The Sweet Smell of Success—A Protein in the Kidney Helps the Body Retain Sugar

In a new study, scientists identified a protein in the mouse kidney that helps prevent the body from excreting glucose (sugar), potentially revealing a molecular target for novel treatment strategies for type 2 diabetes. This protein is one of a family of proteins called olfactory receptors. Decades ago, these receptors were discovered in mammals as the molecular sensors of odorants. Olfactory receptors were originally found in the nose, detecting chemicals to give us our sense of smell. Members of this protein family have since also been found in numerous other tissues throughout the body, recognizing a variety of substances and serving an array of physiological functions. Scientists previously discovered one particular olfactory receptor, called Olfr1393, in the mouse kidney, but its physiological function was unknown.

To extend their previous research, the scientists investigated the role of Olfr1393 in the kidneys of male and female mice. They determined that the Olfr1393 gene was turned on specifically in the kidney’s proximal tubules, basic functional units of the kidney. Tubules reabsorb various substances filtered from the blood to retain nutrients, such as glucose, in the body, so they are not excreted in the urine. The scientists then genetically engineered mice to lack the Olfr1393 gene. In many ways, Olfr1393-deficient mice were similar to normal mice: their kidneys were of similar size and filtered blood at the same rate, and the mice had similar blood pressures and body weights. However, the researchers observed that the urine of Olfr1393-deficient mice contained significantly higher levels of glucose, suggesting that their kidneys did not reabsorb the sugar as well as their normal counterparts. Mice lacking Olfr1393 also tolerated higher levels of glucose than the normal mice could.

Glucose reabsorption is a critical function of the kidney. Two related proteins in the kidney proximal tubule are responsible for glucose reabsorption: Sglt1 and Sglt2. Sglt2 returns 90 percent of the filtered glucose to the blood, and Sglt1 returns the remaining 10 percent.* The scientists found that overall levels of Sglt1 and Sglt2 were normal in Olfr1393-deficient mice. They also examined some of the traits of the mice for potential differences between the sexes, and, interestingly, found that the kidneys of male mice that lacked Olfr1393 contained higher levels of Sglt2 protein than did kidneys from female mice lacking Olfr1393; this finding is consistent with reduced levels of urine glucose observed in these male mice. Next, the researchers more closely examined the kidney tissue and found that while overall Sglt1 levels were similar in all mice, the protein was not found in its normal location, the cell membranes of proximal tubule cells, in mice deficient in Olfr1393. These data suggest that Sglt1 function was impaired due to its inability to reach its intended location within the cell.

These results demonstrate the critical role of Olfr1393 in regulating glucose reabsorption by the kidney. Improved tolerance of glucose in Olfr1393-deficient mice suggests that the olfactory receptor could influence the body’s ability to regulate glucose levels. If Olfr1393 functions similarly in people, it could represent a potential new target for the development of therapeutic strategies for type 2 diabetes.

References

*Sglt2 inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 diabetes. In conjunction with exercise and a healthy diet, they can improve glycemic control.