ch0576: the biology of disease-dr richard n. ranson
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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. - PowerPoint PPT PresentationTRANSCRIPT
CH0576: The Biology of Disease-Dr Richard N. Ranson
Endocrine Disorders 2: Diabetes
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
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
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
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
2. Diabetes Insipidus- Neurogenic- Case Study 1:
Posterior
ADH
H20 reabsorption
Consequences: Polyuria (frequent urination) Polydipsia (frequent drinking)
Hypernatremia (increased plasma Na2+ )
VP rcpt
3. Diabetes Insipidus- Neurogenic- Case Study 1:
Desmopressin
Synthetic vasopressin analog
PVN
Molecular basis of water reabsorption: role of Vasopressin (ADH) receptors.
Aquaporins = water pores = membrane channels
Apical membrane
Osmosis
Kidney
Silverthorn et al
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+)
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
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:
Pancreas and regulation of glucose homeostasis- Quick
Summary
Marieb & Hoehn
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
Type 2 diabetes (Non-insulin dependent)
Akio_Takamori_Sleeping_Man
Cumulative effects
Regulate Diet
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
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
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 acidsProtein
Tissue WastingTissue Breakdown
Increased Blood Glucose
Weight Loss
Body Fat catabolism
Energy
Ketoacidosis
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
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
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
Long-term complications of Diabetes Mellitus: Cardiovascular
Diabetic macroangiopathy
Atheroma
Calcification
Myocardial infarction, Cerebral ischemia and infarction
Long-term complications of Diabetes Mellitus: Cardiovascular
Diabetic microangiopathy
● Thickening of Basement membrane
● Arterioles/capillaries
Peripheral Vascular disease
Gangrene
Microaneurysms
Small Haemorrhages
Retinopathy
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
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
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.