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 Mellitus

Hyperglycaemia (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

HyperventilationAcid urine

High filtrate pressure

Electrolyte 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.