FOUNDATION MODULE

SGD: TRANSPORT ACROSS PLASMA MEMBRANE

READING MATERIAL
LEARNING OBJECTIVES: Note: Refer to ppt for LO no.1 and 2. Refer to this word
document for LO no 3 and 4
1. Enumerate various types of transport processes.
2. Describe the mechanisms involved in various transport systems along with importance.
3. Correlate the disease process in nephrogenic diabetes inspidus with the genetic defect in aqua
porin channels.
4. Correlate the clinical significance of SGLT2 inhibitors in treatment of type-2 diabetes
mellitus

NEPHROGENIC DIABETES INSPIDUS

Nephrogenic diabetes insipidus (NDI) is an inability to concentrate urine due to impaired renal tubule
response to vasopressin (ADH), which leads to excretion of large amounts of dilute urine. It can be
inherited or occur secondary to conditions that impair renal concentrating ability.

Causes
Diabetes insipidus occurs when body can't properly balance the body's fluid levels.

Our kidneys filter the fluid portion of blood to remove waste products. The majority of the fluid is
returned to the bloodstream while the waste and a smaller amount of fluid make up urine. Urine is
excreted from body after being temporarily stored in your bladder.

A hormone called anti-diuretic hormone (ADH), or vasopressin, is needed for the fluid that's filtered
by the kidneys to go back into the bloodstream. ADH is made in a part of the brain called the
hypothalamus and stored in the pituitary gland, a small gland found in the base of the brain.
Conditions that cause a deficiency of ADH or block the effect of ADH result in production of excess
urine.

If you have diabetes insipidus, your body can't properly balance fluid levels. The cause depends on
the type of diabetes insipidus you have. Types include:

 Central diabetes insipidus. Damage to the pituitary gland or hypothalamus from surgery, a tumor,
head injury or illness can cause central diabetes insipidus by affecting the usual production, storage
and release of ADH. An inherited genetic disease also can cause this condition.
 Nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus occurs when there's a defect in the
structures in your kidneys that makes your kidneys unable to properly respond to ADH.

The defect may be due to:

 Certain drugs, such as lithium or antiviral medications such as foscarnet (Foscavir), also can cause
nephrogenic diabetes insipidus.
 An inherited (genetic) defect (mutation) in arginine vasopressin V2 receptor (AVPR2) or
Aquaporin 2 (AQP2) receptor. This results in congenital nephrogenic diabetes inspidus.

 AQP2 is a key factor for maintaining normal body water homeostasis. When the plasma osmolality
increases, antidiuretic hormone (AVP) is released from the pituitary gland and binds to AVPR2 in
principal cells of the kidney collecting duct, resulting in the accumulation of AQP2 in the apical
plasma membrane, which is responsible for water reabsorption

USE OF SODIUM-DEPENDENT GLUCOSE TRANSPORTER (SGTL2)

INHIBITORS AS A TREATMENT OF TYPE 2 DIABETES MELLITUS:

 SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and
exercise to lower blood sugar in adults with type 2 diabetes. SGLT2 inhibitors lower blood sugar by
causing the kidneys to remove sugar from the body through the urine.

 SGLT2 inhibitor ipragliflozin induces a sustained glucosuria, diuresis, and natriuresis, with
compensatory increases in fluid intake and vasopressin‐induced aquaporin‐2 phosphorylation. This
results in a solute‐free water reabsorption in proportion to the reduced fluid balance to maintain body
fluid volume. This indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates
compensatory fluid intake and renal water reabsorption to maintain body fluid volume.

REFERENCES:

https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/sodium-glucose-cotransporter-2-sglt2-inhibitors

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987478/