Diabetes Mellitus and Polyuria

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 cause polyuria, or excessive urine output. Diabetes insipidus is a disorder of urine concentration which we will discuss in spring quarter.

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 resitance (type 2 diabetes mellitus). With either disorder, the result is hyperglycemia, or high levels of glucose in the plasma.

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 lining 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).

Under normal circumstances, 100% of the glucose that is filtered is reabsorbed. Glucose reabsorption involves transport proteins that require specific binding. 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 causes a diabetic to produce a high volume of glucose-containing urine.

In the past few years, new drugs have been developed that exploit glucose loss in the urine as a means to counteract hyperglycemia in diabetes.  If glucose is lost from the body via the urine, that is less glucose in the circulation. These new drugs are SGLT2 inhibitors, inhibiting the sodium-glucose cotransporter (SGLT2) that is specific to the kidney tubules and responsible for 90% of glucose reabsorption.  There are now four FDA-approved SGLT2 inhibitors on the market--these drugs all have the suffix "-gliflozin" in their generic name.  In clinical trials, SGLT2 inhibitors were found to effectively reduce hyperglycemia and promote weight loss.  Although the drugs increase urine flow, it is not enough of an increase to bother most patients.  There is excitement about these drugs because they improve glycemic control via a mechanism that is independent of insulin secretion or action, and thus it should be safe to use them as an added treatment when existing drugs fail to fully control hyperglycemia.

In clinical trials leading up to drug approval, the main adverse effect of SGLT2 inhibitors was an increased risk of genital and urinary tract infections.  However, since SGLT2 inhibitors have been approved, there have been reports of ketoacidosis, a serious condition that usually only occurs in type 1 diabetes when insulin levels are too low. There have also been reports of serious urinary tract infections.  The FDA issued a warning in December 2015 to advise patients and doctors of these risks.  The FDA is continuing to monitor the safety of these drugs.

There are now four SGLT2 inhibitors approved by the FDA.  Canagliflozin (tradename:  Invokana) was approved in May 2013.  Dapagliflozin (tradename:  Forxiga) was approved in January 2014.  Empagliflozin (tradename:  Jardiance) was approved in August 2014.  Ertugliflozin (tradename:  Steglatro) was approved in December 2017.

Quick Quiz

Fill in Answer Correct False Correct Answer
1. Name the specific protein that is responsible for the first step in glucose reabsorption in the kidney.
2. What causes a high filtered load of glucose in diabetes mellitus?
3. When there is a high concentration of glucose in the forming urine, some glucose does not get reabsorbed because transport proteins become ___________.
4. Glucose in the urine increases urine volume because it draws water into the urine by __________.
5. Name the term that means an excessive output of urine.
6. An advantage of SGLT2 inhibitors is that they lower blood glucose through a mechanism that is independent of __________.

(Spelling must be correct)