CH0576: The Biology of Disease-Dr Richard N. Ranson

1. Endocrine Disorders 2: Diabetes CH0576: The Biology of Disease-Dr Richard N. Ranson

2. Diabetes History/ definitions: 100-200 AD Aretaeus (Greek physician) – Patients: excessive thirst and urination ‘Diabetes’ – to siphon or pass through Thomas Willis (1621-1675) in Practice of physick, London, 1684 : penned the term ‘mellitus’ (Latin for honeyed or sweet) Diabetes Mellitus – raised levels of blood and urinary glucose (pancreatic) ● Distinct from Diabetes Insipidus ● ‘insipidus’ – Latin word for tasteless ● Consequence of changes in levels of/sensitivity to ADH (pituitary) 2 types Neurogenic and Nephrogenic

3. Diabetes Insipidus Prevalence: ‘Rare’ – Difficult to Quantify- Varied aetiology Neurogenic (Central) Congenital ● Malformation ● AVP-neurophysin gene mutations Drug/toxin e.g. ethanol Neoplastic e.g. meningioma, pituitary tumour Infectious e.g. Meningitus, encephalitus Trauma(surgery, deceleration injury) Vascular ● Cerebral hemorrhage ● Infarction

4. Congenital – AVP-Neurophysin Gene mutations e.g. Brattleboro rat ● Single base pair deletion in AVP (ADH) gene ● Synthesis of an altered VP precursor ● Unable to enter the secretory pathway (endoplasmic reticulum) ● No AVP secretory vesicles formed ● No circulating ADH ● Rat displays symptoms of DI NB. Transplantation of foetal neurons can reverse effects In Humans Familial Neurogenic Diabetes Insipidus (mutation of vasopressin gene)- very rare

5. 1.Diabetes Insipidus- Neurogenic- Case Study 1: 28 year old woman with pituitary tumour Preoperative Postoperative From J. A. Loh and J. G. Verbalis (2007) Nature Clinical Practice (Endocrinology & Metabolism. 3(6) 489-494)

6. 2. Diabetes Insipidus- Neurogenic- Case Study 1: H20 reabsorption Posterior VP rcpt ADH Consequences: Polyuria (frequent urination) Polydipsia (frequent drinking) Hypernatremia (increased plasma Na2+ )

7. PVN Desmopressin 3. Diabetes Insipidus- Neurogenic- Case Study 1: Synthetic vasopressin analog

8. Molecular basis of water reabsorption: role of Vasopressin (ADH) receptors. Kidney Osmosis Apical membrane Silverthorn et al Aquaporins = water pores = membrane channels

9. Nephrogenic Diabetes insipidus: Inadequate response to ADH at Kidney level Congenital X- linked recessive: AVP V2 receptor gene mutations Autosomal recessive: Aquaporin-2 water channel gene mutations Drug induced (reversible) Lithium carbonate (anti-psychotic) Methoxyflurane (anaesthetic) Lesions Hypercalcemia (increased blood levels of Ca2+)

10. Nephrogenic Diabetes insipidus: Receptor dysfunction Golan et al Treatment: Restriction of fluid intake Administration of diuretic (not acting via V2 receptor) – natriuretic peptides Collecting duct cell Means no specific pharmacological intervention

11. Diabetes mellitus (raised blood glucose) The stats: ● 1.3 M people in UK affected (Type I, 15% c.f. Type II, 85%) ● Incidence increasing in all age groups (Obesity link?) ● 1 in 5 people over 85 will develop symptoms ● Linked to ethnicity i.e. more likely in South Asian, African, Afro-Caribbean, Middle eastern ● Reduced Life expectancy 20 yrs (type I), 10 yrs (type II) ● Cost, £4.9 billion p.a. (9% of total NHS budget)

12. Pancreas and regulation of glucose homeostasis- Quick Summary Marieb & Hoehn

13. Insulin dependant Type I-Diabetes Mellitus: Children/young adults-sudden onset 90%- Immune mediated T-cell derived Auto-antibodies islet cells and/or insulin 10-13 % Parent or sibling-Genetic Initiates signalling responses resulting in apoptosis 10%- Environmental factors: - Viruses (Cytomegalavirus, mumps) Drugs /chemicals e.g. – Streptozotocin (antibiotic), Vacor (rat poison) Nutritional intake e.g. Cows Milk, Nitrosamines in beer and fish. Destruction of b- islet cells-marked decrease in Insulin levels

14. Akio_Takamori_Sleeping_Man Regulate Diet Cumulative effects Type 2 diabetes (Non-insulin dependent)

15. Other forms of Diabetes Mellitus: Secondary diabetes- ● Pancreatic disease (pancreatitis due to alcohol abuse) ● Drug or chemical induced Corticosteroids, Phenytoin (anti-seizure medication) Gestational Diabetes- (raised glucose, maternal, foetus) ● Glucose intolerance – 3rd trimester ● Placental hormones block effects maternal insulin (insulin resistance) ● 40-60% of women develop diabetes mellitus with 15 yrs post gestation Large babies, stillbirths, diabetes mellitus in later life 1-14% of all pregnancies

16. Effects of Diabetes Mellitus Hyperglycaemia (Raised blood glucose levels) 80-90% of function of insulin secreting b cells lost ● Cellular uptake/use of glucose defective ● Glucose-Glycogen for energy storage in liver/muscles reduced ● Deficiency of intracellular glucose stimulates gluconeogenesis from protein Carbohydrate meal Type I

17. Effects of Diabetes Mellitus :Glycosuria and polyuria (Type I and II) Glycosuria = excretion of glucose into the urine ●At normal plasma glucose concentrations all glucose entering kidney reabsorbed ●Achieves this via carrier proteins ●In DM glucose filtered faster than carriers can reabsorb – ‘honeyed urine’ Elevated Glucose (solute) in lumen (collecting duct, nephron) Decrease in water reabsorption Increased water exretion Large Urine volume (Polyuria) Osmotic Diuresis Hypovolaemia, extreme thirst and polydipsia

18. Diabetes Mellitus (Type I)-Weight loss Gluconeogenesis Amino acids Protein Tissue Wasting Tissue Breakdown Increased Blood Glucose Energy Weight Loss Body Fat catabolism Ketoacidosis

19. Ketoacidosis Decreased Glucose metabolism Reduced Oxaloacetic acid Acetyl coenzyme A excess Converted to Ketones Blood pH falls Acidic Acid urine High filtrate pressure Electrolyte loss Hyperventilation Urine Excretion (Ketonuria) + Lungs Coma Polyuria Waugh & grant

20. Acute complications of diabetes mellitus (untreated): Diabetic coma Increased Insulin resistance Decreased Insulin Ketoacidosis Dehydration and electrolyte imbalance Pancreatic damage Patient forgets! Stress e.g. Pregnancy, infection Type I – Insulin dependent

21. Acute complications of Diabetes: Hypoglycaemic coma Hypoglycaemic coma – Consequence of excess insulin ● Accidental overdose ● Low Carbohydrate – delay in eating post admin or due to vomiting, diarrhoea ● Increased metabolic rate – exercise ● Insulin secreting tumour ● Diabetics monitor blood glucose levels ● Inject insulin up to 3 times per day Symptomology: Drowsiness Confusion Speech difficulty Anxiety Disturbed Neural Function Type I and II – Insulin dependent

22. Long-term complications of Diabetes Mellitus: Cardiovascular Diabetic macroangiopathy Calcification Atheroma Myocardial infarction, Cerebral ischemia and infarction

23. Long-term complications of Diabetes Mellitus: Cardiovascular Diabetic microangiopathy Peripheral Vascular disease Microaneurysms Small Haemorrhages Gangrene ● Thickening of Basement membrane ● Arterioles/capillaries Retinopathy

24. Long-term complications of Diabetes Mellitus: Infection Decreased intracellular glucose Phagocyte depression ● Boils/Carbuncles ● Vaginal candidiasis ● Pyelonephritis – infection in nephrogenic kidney areas – atrophy and scarring Bacterial/fungal infections

25. Long-term complications of Diabetes Mellitus: Renal failure Glomerulosclerosis (scarred tissue) impairs filtration- tubule atrophy Nephrotic syndrome Waugh & Grant Albumin loss Death in 10 % of all diabetics 50% in insulin dependent (type 1).

26. References Bracewell et al (2005) Essential facts in geriatric medicine. Radcliffe Publishing Ltd, Oxford. Golan, D. E. et al (2008) Principles of Pharmacology, 2nd Edit, Wolters Kluwer. Hadley, M.C. & Levine J.E. (2007). Endocrinology. 6th Edit, Pearson International. Loh, J. A. & Verbalis J. G. (2007). Diabetes insipidus as a complication after pituitary surgery. Nature Clinical Practice, Endocrinology & Medicine, 3(6), 489-494. McCance, K. L. & Huether, S. E. (2006). Pathophysiology. (The Biologic Basis for Disease in Adults and Children). 5th Edit. Elsevier Mosby. Marieb, E. N. (2009) Essentials of Human Anatomy & Physiology. 9th Edit, Pearson International Purves, D et al (2008). Neuroscience. 4th Edit. Sinauer. Tortora G. J. & Derrickson B.(2006). Principles of Anatomy and Physiology. 11th Edit, Wiley. Unglaub Silverthorn D. et al (2007) Human Physiology (An integrated approach), 4th Edit, Pearson International. Waugh, A & Grant (2005). Anatomy & Physiology. 9th Edit, Elsevier.