Diabetes Insipidus

Question 1

Describe the process of storage and release of vasopressin. Include the pathway of release and organ involvement

Answer 1

• Pre-pro-vasopressin is produced within the hypothalamus
• The signal peptide is cleaved and pro-vasopressin is transported to the endoplasmic reticulum
• The pro-hormone is transported via the hypothalamic-neurohypophyseal tract to be stored within the posterior pituitary gland
• During transport and storage, pro-vasopressin is cleaved into the constituent peptides:
  
  • ADH / vasopressin
  • Neurophysin 2 - necessary for correct cleavage and to prevent enzymatic degradation
  • Copeptin (Glycoprotein) - role unknown

Question 2

Note the factors that cause stimulation of vasopressin release.

What provides inhibitory inputs to vasopressin release?

Answer 2

• The major stimulus for release is an increase in plasma osmolality
• Circumventricular organs act as osmoreceptors and can alter vasopressin release and directly affect thirst
• High pressure baroreceptors in the aortic arch and low pressure receptors in the atria can inhibit vasopressin release
  
  • Acts via the glosopharyngeal and vagus nerves respectively
• Note: the half life of vasopressin is ~ 6 minutes, so after correction of osmolality, the plasma concentration drops quickly
• Other factors that can influence vasopressin release include:
  
  • stress
  • nausea
  • pain
  • structural brain disease
  • drugs / medications
  • hypoglycaemia
  • Exercise

Question 3

Describe the process by which ADH effects water resorption in the collecting duct

Answer 3

• Vasopressin binds to V2 receptors on the basolateral surface of the collecting duct epithelial cells within the kidney
• V2 binds activates G-protein pathways, increasing cAMP and activates protein kinase A
• This activation leads to binding of vasicles containing aquaporin 2 to the apical surface
  
  • Increased expression of the aquaporin 2 receptor
  • Increased passive movement of free water from the hypotonic lumen to the isotonic cortex or hypertonic medullary interstitium

Question 4

Vasopressin’s primary function is considered the mediation of water resorption within the collection duct.

Describe the other functions of ADH on various target organs

Answer 4

1. Release of vWF
2. Stimulation of NO release into the circulation
3. Increase concentrations of Factor VIII
4. Smooth muscle contraction
   
   • Via V1a receptors
5. Glycogenolysis
6. Augmentation of ACTH release
   
   • V1b receptors in the anterior pituitary
7. Release of catecholamine and insulin
   
   • V1b receptors in the adrenal gland and pancreas
8. Neurotransmitter within the brain - numerous effects

Question 5

What are the potential causes of diabetes insipidus in dogs and cats?

Answer 5

1. Central diabetes insipidus
   
   • Lack of ADH production
   • Congenital
   • Head trauma (most common in cats)
   • Post-surgery - hypophysectomy
   • Neoplasia with posterior pituitary damage (most common in dogs
   • Idiopathic, infection and inflammatory causes have been suggested
2. Nephrogenic diabetes insipidus
   
   • Decreased action of AVP at the collecting duct
   • Lack of or ineffective V2 receptors
     
     • Likely to be the most common
     • X-linked in people and a litter or Siberian Huskies (males affected)
     • 10x less binding affinity between V2 and ADH
   • Lack of aquaporin 2 channel expression

Question 6

Describe the pathophysiology of nephrogenic diabetes insipidus in dogs.

Answer 6

• Nephrogenic diabetes is caused by decreased expression in the aquaporin 2 channel
  
  • The decreased expression could be due to defects in the channel production
  • Most commonly there is decreased expression of the channel due to abnormalities in the vinding of ADH to the V2 receptor
    
    • V2 receptor mutations result in decreased ADH binding afinity
• Nephrogenic diabetes insipidus causes increase water loss from the kidney causing primary polyuria
• Secondary polydipsia occurs due to increased plasma osmolality

Question 7

What are the common clinical signs of diabetes insipidus?

What are the pathophysiological causes for the potential neurological signs?

Answer 7

• Severe polyuria and polydipsia is the most common clinical sign
• Water may be ingested in preference to food leading to weight loss
• Excessive drinking may be followed by vomiting
• Nocturia and incontinence may occur secondary to the production of vast quantities of urine
• Neurological signs in association with DI is common in dogs - common secondary to neoplasia causing destruction or compression of the pituitary gland/hypothalamus
• Variations in access to water can cause neurological signs
  
  • Water restriction - rapid hypertonic dehydration - osmotic demyelination
  • Access to water after restriction - rapid change / decrease in osmolality can lead to cerebral oedema
• Other endocrine deficiencies may also be present with neoplasia

Question 8

What abnormalities may be seen on routine clinicopathological testing in dogs or cats with diabetes insipidus?

Answer 8

• No abnormalites may be seen if water has not been restricted
• Low BUN due to medullary solute washout
• With water restriction, hyperosmolar dehydration
  
  • Increase sodium and HCT +/- increased chloride
    *

Question 9

What are the difficulties in differentiating central diabetes insipidus and primary polydipsia?

Answer 9

• The clinical signs and initial clinicopathological testing can be identical
• There are similarites in the pathophysiology of two conditions, with AVP release
• AVP is absent in CDI
• AVP is present, but regulation can be abnormal in PP
• People with PP have been shown to have altered rates and set points for AVP release
• Dogs with primary polydipsia should concentrate urine with a modified water deprivation test alone

Question 10

Briefly describe the MWDT specifically noting the risks.

Why is the ADH response test more appropriate and at least as uesful?

Answer 10

• 3-5 days of slow and gradual water deprivation.
  
  • Dry food only
  • Water spread out over the day in small quantities
    
    • Day 1: 120-150 ml/kg
    • Day 2: 80-100 ml/kg
    • Day 3: 60-80 ml/kg
  • This should improve the medullary concentrating gradient
• Remove water - hospitalise - monitor body weight after emptying the bladder
  
  • Measure USG, HCT, TP, sodium and urea
• Monitor above parameters q 1-2 hours
• After loss of 5% of body weight, administer desmopressin IV
  
  • Recheck USG +/- HCT/TP q 30 minutes for 2 hours, then each hour for 8 hours.

Interpretation:

• Increase USG with water deprivvation alone - primary polydipsia
• Increase in USG after ADH - central diabetes insipidus
• No response to ADH - nephrogenic diabetes insipidus

Question 11

Apart from the water deprivation test and desmopressin response test, how else can a potential diagnosis of DI be investigated?

Answer 11

• MRI of the pituitary
  
  • Absence of a hyperintense signal in the sella turcica suggests absence of ADH
  • Hyperintense signal reflects the phospholipid of the secretory granules within the neurohypophysis
• Measurement of serum copeptin
  
  • Cleavage product of the pro-AVP molecule
  • Not been assessed in dogs/cats, but useful in humans