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 (see 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 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.

Interestingly, new drugs are being 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 inhibitors of a sodium-glucose cotransporter (SGLT2).  SGLT2 is specific to the kidney tubules, and is the protein responsible for 90% of glucose reabsorption.  In trials with patients, these drugs 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.  An advantage of these drugs is that they lower blood glucose through a mechanism that is entirely independent of insulin, making it easier for them to be used in combination with other drugs.

  Canagliflozin (tradename:  Invokana) is an SGLT2 inhibitor that was approved by the FDA in May 2013.  Dapagliflozin (Forxiga) is an SGLT2 inhibitor that has been approved in Europe.  The FDA is requiring further safety studies before approval of dapagliflozin in the U.S. The FDA will decide whether to approve dapagliflozin within the next few months.