Although SGLT-2 inhibitors are central to the treatment of diabetes, their exact mode of action was previously unknown. In a study by a research group headed by Peter Wolf, Martin Krssak and Michael Krebs from Medical Department III at MedUni Vienna, magnetic resonance spectroscopy (MRS) was used to show that there is a direct connection between the elimination of glucose via the kidneys and new glucose production in the liver.
A single dose of the SGLT-2 inhibitor dapagliflozin leads to an advantageous regulatory mechanism in which the glucose loss due to the drug-induced SGLT-2 inhibition is precisely compensated for by a steady increase in new glucose production in the liver. The study was published in the leading journal Diabetes Care.
Dapagliflozin is a drug in the group of SGLT-2 inhibitors that are commonly used to treat diabetes. They increase the amount of glucose that is excreted in the urine. This lowers blood sugar levels and patients lose weight too. A beneficial effect on fatty liver, which is widespread in diabetics, has also been described after taking the drug for twelve weeks. Notably, this group of drugs also appears to have protective effects on the heart and kidneys. The acute effects on lipid and energy metabolism had not yet been investigated in detail.
A research group led by Peter Wolf, Martin Krssak and Michael Krebs from the Department of Endocrinology and Metabolism of the Department of Medicine III has now conducted a study of MRS in which six diabetics and a control group of ten healthy volunteers were observed after they had Dapagliflozin taken.
The amount of extra glucose produced in the liver was found to be exactly the same in the short term as the amount lost in the urine due to the action of the drug. This suggests that the increased elimination of glucose by the kidneys immediately triggers a number of regulatory mechanisms that affect metabolism in several organs and therefore could play a role in the beneficial effects of this drug.
The study was carried out in cooperation with the competence center for high-field MRI of the department for biomedical imaging and image-guided therapy at MedUni Vienna. With the high-resolution magnetic resonance imaging, serial measurements of glucose and fat storage in the liver could be quantified non-invasively.
In combination with the infusion of tracers (such as a labeled glucose solution) it is possible to use this “virtual biopsy” to identify changes in glucose and lipid metabolism in vivo and to study the acute, short-term effects of drugs.
medical university Vienna
Wolf, P. et al. (2021) Gluconeogenesis, but not glycogenolysis, contributes to an increase in endogenous glucose production through SGLT-2 inhibition. Diabetes treatment. doi.org/10.2337/dc20-1983.