Back to medical school: beginners guide to type 1 DM SG Gilbey 24/5/07 1) What is type 1 diabetes mellitus?

1. Back to medical school: beginners guide to type 1 DM SG Gilbey 24/5/07 1) What is type 1 diabetes mellitus?

2. 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. 3) How is it treated? Kinds and choice of insulin Different methods of administration Aims of treatment Complications of treatment: eg hypoglycaemia

4. 4) Practical skills of diabetes management Hypers and hypos Dose adjustment Recognizing disaster: when to admit/refer Patient advice eg travel, driving, pregnancy

6. 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

8. Glucose & insulin fluctuations compared

9. 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

10. Islet cell: lymphocytic infiltration

11. 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

12. Making the diagnosis: Clinical history Family history Hyperglycaemia Ketonuria Recheck if not certain Other tests autoantibodies: GAD, Islet Cell

13. 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)

14. 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?

15. Balanced metabolism Moderately reduced Raised glucose Severely reduced Protein (muscle) breakdown Absent Breakdown of fats Progressive shortfall of insulin Normal insulin Insulin supply 

16. Liver Ketosis Insulin Fat stores fatty acids Energy

17. Liver Ketone bodies = acids Excreted via kidneys Buffer by overbreathing Ketosis Adrenaline/noradrenaline Fat stores fatty acids Energy

18. 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

19. 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)

20. Problems with differential diagnosis 15 0 20 20 40 25 60 30 35 80 years kg.m-2 Type 1 Type 2 Type 1 Type 2 Age BMI • Differentiation • Profound insulin deficiency (keto-acidosis) • Type 1 autoimmunity: islet cell antibodies • anti-GAD antibodies • (Family history) • (‘Metabolic syndrome’)

21. Type 1 Type 2 Incidence of diabetes rapidly increasing 3000 2500 2000 Diabetes prevalence (thousands) 1500 1000 500 0 2010 2000 1995 Amos AF et al. Diabet Med 1997;14(Suppl 5);S1–S85

22. Life for a type 1 diabetic Condition for life Condition affecting • every day • every meal • every physical activity • every social relationship • Parent-child relationship

23. 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?)

24. Aims of treatment • Stay alive and well • Maintain quality of life • Avoid complications • Microvascular • Macrovascular • 4) Avoid premature death: diabetics diagnosed between 25 and 35 years lose 15 years of life expectancy

25. Hard exudates Capillary damage Microaneurysms

26. Haemorrhages

31. Diabetic feet Neuropathic heel ulcer Ischaemic ulcer and gangrene Toe deformity and ulcer Charcot foot + ‘rocker’ ulcer

33. 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

34. FPG 7.0 mmol/l 2hPG 11.1 mmol/l Prevalence of retinopathy in a population survey by deciles of glycaemia Threshold for retinopathy

35. Glucose molecules HbA1c value Not diagnostic

36. 5 p<0.0001 Hazard ratio 1 12% decrease per 10 mm Hg decrement in BP 0 . 5 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 Updated mean systolic blood pressure UKPDS 36. BMJ 2000; 321: 412-19 Any Diabetes Related Endpoint

37. Any diabetes endpoint

38. Hypertension Hyperglycaemia Coagulopathy Dyslipidaemia Smoking Risk factors and complications Macrovascular disease Ischaemic heart disease Strokes Peripheral vascular disease Microvascular disease Eyes Kidneys Nerves Feet

39. 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

40. 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?)

41. Choices of insulin Fast acting: cover a meal Intermediate: 6-12 hours Long acting: up to 24 hours Beef—Pork—Human—Analogue

42. 1.10 24-hour plasma glucose and insulin profiles in healthy individuals ©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

43. 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)

46. Lispro insulin (Humalog)

49. COOH A-chain A21[Gly] NH2 COOH S B31[Arg] B32[Arg] S B-chain S NH2 S S S Primary structure of insulin glargine