Diabetes insipidus

Definitions & Key takeaways

Diabetes insipidus is when the body cannot regulate its fluid levels properly and loses a lot of water in the urine. There are two major types of diabetes insipidus, which are central and nephrogenic diabetes insipidus. Central diabetes insipidus occurs when the hypothalamus is not producing enough antidiuretic hormone (ADH). ADH ensures that the kidneys produce less urine and reduce water loss. On the other hand, nephrogenic diabetes insipidus results from the kidneys failing to respond to ADH. People with diabetes insipidus present with excessive quantities of diluted urine (polyuria), resulting in excessive thirst (polydipsia).

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Introduction0:00–0:31

. With diabetes insipidus, diabetes comes from the Greek word for siphon, referring to an increased urine output, while insipidus means tasteless.
So in diabetes insipidus, the body produces large amounts of diluted, tasteless urine. The tasteless urine sets diabetes insipidus apart from diabetes mellitus, where mellitus means sweet because the urine contains glucose.
Now, in the brain, there's a region called the hypothalamus, which plays a crucial role in maintaining fluid balance. Inside the hypothalamus, there are special sensors called osmo receptors, which monitor plasma osmolarity or the concentration of dissolved substances in the plasma.

Physiology0:31–3:16

Normally these dissolved substances such as sodium and glucose keep plasma osmolarity between 280 and 295 milliosmoles per kilogram.
The hypothalamus also contains large neurons in the supra-optic and paraventricular nuclei that produce a precursor protein called preprovasopressin.
Next, they pack it into vesicles and send it along their axons through the pituitary stalk to the terminal axons in the pituitary gland.
As the vesicles travel, the body breaks down preprovasopressin into vasopressin and copeptin. By the time the vesicles reach the terminal axons, they're filled with both vasopressin and copeptin.
Vasopressin works by constricting small blood vessels, subsequently increasing peripheral resistance and BP. It's also known as the anti-diuretic hormone because it promotes water reabsorption in the renal tubules, thereby reducing urine output.
Now imagine an extremely hot day and you're rushing to make it to your pathology class on time. As you run, you become dehydrated, causing the water content in your blood to drop.
As a result, the concentration of dissolved particles like sodium increases, raising the plasma osmolarity. Here, osmo receptors come into action.
First, they trigger the feeling of thirst, signaling you to drink water. Once you do, your body absorbs the water, diluting the blood and bringing the osmoality back to normal.
Second, they signal the neurons in the supra-optic and paraventricular nuclei to release vasopressin and copeptin into the capillary network of the posterior pituitary.
Next, vasopressin enters the bloodstream to reach the kidneys, specifically the cells lining the distal tubule and collecting ducts of the nephrons.
Here, vasopressin binds to vasopressin receptor too, triggering the cells to insert vesicles rich in aquaporins into the apical surface, which faces the lumen of the tubule.
These aquaporins allow water to pass from the lumen through the cells lining the tubule back into the bloodstream. So just like drinking more water, this process dilutes the blood and returns plasma osmolarity to a normal level.
At the same time, by reducing water excretion, vasopressin raises urine osmolarity, which normally ranges from 500 to 800 milliosmoles per kilogram.
Now there are two main types of diabetes insipidus. First, there's central diabetes insipidus, which can happen if there's a disruption in vasopressin production in the supra optic and paraventricular nuclei, an issue with storing vasopressin in the terminal axons, or interference with its release into the capillary network of the posterior pituitary.

Pathology3:16–3:39

Regardless of the cause, when the osmoreceptors detect high osmolarity, the body fails to release vasopressin into the bloodstream.

Central diabetes insipidus3:39–4:17

As a result, the body can't activate vasopressin receptors, so aquaporins remain inside the cells. So instead of water reabsorption, there's excessive urine production.
Common causes of central diabetes insipidus include head trauma, pituitary surgery, pituitary tumors, and infiltrative conditions like lymphomas and sarcoidosis.
In some cases, the cause isn't clear, which is known as idiopathic central diabetes insipidus. Next, there's nephrogenic diabetes insipidus, which can be further subdivided into hereditary and acquired.

Nephrogenic diabetes insipidus4:17–4:49

In hereditary forms, genetic mutations result in defective vasopressin receptors or aquaporin proteins. As a result, even though the osmo receptors detect high osmolarity and the body releases vasopressin, the kidneys cannot respond to reabsorb water.
Again, this leads to excessive urine production. On the flip side, acquired forms might occur due to electrolyte imbalances such as hypokalemia and hypercalcemia, which can damage aquaporin proteins.
So even though vasopressin activates its receptors, no aquaporins are available to reach the membrane and reabsorb water.

Gestational diabetes insipidus4:49–5:29

Also, some medications can cause nephrogenic diabetes insipidus. For example, lithium can interfere with vasopressin receptors, while democlocycline, which is a vasopressin antagonist, blocks receptors entirely.
Whether it's central or nephrogenic diabetes insipidus, clinical features are the same because the kidneys can't reabsorb water.
This results in excessive urine production, over 3 L per day, which is called polyuria. As the body loses water, plasma osmolarity rises, triggering intense thirst, which makes people drink more water.

Dipsogenic diabetes insipidus5:29–6:04

This is called polydipsia. By drinking more water, individuals help restore balance and keep their plasma osmolarity in check.
But if the thirst center is impaired or access to water is limited, like after major surgery, the body's natural defense system fails.
Without sufficient water intake, plasma osmolarity continues to rise, which can eventually lead to confusion, seizures, or even coma.
Diagnosis primarily relies on urine and plasma osmorality, as well as serum sodium levels. Since the body is producing large volumes of diluted urine, urine osmorality will typically be below 300 milliosmoles per kilogram.

Symptoms6:04–6:27

And if plasma osmorality is 300 milliosmoles per kilogram or higher, and the sodium level is 146 milliequivalents per liter or more, you can diagnose diabetes insipidus.

Diagnosis6:27–7:55

However, since most individuals have an intact thirst center, they will drink enough fluids to keep plasma osmorality and sodium levels normal.
In this case, perform a water deprivation test. First, restrict the fluid intake for several hours and check the urine osmoality every 1 to 2 hours.
Normally, when a person is not drinking water, the body releases vasopressin to increase water reabsorption, concentrating the urine and raising its osmoality.
But in diabetes insipidus, there's no water reabsorption, so urine osmolarity stays low, usually below 300 milliosmoles per kilogram.
At this point, diagnose diabetes insipidus, so your next step is to determine the type. You can perform the desmopressin test by administering desmopressin, which is a synthetic vasopressin analog.
Next, wait one hour and check the urine osmoality. If urine osmoality increases, the kidneys are responding to desmopressin, so diagnose central diabetes insipidus.
But if the urine osmoality remains low, the kidneys are not responding to desmopressin, so the underlying cause is nephrogenic diabetes insipidus.
Alternatively, you can measure copeptin levels since this peptide mirrors vasopressin concentration. Low copeptin levels suggest the hypothalamus is not producing enough vasopressin, indicating central diabetes insipidus.
On the other hand, high copeptin levels suggest the body is producing vasopressin, but the kidneys are not responding, pointing to nephrogenic diabetes insipidus.

Treatment7:55–8:29

Finally, treatment for central diabetes insipidus typically involves desmopressin to replace the missing hormone. For nephrogenic diabetes insipidus, management focuses on addressing underlying causes, such as correcting electrolyte imbalances or stopping offending medications.
Alright, as a quick recap, in central diabetes insipidus, the issue lies in the production, storage or release of vasopressin, meaning the body fails to send the signal to the kidneys to reabsorb water.

Review8:29–8:51

In nephrogenic diabetes insipidus, the body produces enough vasopressin so the signal reaches the kidneys, but the kidneys can't respond.
In both scenarios, the kidneys fail to reabsorb water, leading to polyuria, which subsequently raises plasma osmolarity and triggers