1. Pharmacology of Diabetes Mellitus 1 Dr Emma Baker Consultant Physician/Senior Lecturer in Clinical Pharmacology

2. Sometime in the 19th century… 14 year old boy, obvious weight loss Passing increased amounts of urine, getting up 4 times at night to empty bladder. Urine sticky and sweet Very thirsty, drinking litres of water per day Questions What is the diagnosis? What is going to happen to this boy and why?

3. Insulin - physiology revisited Pancreas Glucose Insulin BrainHeart Liver Adipose Muscle Glucose: Utilised Stored as glycogen, fat Protein: Increased synthesis, decreased catabolism GUT Insulin receptors

4. No Insulin Pancreas 1. Glucose  BrainHeartLiverAdipose Muscle GUT  Lipase 2. Fatty acids  Used as energy 3.  Acetoacetic acid  Cholesterol  Triglycerides

5. No Insulin Increased plasma and urinary glucose Glucose in urine has osmotic effect diuresis dehydration circulatory collapse Increased acetoacetic acid, acidosis myocardial and cerebral dysfunction venoconstriction, arterial vasodilation Untreated leads to certain death

6. Insulin 11th January 1922 - pancreatic islet cell extract first administered to 14 year old insulin deficient patient Bovine and porcine pancreatic extracts 1980 human insulin available –amino acid modification of porcine insulin –synthesised by introducing DNA for human insulin into bacteria or yeast

7. Sometime in the late 20th century… 17 year old girl, obvious weight loss Passing increased amounts of urine, getting up 4 times at night to empty bladder. Very thirsty, drinking litres of water per day Urinalysis glucose ++++, ketones ++++ Questions What is the diagnosis? How should this girl be treated? What health problems do you anticipate and how could these be prevented?

8. Diagnosis Diagnosis - ketoacidosis secondary to type 1 diabetes Treatment - insulin replacement

9. Insulin replacement Pancreas 1. Glucose  BrainHeartLiverAdipose Muscle GUT  Lipase 2. Fatty acids  Used as energy 3.  Acetoacetic acid  Cholesterol  Triglycerides Insulin

10. Insulin prevents death from ketoacidosis But does it restore normal life expectancy???

11. Type 1 diabetes with insulin replacement Insulin Carbohydrate metabolism Prevents dehydration and collapse from hyperglycaemia BUT Does not restore normal glycaemia Thickening of basement membrane Microvascular disease Lipid metabolism Prevents ketoacidosis BUT Increased plasma cholesterol and triglycerides Other mechanisms Macrovascular disease

12. Diabetes Control and Complications Trial 1441 people with type 1 diabetes mellitus Randomised into conventional and intensive therapy Trial duration 6.5 years Intensive group achieved HBA1C 2.0% lower than conventional group

13. People receiving intensive therapy were less likely to have: Microvascular disease: –Retinopathy development OR 0.22, NNT 6 progression OR 0.39, NNT 5 –Nephropathy OR 0.5, NNT 7 –Neuropathy OR 0.36, NNT 13 Macrovascular disease –reduction from 0.8 to 0.5 per 100 patient years

14. What problems might be experienced by patients on an intensive insulin regime?

15. Intensive insulin regime Requires frequent injections May be difficult with normal life style Increases risks of hypoglycaemia Other complications?

16. Sometime in the 21st century... 53 year old Asian woman living in the UK BMI 38Kg/m 2, but recent weight loss Tired, mild thirst, new nocturia x 2 Known hypertension, hypercholesterolaemia Questions What is the likely cause of her new symptoms? What is going to happen to this woman and why?

17. Type 2 diabetes mellitus Pancreas  Plasma glucose  Insulin BrainHeart Liver Adipose Muscle GUT Some  - cell loss  Insulin receptors  Cholesterol  Triglycerides

18. Complications Hyperosmolar, non-ketotic coma Macrovascular disease –stroke  2x –MI  3-5x –Amputation of foot for gangrene  50x Microvascular disease

19. How could type 2 diabetes be treated?

20. Type 2 diabetes mellitus Pancreas  Plasma glucose  Insulin BrainHeart Liver Adipose Muscle GUT Some  - cell loss  Insulin receptors  Cholesterol  Triglycerides

21. Treatment of type 2 diabetes mellitus Pancreas  Plasma glucose  Insulin BrainHeart Liver Adipose GUT Some  - cell loss C.  Insulin resistance Weight reduction Biguanides Glitazones Muscle  Cholesterol  Triglycerides B. Sulphonyl ureas Statins Fibrates D. Acarbose A. Insulin

22. UK Prospective Diabetes Study 3876 people with type 2 diabetes mellitus Randomised controlled trial examining the effects of intensive v conventional glucose control Also looked at the effects of controlling other cardiovascular risk factors Study duration 10 years

23. Intensive blood sugar control: Reduced microvascular complications –retinopathy OR 0.66, NNT 10 –neuropathy OR 0.42, NNT 5 Did not significantly reduce macrovascular complications Control of other cardiovascular risk factors also crucial in reducing morbidity and mortality

24. Last week... 48 year old woman with chronic asthma Complained of tiredness, thirst, weight loss, polyuria Urinalysis - glucose ++, Plasma glucose 14mmol/l Medications: –salbutamol, salmeterol, becloforte inhalers –prednisolone 10mg daily for 6 months Question What is the diagnosis? Why has this occurred?

25. Glucocorticoid-induced diabetes mellitus Pancreas  Glucose Insulin BrainHeart Liver GUT Adipose Muscle Gluco corticoids Fatty acids Amino acids  Gluco neogenesis

26. Drugs which cause an increase in plasma glucose Glucocorticoids Thiazide diuretics Loop diuretics Oral contraceptive pill Diazoxide

27. Summary Insulin deficiencyInsulin resistance Type 1Type 2 Insulin Sulphonylureas Metformin Glitazones Pathology Treatment Acute complications Ketoacidosis HONC

28. Drugs used to treat diabetes mellitus Gut Food Absorption Glucose Insulin Pancreas Insulin stored in  -islet cells Liver Reduced gluconeogenesis Glycogenesis Reduced lipolysis Receptor (tyrosine kinase) Complex internalised Muscle/fat cell Stimulates glucose uptake Adipose cell Insulin receptor Peroxisome proliferator- activated receptor Insulin Sulphonyl ureas Metformin Acarbose Glitazones