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Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Open accessAbstract
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. METHODS: We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry. RESULTS: Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged. CONCLUSIONS: In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.
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“Previous RCTs reported that selective SGLT2 inhibitors, a new class of anti-diabetes drugs, have been shown to reduce body weight (1–3 kg reduction) in diabetic patients with and without obesity [99–102].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [99]
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“[29] used dualtracer methodology and calorimetry in 66 patients”
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“This increased glucagon presents a dual problem: it not only increases endogenous glucose production (9), thereby diminishing the glucose-lowering effect of SGLT2 inhibitors (10,11), but it also enhances ketone production, especially under insulinopenic conditions (12,13).”
Muscelli, E., Astiarraga, B., Barsotti, E., Mari, A., Schliess, F., Nosek, L., Heise, T., Broedl, U. C., Woerle, H., & Ferrannini, E. (2015) · Diabetologia · doi:10.1007/s00125-015-3845-8 · Cited by 25
Self-citationBando, Y., Tohyama, H., Aoki, K., Kanehara, H., Hisada, A., Okafuji, K., & Toya, D. (2016) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2016.06.001 · Cited by 23
“At the same time, this Dōjiniclass of agents decreases body weight mainly due to reduction in visceral or subcutaneous fat mass [11], which are the main production sites of free fatty acid [37,38].”
BackgroundSodium–Glucose Cotransporter 2 Inhibitor Improves Complications of Lipodystrophy: A Case Report
Kawana, Y., Imai, J., Sawada, S., Yamada, T., & Katagiri, H. (2017) · Annals of Internal Medicine · doi:10.7326/l16-0372 · Cited by 25
Goldman, J. D. (2018) · Clinical Medicine Insights Endocrinology and Diabetes · doi:10.1177/1179551418786258 · Cited by 27
Lu, Y., Ma, X., Xu, Y., Hu, J. Y., Wang, F., Qin, W., & Xiong, W. (2018) · Natural Products and Bioprospecting · doi:10.1007/s13659-018-0188-4 · Cited by 24
A Variation on the Theme: SGLT2 Inhibition and Glucagon Secretion in Human Islets
Hodson, D. J., & Rorsman, P. (2020) · Diabetes · doi:10.2337/dbi19-0035 · Cited by 25
“, via somatostatin or hypoglycemia) SGLT2i actions on glucagon secretion in vivo in humans? As for in vitro experiments, studies have shown opposing effects of SGLT2i in volunteers: under isoglycemic/euglycemic hyperinsulinemic conditions, glucagon has been reported to either increase (19) or remain unchanged (2,20).”
BackgroundSauer, F., Riou, M., Charles, A., Meyer, A., Andrès, E., Gény, B., & Talha, S. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030741 · Cited by 25
Luo, Z.-C., Jin, Z., Jiang, Y., Wei, T., Cao, Y., Zhang, Z., Wei, R., & Jiang, H. (2022) · Asian Journal of Andrology · doi:10.4103/aja202242 · Cited by 24
Zhou, H., Peng, W., Li, F., Wang, Y., Wang, B., Ding, Y., Lin, Q., Zhao, Y., Pan, G., & Wang, X. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.875327 · Cited by 31
“SGLT2 inhibitors induce ketogenic metabolism, which results in utilization of energy-efficient ketones over less efficient fatty acid and glucose oxidation to generate myocardial energy, thereby improving efficiency and function of both myocardium and the kidneys (81, 84, 85).”
BackgroundPatoulias, D., Stavropoulos, K., Imprialos, K. P., Katsimardou, A., Kalogirou, M., Koutsampasopoulos, K., Zografou, I., Papadopoulos, C. E., Karagiannis, A. I., & Doumas, M. N. (2019) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2019.107927 · Cited by 24
Sodium-Glucose Co-transporter 2 Inhibitors in the Failing Heart: a Growing Potential
Brito, D. A., Bettencourt, P., Carvalho, D. M., Ferreira, J., Fontes‐Carvalho, R., Franco, F., Moura, B., Silva‐Cardoso, J., de Melo, R. T., & Fonseca, C. (2020) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-020-06973-3 · Cited by 24
“The “Super Fuel” Hypothesis The healthy myocardium is metabolically “omnivorous” and able to switch between different sources of energy; it can use carbohydrates, ketones, lactate and certain amino acids as fuel, but utilizes preferentially free fatty acids (FFA) for energy production, which yield substantial amounts…”
BackgroundIs it time to think about the sodium glucose co‐transporter 2 sympathetically?
Elliott, R. H., Matthews, V. B., Rudnicka, C., & Schlaich, M. P. (2016) · Nephrology · doi:10.1111/nep.12620 · Cited by 23
Åkerblom, A., Oldgren, J., Latva‐Rasku, A., Johansson, L., Lisovskaja, V., Karlsson, C., Oscarsson, J., & Nuutila, P. (2019) · Upsala Journal of Medical Sciences · doi:10.1080/03009734.2018.1515281 · Cited by 23
“Increased hematocrit and an increase in plasma levels of ketones have been suggested to improve oxygenation and mitochondrial energy metabolism of the myocardium, respectively (8,14,21,24).”
BackgroundLuo, M.-H., Kong, X., Wang, H., Zhai, X., Cai, T., Ding, B., Hu, Y., Jing, T., Su, X., Li, H., et al. (2020) · Journal of Diabetes Research · doi:10.1155/2020/6666403 · Cited by 24
Moinul, M., Amin, S. A., Kumar, P., Patil, U. K., Gajbhiye, A., Jha, T., & Gayen, S. (2021) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2021.108106 · Cited by 23
Monteyne, A. J., Falkenhain, K., Whelehan, G., Neudorf, H., Abdelrahman, D. R., Murton, A. J., Wall, B. T., Stephens, F. B., & Little, J. P. (2024) · Diabetologia · doi:10.1007/s00125-024-06122-7 · Cited by 23
“However, approaches similar to ours have previously yielded accurate results [14] and detected differences in EGP with pharmacological intervention in individuals with type 2 diabetes [15].”
ResultArgento, N. B., & Nakamura, K. (2015) · Endocrine Practice · doi:10.4158/ep151016.or · Cited by 23
Furuhashi, M., Matsumoto, M., Hiramitsu, S., Omori, A., Tanaka, M., Moniwa, N., Yoshida, H., Ishii, J., & Miura, T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0154482 · Cited by 23
“On the other hand, SGLT2 inhibitors have been reported to enhance hepatic glucose production [27, 28] by an unknown molecular mechanism.”
BackgroundBaron, K. T., Macha, S., Broedl, U. C., Nock, V., Retlich, S., & Riggs, M. M. (2016) · Diabetes Therapy · doi:10.1007/s13300-016-0174-y · Cited by 23
“Although this observation might be the result of a study effect (since most patients taking background SU therapy came from two studies: 6 and 9), data suggest that empagliflozin may improve b-cell function [29], and hence, might lead to a better response to pre-existing SU treatment.”
ResultSelf-citationKum-Nji, J. S., Gosmanov, A. R., Steinberg, H. O., & Dagogo-Jack, S. E. (2016) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2016.11.004 · Cited by 23
Færch, K., Amadid, H., Bruhn, L., Ried‐Larsen, M., Karstoft, K., Persson, F., & Jørgensen, M. E. (2017) · BMJ Open · doi:10.1136/bmjopen-2016-013802 · Cited by 23
“38 Treatment with SGLT2 inhibitors has shown to lower the renal threshold for glucose excretion in a dose-dependent manner both in individuals with type 2 diabetes and normal glucose regulation.”
Minireview: are SGLT2 inhibitors heart savers in diabetes?
Rotkvić, P. G., Berković, M. C., Bulj, N., & Rotkvić, L. (2019) · Heart Failure Reviews · doi:10.1007/s10741-019-09849-3 · Cited by 23
Aguilar-Ballester, M., Hurtado-Genovés, G., Taberner-Cortés, A., Herrero-Cervera, A., Martínez‐Hervás, S., & Navarro, H. G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020660 · Cited by 25
Gaggini, M., Sabatino, L., Suman, A. F., Chatzianagnostou, K., & Vassalle, C. (2025) · Cells · doi:10.3390/cells14050387 · Cited by 29
Hanke, J., Romejko, K., & Niemczyk, S. (2025) · Molecules · doi:10.3390/molecules30204125 · Cited by 33
“Simultaneously, hepatic glycogen depletion and relative hypoinsulinemia favor a metabolic shift toward lipolysis and ketogenesis [5,62].”
Chen, M.-B., Wang, H., Cui, W.-Y., Xu, H.-L., & Zheng, Q.-H. (2021) · Medicine · doi:10.1097/md.0000000000024593 · Cited by 22
“Compared with other hypoglycemic drugs, the advantage of SGLT-2 inhibitors is that they induce weight loss in patients with T2DM and simultaneously have a beneficial effect on lipid metabolism.([55]) The results of our study corroborate this conclusion.”
ResultKohlenberg, J. D., LAURENTI, M. C., Egan, A. M., Wismayer, D. S., Bailey, K. R., Cobelli, C., Man, C. D., & Vella, A. V. (2022) · Diabetologia · doi:10.1007/s00125-022-05794-3 · Cited by 23
“In a setting where alpha cell function is a significant contributor to hyperglycaemia, it may be reasonable to avoid pharmacotherapy that significantly increases fasting glucagon secretion [44].”
BackgroundTsimihodimos, V., Filippatos, T. D., & Elisaf, M. (2016) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2017.1258055 · Cited by 24
“This increased glucose production could offset the glycosuria-associated antidiabetic effect of these drugs [57-60].”
BackgroundJung, C., & Mok, J. (2019) · Journal of Obesity & Metabolic Syndrome · doi:10.7570/jomes.2019.28.1.18 · Cited by 22
Vaduganathan, M., Inzucchi, S. E., Sattar, N. A., FITCHETT, D. H., Ofstad, A. P., Brueckmann, M., George, J. T., Verma, S., Mattheus, M., Wanner, C., et al. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14535 · Cited by 21
“tion and peripheral insulin sensitivity; these metabolic changes are apparent even after single doses of SGLT-2 inhibitors.(12) Posited mechanisms underlying these effects include weight loss, reductions in liver fat, lowering tissue inflammation, modulation of adipocytederived hormonal activity, and increased β-cell…”
BackgroundKosugi, R., Nakatani, E., Okamoto, K., Aoshima, S., Arai, H., & Inoue, T. (2019) · Endocrine Journal · doi:10.1507/endocrj.ej19-0013 · Cited by 21
“The acute reaction of glucagon secretion to SGLT2 inhibition was reported to be significantly eleva‐ ted, which in turn stimulates hepatic glucose production and ketogenesis [14, 15].”
BackgroundKitazawa, T., Seino, H., Ohashi, H., Inazawa, T., Inoue, M., Ai, M., Fujishiro, M., Kuroda, H., Yamada, M., Anai, M., et al. (2020) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14059 · Cited by 21
Metadata
- Authors
- Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., Broedl, U. C., & Woerle, H.-J.
- Affiliations
- University of Pisa (IT)
- National Research Council (IT)
- Profil Institute for Metabolic Research (DE)
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Ferrannini, Ele
- Venue
- Journal of Clinical Investigation
- Published
- 2014-01-27
- Volume
- 124
- Issue
- 2
- Pages
- 499-508
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3904627
- OpenAlex
- W2157405334
- Cited by
- 1,134
- References
- 45
- Citations by year
- 2026: 55 · 2025: 68 · 2024: 80 · 2023: 81 · 2022: 92 · 2021: 117 · 2020: 106 · 2019: 103 · 2018: 97 · 2017: 90 · 2016: 121 · 2015: 83 · 2014: 39
- FWCI
- 89.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- American Diabetes Association
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- Novo Nordisk
- Astellas Pharma
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SGLT2 inhibitors, empagliflozin, type 2 diabetes, glycosuria, endogenous glucose production, glucose oxidation, nonoxidative glucose disposal, lipid oxidation, beta-cell glucose sensitivity, glucagon response, insulin response, glucose metabolism, indirect calorimetry, mixed meal tolerance, urinary glucose excretion, glucose homeostasis
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Aged, Benzhydryl Compounds, Blood Glucose, Calorimetry, Diabetes Mellitus, Type 2, Female, Glucose, Glucosides, Glycosuria, Glycated Hemoglobin, Humans, Insulin, Male, Metformin, Middle Aged, Oxygen, Body Mass Index, Postprandial Period, Area Under Curve, Insulin-Secreting Cells, Sodium-Glucose Transporter 2
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