The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Shift to Fatty Substrate Utilization in Response to Sodium–Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes
Abstract
Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium–glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [2H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating β-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting β-hydroxybutyrate levels rose from 246 ± 288 to 561 ± 596 µmol/L (P < 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis.
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Cites
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504720 · Cited by 12,315
Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., Broedl, U. C., & Woerle, H.-J. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72227 · Cited by 1,134
Self-citationEffect of fatty acids on glucose production and utilization in man.
Ferrannini, E., Barrett, E. J., Bevilacqua, S., & DeFronzo, R. A. (1983) · Journal of Clinical Investigation · doi:10.1172/jci111133 · Cited by 1,050
Self-citationBonner, C., Kerr-Conte, J., Gmyr, V., Queniat, G., Moerman, E., Thévenet, J., Beaucamps, C., Delalleau, N., Popescu, I., Malaisse, W. J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3828 · Cited by 670
Rosenstock, J., & Ferrannini, E. (2015) · Diabetes Care · doi:10.2337/dc15-1380 · Cited by 664
Self-citationInsulin within islets is a physiologic glucagon release inhibitor
Maruyama, H., Hisatomi, A., Orci, L., Grodsky, G. M., & Unger, R. H. (1984) · Journal of Clinical Investigation · doi:10.1172/jci111658 · Cited by 303
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CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis
Ferrannini, E., Mark, M., & Mayoux, E. (2016) · Diabetes Care · doi:10.2337/dc16-0330 · Cited by 975
Self-citationInzucchi, S. E., Zinman, B., Fitchett, D., Wanner, C., Ferrannini, E., Schumacher, M., Schmoor, C., Ohneberg, K., Johansen, O. E., George, J. T., et al. (2018) · Diabetes Care · doi:10.2337/dc17-1096 · Cited by 740
Self-citationMudaliar, S., Alloju, S., & Henry, R. R. (2016) · Diabetes Care · doi:10.2337/dc16-0542 · Cited by 571
Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program
Rådholm, K., Figtree, G., Perkovic, V., Solomon, S. D., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Barrett, T. D., Shaw, W., Desai, M., et al. (2018) · Circulation · doi:10.1161/circulationaha.118.034222 · Cited by 488
Metadata
- Authors
- Ferrannini, E., Baldi, S., Frascerra, S., Astiarraga, B., Heise, T., Bizzotto, R., Mari, A., Pieber, T. R., & Muscelli, E.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-02-09
- Volume
- 65
- Issue
- 5
- Pages
- 1190-1195
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2341611738
- Cited by
- 712
- References
- 6
- FWCI
- 45.03
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Shift to Fatty Substrate Utilization in Response to Sodium–Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. https://app.cochat.ai/papers/10.2337/db15-1356
- The paper
- Ferrannini, E., Baldi, S., Frascerra, S., Astiarraga, B., Heise, T., Bizzotto, R., Mari, A., Pieber, T. R., & Muscelli, E. (2016). Shift to Fatty Substrate Utilization in Response to Sodium–Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. https://doi.org/10.2337/db15-1356
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