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 (see "Regulation of Water Balance").

The urinary symptom of polyuria may often be the first indication that a person has diabetes mellitus. 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.

renal glucose handlingHow does hyperglycemia cause excessive urine production? To answer this, we need to look at the renal handling of glucose. Being a small molecule, glucose is freely filtered. The glucose that is filtered is then completely reabsorbed in the proximal tubule, by the mechanism shown in the figure at the right. Under normal circumstances, 100% of the glucose that is filtered is reabsorbed. Glucose reabsorption involves transport proteins (specifically, sodium-glucose cotransporters) that require specific binding. As shown in the figure below, hyperglycemia causes such a high filtered load of glucose, that it exceeds the capacity of the kidney tubules to reabsorb it. (Filtered load is the amount filtered, and is calculated by multiplying the plasma concentration by the GFR).  The transport proteins become saturated, and the result is that glucose ends up 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.


nephrons

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 three FDA-approved SGLT2 inhibitors on the market.  In trials, these drugs have been shown to modestly reduce hyperglycemia and to promote weight loss.  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.

SGLT2 inhibitors all have "-gliflozin" as a suffix in their generic name.  Canagliflozin (tradename:  Invokana) was approved in May 2013.  Dapagliflozin (tradename:  Forxiga) was approved in January 2014.  Empagliflozin (tradename:  Jardiance) was approved in August 2014.


Quick Quiz


Fill-in Answer Correct False Correct Answer
1. Production of a high volume of urine is referred to as ____________.
2. In diabetes mellitus, an increased plasma concentration of glucose results in a high _________ of glucose in the Bowman's space.
3. Urine volume increases in diabetes mellitus because glucose draws water into the urine by _________.
4. Name the specific protein responsible for glucose reabsorption from the lumen of the proximal tubule.
5. Name a type of drug that decreases blood glucose by increasing excretion of glucose in the urine.


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