CH0576: The Biology of Disease-Dr Richard N. Ranson
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Transcript of CH0576: The Biology of Disease-Dr Richard N. Ranson
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CH0576: The Biology of Disease-Dr Richard N. Ranson
Endocrine Disorders 2: Diabetes
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Diabetes History/ definitions:
100-200 AD Aretaeus (Greek physician) – Patients: excessive thirst and urination
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)
‘Diabetes’ – to siphon or pass through
2 types Neurogenic and Nephrogenic
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Diabetes InsipidusPrevalence: ‘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
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Congenital – AVP-Neurophysin Gene mutations e.g. Brattleboro rat
In Humans Familial Neurogenic Diabetes Insipidus (mutation of vasopressin gene)- very rare
● 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
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1.Diabetes Insipidus- Neurogenic- Case Study 1:
From J. A. Loh and J. G. Verbalis (2007) Nature Clinical Practice (Endocrinology & Metabolism. 3(6) 489-494)
28 year old woman with pituitary tumour
Preoperative Postoperative
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2. Diabetes Insipidus- Neurogenic- Case Study 1:
Posterior
ADH
H20 reabsorption
Consequences: Polyuria (frequent urination) Polydipsia (frequent drinking)
Hypernatremia (increased plasma Na2+ )
VP rcpt
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3. Diabetes Insipidus- Neurogenic- Case Study 1:
Desmopressin
Synthetic vasopressin analog
PVN
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Molecular basis of water reabsorption: role of Vasopressin (ADH) receptors.
Aquaporins = water pores = membrane channels
Apical membrane
Osmosis
Kidney
Silverthorn et al
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Nephrogenic Diabetes insipidus:
Inadequate response to ADH at Kidney level
CongenitalX- linked recessive: AVP V2 receptor gene mutationsAutosomal recessive: Aquaporin-2 water channel gene mutations
Drug induced (reversible)Lithium carbonate (anti-psychotic)Methoxyflurane (anaesthetic)
Lesions
Hypercalcemia (increased blood levels of Ca2+)
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Golan et al
Nephrogenic Diabetes insipidus: Receptor dysfunction
Collecting duct cell
Means no specific pharmacological intervention
Treatment:
Restriction of fluid intake
Administration of diuretic (not acting via V2
receptor) – natriuretic peptides
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Diabetes mellitus(raised blood glucose)
● 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)
The stats:
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Pancreas and regulation of glucose homeostasis- Quick
Summary
Marieb & Hoehn
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Type I-Diabetes Mellitus:
Destruction of b- islet cells-marked decrease in Insulin levels
Children/young adults-sudden onset
90%- Immune mediated
10-13 % Parent or sibling-Genetic
T-cell derived Auto-antibodies islet
cells and/or insulin
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.
Insulin dependant
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Type 2 diabetes (Non-insulin dependent)
Akio_Takamori_Sleeping_Man
Cumulative effects
Regulate Diet
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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
1-14% of all pregnancies
● 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
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Effects of Diabetes MellitusHyperglycaemia (Raised blood glucose levels)
80-90% of function of insulin secreting b cells lost
Carbohydrate meal
● Cellular uptake/use of glucose defective
● Glucose-Glycogen for energy storage in liver/muscles reduced
● Deficiency of intracellular glucose stimulates gluconeogenesis from protein
Type I
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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
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Diabetes Mellitus (Type I)-Weight loss
Gluconeogenesis Amino acidsProtein
Tissue WastingTissue Breakdown
Increased Blood Glucose
Weight Loss
Body Fat catabolism
Energy
Ketoacidosis
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KetoacidosisDecreased Glucose metabolism
Reduced Oxaloacetic acid
Acetyl coenzyme A excess
Converted to Ketones
Acidic
Urine Excretion
(Ketonuria)+
Lungs
Blood pH falls
Waugh & grant
Hyperventilation Acid urineHigh filtrate
pressureElectrolyte loss
PolyuriaComa
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Acute complications of diabetes mellitus (untreated): Diabetic coma
Type I – Insulin dependent
KetoacidosisDecreased Insulin
Increased Insulin
resistance
Stress e.g. Pregnancy,
infection
Pancreatic damagePatient forgets!
Dehydration and electrolyte imbalance
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Acute complications of Diabetes: Hypoglycaemic coma
Type I and II – Insulin dependent
● Diabetics monitor blood glucose levels
● Inject insulin
up to 3 times per day
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
Symptomology:DrowsinessConfusionSpeech difficultyAnxiety
Disturbed Neural Function
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Long-term complications of Diabetes Mellitus: Cardiovascular
Diabetic macroangiopathy
Atheroma
Calcification
Myocardial infarction, Cerebral ischemia and infarction
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Long-term complications of Diabetes Mellitus: Cardiovascular
Diabetic microangiopathy
● Thickening of Basement membrane
● Arterioles/capillaries
Peripheral Vascular disease
Gangrene
Microaneurysms
Small Haemorrhages
Retinopathy
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Long-term complications of Diabetes Mellitus: Infection
Decreased intracellular glucose
Phagocyte depression
Bacterial/fungal infections● Boils/Carbuncles
● Vaginal candidiasis
● Pyelonephritis – infection in nephrogenic kidney areas – atrophy and scarring
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Long-term complications of Diabetes Mellitus: Renal failure
Glomerulosclerosis (scarred tissue) impairs filtration- tubule atrophy
Nephrotic syndrome
Death in 10 % of all diabetics
50% in insulin dependent (type 1).
Albumin loss
Waugh & Grant
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ReferencesBracewell 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.