Polyuria in Diabetes Mellitus

Diabetes comes from the Greek word which means “siphon”. There are two distinct disorders that share the first name diabetes: diabetes mellitus and diabetes insipidus. This is because both disorders can cause polyuria, or excessive urine output. Diabetes insipidus is a disorder or urine concentration that we will consider in the next quiz section.

Diabetes mellitus is a disorder of blood glucose regulation, which results from a deficiency in the action of the hormone insulin. This may be due to autoimmune destruction of the insulin-secreting cells of the pancreas (type 1 diabetes mellitus) or it may result from a problem in the responsiveness of tissues to insulin, known as insulin resistance (type 2 diabetes mellitus). With either disorder, the result is hyperglycemia, or high levels of glucose in the plasma.  In many cases hyperglycemia does not cause any symptoms, but in some individuals it causes excessive urination and increased thirst.

How does hyperglycemia cause excessive urine production? To answer this, we need to understand a little bit about how the kidney works. Each kidney contains about a million functional units called nephrons (blue structure in the figure). The first step in the production of urine is a process called filtration (green arrow). In filtration, there is bulk flow of water and small molecules from the plasma into Bowman’s capsule (the first part of the nephron). Because of the nonspecific nature of filtration, useful small molecules such as glucose, amino acids, and certain ions end up in the forming urine, which flows into the kidney tubules. To prevent the loss of these useful substances from the body, the cells of the kidney tubules use epithelial transport to transfer these substances out of the forming urine and back into the extracellular fluid. This process is known as reabsorption (purple arrows). Reabsorption of glucose specifically occurs in the proximal tubule.

Under normal circumstances, 100% of the glucose that is filtered is reabsorbed. Glucose reabsorption in the kidney proximal tubule utilizes the same basic process as glucose absorption in the small intestine (as outlined in the page on Epithelial Transport). In a diabetic that has hyperglycemia, the filtered load of glucose (amount of glucose filtered) can exceed the capacity of the kidney tubules to reabsorb glucose, because the transport proteins become saturated. The result is glucose in the urine.  Glucose is a solute that draws water into the urine by osmosis. Thus, hyperglycemia can cause a diabetic to produce a high volume of glucose-containing urine.

SGLT2 Inhibitors

In the past few years, drugs have been developed that exploit glucose loss in the urine as a means to counteract hyperglycemia in diabetes mellitus.  These new drugs are SGLT2 inhibitors, inhibiting the sodium-glucose cotransporter (SGLT2) that is specific to the kidney tubules.  About 90% of renal glucose reabsorption occurs via SGLT2.  There are now five FDA-approved SGLT2 inhibitors on the market*.  In trials, these drugs have been shown to reduce hyperglycemia, promote weight loss, and cause a small reduction in blood pressure.

SGLT2 inhibitors are important new drugs for the treatment of diabetes mellitus for several reasons. Since they work via a mechanism that is independent of insulin secretion or action, it may be safer to add them to existing treatments. Perhaps most encouraging, however, is that several large studies have shown than SGLT2 inhibitors are able to decrease the risk for cardiovascular disease and to slow the progression of diabetic kidney disease.  Preventing or delaying cardiovascular and kidney disease is an important goal since these diseases are major causes of mortality in diabetics.  

*SGLT2 inhibitors all have "-gliflozin" as a suffix in their generic name.  Canagliflozin (tradename:  Invokana) was approved in May 2013.  Dapagliflozin (tradename:  Farxiga) was approved in January 2014.  Empagliflozin (tradename:  Jardiance) was approved in August 2014.  Ertugliflozin (tradename:  Steglatro) was approved in December 2017.  Bexagliflozin (tradename:  Brenzavvy) was approved in January of 2023.