Transcript Diabetes Mellitus

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.