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Endocrine Disorders 2: Diabetes CH0576: The Biology of Disease-Dr Richard N. Ranson 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 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 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 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) 2. Diabetes Insipidus- Neurogenic- Case Study 1: H20 reabsorption Posterior VP rcpt ADH Consequences: Polyuria (frequent urination) Polydipsia (frequent drinking) Hypernatremia (increased plasma Na2+ ) PVN Desmopressin 3. Diabetes InsipidusNeurogenic- Case Study 1: Synthetic vasopressin analog Molecular basis of water reabsorption: role of Vasopressin (ADH) receptors. Kidney Osmosis Apical membrane Silverthorn et al Aquaporins = water pores = membrane channels 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+) Nephrogenic Diabetes insipidus: Receptor dysfunction Golan et al Treatment: Collecting duct cell Restriction of fluid intake Administration of diuretic (not acting via V2 receptor) – natriuretic peptides Means no specific pharmacological intervention 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) Pancreas and regulation of glucose homeostasis- Quick Summary Marieb & Hoehn Insulin dependant Type I-Diabetes Mellitus: Children/young adults-sudden onset 90%- Immune mediated T-cell derived Autoantibodies 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 Regulate Diet Cumulative effects Akio_Takamori_Sleeping_Man Type 2 diabetes (Non-insulin dependent) 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 1-14% of all pregnancies Large babies, stillbirths, diabetes mellitus in later life 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 Carbohydrate meal ● Glucose-Glycogen for energy storage in liver/muscles reduced ● Deficiency of intracellular glucose stimulates gluconeogenesis from protein Type I 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 Diabetes Mellitus (Type I)-Weight loss Gluconeogenesis Amino acids Protein Increased Blood Glucose Tissue Wasting Tissue Breakdown Energy Weight Loss Body Fat catabolism Ketoacidosis Ketoacidosis Decreased Glucose metabolism Reduced Oxaloacetic acid Acetyl coenzyme A excess Converted to Ketones Blood pH falls Acidic Urine Excretion (Ketonuria) + Lungs Waugh & grant Hyperventilation Coma Acid urine High filtrate pressure Electrolyte loss Polyuria Acute complications of diabetes mellitus (untreated): Diabetic coma Decreased Insulin Ketoacidosis Increased Insulin resistance Dehydration and electrolyte imbalance Pancreatic damage Patient forgets! Stress e.g. Pregnancy, infection Type I – Insulin dependent Acute complications of Diabetes: Hypoglycaemic coma Hypoglycaemic coma – Consequence of excess insulin ● Diabetics monitor blood glucose levels ● Inject insulin up to 3 times per day ● Accidental overdose ● Low Carbohydrate – delay in eating post admin or due to vomiting, diarrhoea ● Increased metabolic rate – exercise ● Insulin secreting tumour Symptomology: Drowsiness Confusion Speech difficulty Anxiety Type I and II – Insulin dependent Disturbed Neural Function Long-term complications of Diabetes Mellitus: Cardiovascular Diabetic macroangiopathy Calcification Atheroma Myocardial infarction, Cerebral ischemia and infarction Long-term complications of Diabetes Mellitus: Cardiovascular Diabetic microangiopathy Peripheral Vascular disease Microaneurysms Small Haemorrhages Gangrene ● Thickening of Basement membrane Retinopathy ● Arterioles/capillaries Long-term complications of Diabetes Mellitus: Infection Decreased intracellular glucose ● Boils/Carbuncles ● Vaginal candidiasis ● Pyelonephritis – infection in nephrogenic kidney areas – atrophy and scarring Phagocyte depression Bacterial/fungal infections 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). 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.