Diabetes mellitus literally means sweet pee, not to be confused with the flower (click the packet to purchase this sweet pea lithograph on Etsy). A hallmark of the disorder is glucose in the urine as blood glucose levels exceed the transport maximum for the proximal tubule. The latest agents to control hyperglycemia in diabetes work by inhibiting proximal tubular glucose transporters, allowing excess glucose to flow out of the body.
Is that all they do?
Maria Gerasimova, Michael Rose, Hermann Koepsell, Takahiro Masuda, Eric Mayoux, Scott Thomson, Timo Rieg, Volker Vallon
UC San Diego & VA San Diego Healthcare System, San Diego, CADepartment of Molecular Plant Physiology and Biophysics, University of Wuerzburg, Wuerzburg, Germany, Boehringer Ingelheim Pharma, Biberach an der Riss, Germany
Under normal conditions, glucose is freely filtered through the glomerulus into the tubular fluid. As the filtrate flows through the proximal tubule, most of this glucose gets reabsorbed via sodium-linked glucose transporters (SGLT). Two such transporters exist: SGLT2 lies in the most proximal segments and takes up 97 per cent of the filtered glucose under euglycemic conditions. SGLT1 lies further down the proximal tubule and transports an additional 3 per cent. Treatment of wild type mice with an inhibitor of SGLT2, empaglilozin, allows SGLT1 to increase and reabsorb 40-50 per cent of the filtered load and maintain euglycemia.
The situation changes in diabetes, as noted in the Akita mouse model of type 1 disease. Protein of SGLT2 increases and while SGLT1 decreases in the kidneys of these mice, while a principle gluconeogenesis enzyme, PEPCK, is unregulated by 60%. These diabetic mice thus have more target for the drug empagliflozin and less SGLT1 to compensate. Treatment with this agent also reduces PEPCK, subsequently reducing renal glucose production.
Perhaps most surprising in this study are urinary studies. First, in the diabetic Akita mice, epagliflozin reduced blood glucose to near-normal, along with glomerular filtration rate. Urinary losses of glucose were not different than in the untreated Akita mouse; the lower glomerular filtration rate reduced the filtered load, so the same amount of glucose was filtered and excreted as in the more hyperglycemic animal! Of course, we rarely have patients with blood glucoses as high as in the untreated Akita mouse, so parallels in relevant clinical conditions are hard to draw.
When SGLT2 inhibitors hit the drug market last year, we all presumed that their beneficial effects on diabetes resulted from urinary glucose losses. However, as we should realize from past experience, the real story of any drug is seldom so simple. Further studies such as this one may lead to new therapeutic targets in diabetes, a major public health problem.
If you missed this presentation on Sunday, you can catch it as a platform presentation on Tuesday, April 29, at 9:00 am in room 25B of the San Diego Convention Center.