Low-calorie sweeteners augment tissue-specific insulin sensitivity in a large animal model of obesity
Whether low-calorie sweeteners (LCS), such as sucralose and acesulfame K, can alter glucose metabolism is uncertain, particularly given the inconsistent observations relating to insulin resistance in recent human trials. We hypothesized that these discrepancies are accounted for by the surrogate tools used to evaluate insulin resistance and that PET 18FDG, given its capacity to quantify insulin sensitivity in individual organs, would be more sensitive in identifying changes in glucose metabolism. Accordingly, we performed a comprehensive evaluation of the effects of LCS on whole-body and organ-specific glucose uptake and insulin sensitivity in a large animal model of morbid obesity.
Twenty mini-pigs with morbid obesity were fed an obesogenic diet enriched with LCS (sucralose 1 mg/kg/day and acesulfame K 0.5 mg/kg/day, LCS diet group), or without LCS (control group), for 3 months. Glucose uptake and insulin sensitivity were determined for the duodenum, liver, skeletal muscle, adipose tissue and brain using dynamic PET 18FDG scanning together with direct measurement of arterial input function. Body composition was also measured using CT imaging and energy metabolism quantified with indirect calorimetry.
The LCS diet increased subcutaneous abdominal fat by ≈ 20% without causing weight gain, and reduced insulin clearance by ≈ 40%, while whole-body glucose uptake and insulin sensitivity were unchanged. In contrast, glucose uptake in the duodenum, liver and brain increased by 57, 66 and 29% relative to the control diet group (P < 0.05 for all), while insulin sensitivity increased by 53, 55 and 28% (P < 0.05 for all), respectively. In the brain, glucose uptake increased significantly only in the frontal cortex, associated with improved metabolic connectivity towards the hippocampus and the amygdala.
In miniature pigs, the combination of sucralose and acesulfame K is biologically active. While not affecting whole-body insulin resistance, it increases insulin sensitivity and glucose uptake in specific tissues, mimicking the effects of obesity in the adipose tissue and in the brain.
KeywordsBrain connectivity Compartmental analysis Glucose uptake Insulin sensitivity Miniature pig Statistical parameter mapping Sweeteners
Positron emission tomography coupled with computed tomography
Metabolic rate for glucose utilization
Region of interest
Volume of interest
The authors thank staff of the UEPR unit for animal care, Mickael Genissel, Julien Georges, Alain Chauvin, Francis Le Gouevec, and Vincent Piedvache. We also thank Paula Aneb and Emilie Lebrun for their involvement in running the Aniscan imaging, and Raphael Comte (Pegase unit) for insulin measurements. The authors also thank Eric Bobillier for the development of the in-line radiation detector and robotic feeders.
C-H.M. planned the experiments, conducted the studies, analyzed the data and wrote the manuscript. R.Y. and M.H. were involved in planning the experiments, writing the manuscript and interpretation of the data. C-H.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The study was conducted within the Aniscan Imaging Center (Aniscan, INRA), which is supported by BPIFrance within the Investments for the Future Program.
Compliance with ethical standards
Disclosure of potential conflicts of interest
C-H. Malbert declares that he has no conflict of interest. M. Horowitz declares that he has no conflict of interest. R. Young declares that he has no conflict of interest.
All applicable international, national and/or institutional guidelines for the care and use of animals were followed.
- 7.Hess EL, Myers EA, Swithers SE, Hedrick VE. Associations Between Nonnutritive Sweetener Intake and Metabolic Syndrome in Adults. J Am Coll Nutr. 2018:1–7.Google Scholar
- 17.Smith K, Karimian-Azari E, LaMoia TE, Hussain T, Vargova V, Karolyi K, et al. T1R2 receptor-mediated glucose sensing in the upper intestine potentiates glucose absorption through activation of local regulatory pathways. Mol Metab. 2018.Google Scholar
- 20.Goodpaster BH, Bertoldo A, Ng JM, Azuma K, Pencek RR, Kelley C, et al. Interactions among glucose delivery, transport, and phosphorylation that underlie skeletal muscle insulin resistance in obesity and type 2 Diabetes: studies with dynamic PET imaging. Diabetes. 2014;63:1058–68.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Bahri S, Horowitz M, Malbert CH. Inward Glucose Transfer Accounts for Insulin-Dependent Increase in Brain Glucose Metabolism Associated with Diet-Induced Obesity. Obesity (Silver Spring). 2018.Google Scholar
- 29.Ilback N-G, Alzin M, Jahrl S, Enghardt-Barbieri H, Busk L. Estimated intake of the artificial sweeteners acesulfame-K, aspartame, cyclamate and saccharin in a group of Swedish diabetics. Food Addit Contam. 2003;20:115–26.Google Scholar
- 31.Malbert C-H. AniMate-An open source software for absolute PET quantification. Annual Congress of the European Association of Nuclear Medicine. 2016:43.Google Scholar
- 33.Rehal MS, Fiskaare E, Tjäder I, Norberg Å, Rooyackers O, Wernerman J. Measuring energy expenditure in the intensive care unit: a comparison of indirect calorimetry by E-sCOVX and Quark RMR with Deltatrac II in mechanically ventilated critically ill patients. Crit Care. 2016;20:54.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Poulsen PH, Smith DF, Ostergaard L, Danielsen EH, Gee A, Hansen SB, et al. In vivo estimation of cerebral blood flow, oxygen consumption and glucose metabolism in the pig by [15O]water injection, [15O]oxygen inhalation and dual injections of [18F]fluorodeoxyglucose. J Neurosci Methods. 1997;77:199–209.CrossRefPubMedGoogle Scholar
- 40.Honka H, Mäkinen J, Hannukainen JC, Tarkia M, Oikonen V, Teräs M, et al. Validation of [18F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity. Diabetologia. 2013;56:893–900.CrossRefPubMedGoogle Scholar