at max 30oC • use within 4-6 weeks (depending on insulin) • always check SPC for specific insulin Date of Preparation November 2004 • Slide no 29 • MEDINFO/AIRE/182 Insulin regime choices Once a day (eg Glargine): rarely the choice for type 1 DM Twice daily premixed: surprisingly popular (why?) Basal-bolus: the best for flexibility, intensive control – but more injections, more monitoring A simple regime for blood glucose monitoring and dose adjustment Once a day (eg Glargine): measure fasting BG and adjust glargine to keep below 7 mmol/L A simple regime for blood glucose monitoring and dose adjustment Twice a day pre-mix: adjust evening dose to achieve pre-breakfast below 7 mmol/L, and moring dose to achieve pre-evening meal below 7 mmol/L A simple regime for blood glucose monitoring and dose adjustment Basal-bolus: adjust glargine to achieve pre-breakfast below 7 mmol/L, pre-meal analogue to achieve less than 10 mmol/L one hour after meal A simple regime for blood glucose monitoring and dose adjustment If the patient is having hypos: work out when they are. Is it the insulin dose or regime, food intake, or exercise? Do they need a regular snack? Do they need a different regime? Are they being reliable? HBA1c: Quality control Carbohydrate counting Freedom to eat what you like Training in calculating carbohydrate content of meals Adjust bolus insulin dose according to anticipated (eg 2 units per 10grams CHO) Significant learning curve for patient Technological advances Insulin pumps: 24 hr adjustable basal infusion Mealtime bolus doses Continuous glucose monitors 400 300 250 200 Type 1 150 100 Normal 50 Meal Meal 0 Midnight Noon Meal Midnight Meal Meal Noon Meal Midnight 2-day tracing CSII - HbA1c 10.0 9.5 .09 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 Pre-pump Post-pump HbA1c Bell Rudolph Chanteleau Bode Boland Chase n = 58 n = 107 n = 116 n = 50 n = 25 n = 56 Mean dur. = 36Mean dur. = 36 Mean dur. = 54 Mean dur. = 42 Mean dur. = 12 Mean dur. = 12 Adults Adolescents Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327; Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Bell DSH, et al. Endocrine Practice. 2000;6:357– 360; Chase HP, et al. Pediatrics. 2001;107:351–356. Better nocturnal control 6 5 4 3 2 1 0 MIT CSII MIT CSII CSII Reduces Hypoglycemia 160 140 120 100 80 60 Pre-pump Post-pump 40 20 0 Bode n = 55 Mean age 42 Rudolph n = 107 Mean age 36 Chanteleau n = 116 Mean age 29 Boland Chase n = 25 Mean age 14 n = 56 Mean age 17 Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327; Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Chase HP, et al. Pediatrics. 2001;107:351–356. For a patient to be given a pump They must fulfill NICE criteria Committed Able to engage with diabetes team and learn to carbohydrate count At significant risk of hypoglycaemia on conventional regimes Expensive: PCT authorises CGMS 1.13 ―Closed loop‖ systems Will enable the simultaneous measurement of glucose and administration of insulin: no need for any calculations Side effects of insulin HYPOGLYCAEMIA – glucose less than 2.8 mmol/L Insulin allergy Injection site problems lipohypertrophy, lipoatrophy Allergic reactions Needle phobia Causes of hypoglycaemia Inappropriate dosage/poor technique Inappropriate eating Exercise Alcohol Changes in insulin requirement: Weight changes, occupation, life style, pregnancy, breast feeding etc… 3.4 Symptoms of hypoglycaemia Autonomic •Increased heart rate •Sweating Neuroglycopaenic •Impaired intellectual activity •Impaired cognitive function •Increased systolic blood pressure •Tremor •Palpitations •Diminished psychomotor skills •Loss of coordination •Sensation of drowsiness •Coma/fits Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23 Outcomes of hypoglycaemia by blood glucose concentration in healthy individuals 3.5 ©Blackwell Science. Adapted with permission from Blackwell Science (Textbook of Diabetes [2nd edition], 1997, Vol 1, pages 40.1–40.23). Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23 3.6 Hypoglycaemia unawareness Associated with: – tighter glycaemic control – long duration of diabetes Carries 5–6-fold increase in frequency of severe hypoglycaemia More frequent in pregnancy If permanent: disqualifies from holding a driving licence Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23 3.7 Nocturnal hypoglycaemia Occurs after bedtime administration of insulin and prior to waking Prevalence difficult to ascertain Type 1 diabetes (DCCT): ~50% of severe episodes were nocturnal May persist for several hours without waking the patient, increasing the likelihood of coma Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23 DCCT. Am J Med 1991;90:450–459 Alternative delivery Rectal Nasal Inhaled: Exubera – On the market now – NICE say: for needle phobics only Dose Adjustment for Normal Eating DAFNE  Modified 5 day training course  Patients learn to count carbohydrates  Adjust insulin accordingly  Results: no change in weight, lipids, hypoglycaemia   Improvement in HBA1c, QOL Dafne Process of carbohydrate counting Starchy Foods – – – – – – – Bread Potatoes Pasta Rice Cereals Noodles Pulses Process of Carbohydrate Counting Sugar Foods - Sugary Foods e.g chocolate sweets, biscuits, honey - Fruit Sugar (Fructose) - Milk Sugar (Lactose) Process of Carbohydrate Counting  Do Not Count –Protein Meat, Eggs,Fish - Fat Oils, Spreads *Remember processed foods Process of Carbohydrate Counting up total carbohydrate from a meal  Divide total by 10  Multiply answer by ratio required * Ratio is decided based on diet history taken, carbohydrates consumed, insulin given and post prandial blood sugars  Add Process of Carbohydrate Counting  Lunch – 2 slices wholemeal bread = 30g – Packet of crisps = 15g – Total 45g – 1 unit per 10g = 4.5 units of insulin      Main meal 4 Roast Potatoes = 40g Small Yorkshire pudding = 10 Total = 50 1 unit per 10g = 5 units of insulin Process of Carbohydrate Counting  Factors to be considered – Activity – GI of foods – Weight – Nutritional adequacy of diet – Management of hypoglycaemia – Correction doses of insulin – Illness Management Gestational Diabetes (1995) advocate 40 % energy intake from carbohydrate  British advice suggests 45 - 60% in the form of low GI foods (Dornhorst & Frost, 2002)  May impose slight calorie restriction to limit weight gain  As focus is reducing post prandial glycaemia will also look at portion sizes of carbohydrate glycaemic  ADA Special situations Pregnancy including pre-conception Adolescents/Students Very young and very old Diabetes and pregnancy in England and Wales 2005 Increased  Babies England, Wales and N Ireland Stillbirths 4.7x risks for babies of women with diabetes of women with diabetes in continue to have an increased risk of Death of baby in first four weeks 2.6x perinatal mortality and congenital Major congenital anomaly 2x anomaly http://news.bbc.co.uk The End