Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice

Appl Physiol Nutr Metab. 2017 Jan;42(1):77-83. doi: 10.1139/apnm-2016-0346. Epub 2016 Nov 18.


Diet soda consumption has not been associated with tangible weight loss. Aspartame (ASP) commonly substitutes sugar and one of its breakdown products is phenylalanine (PHE), a known inhibitor of intestinal alkaline phosphatase (IAP), a gut enzyme shown to prevent metabolic syndrome in mice. We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE's inhibition of endogenous IAP. The design of the study was such that for the in vitro model, IAP was added to diet and regular soda, and IAP activity was measured. For the acute model, a closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. For the chronic model, mice were fed chow or high-fat diet (HFD) with/without ASP in the drinking water for 18 weeks. The results were that for the in vitro study, IAP activity was lower (p < 0.05) in solutions containing ASP compared with controls. For the acute model, endogenous IAP activity was reduced by 50% in the ASP group compared with controls (0.2 ± 0.03 vs 0.4 ± 0.24) (p = 0.02). For the chronic model, mice in the HFD + ASP group gained more weight compared with the HFD + water group (48.1 ± 1.6 vs 42.4 ± 3.1, p = 0.0001). Significant difference in glucose intolerance between the HFD ± ASP groups (53 913 ± 4000.58 (mg·min)/dL vs 42 003.75 ± 5331.61 (mg·min)/dL, respectively, p = 0.02). Fasting glucose and serum tumor necrosis factor-alpha levels were significantly higher in the HFD + ASP group (1.23- and 0.87-fold increases, respectively, p = 0.006 and p = 0.01). In conclusion, endogenous IAP's protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of ASP, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks.

Keywords: alcaline phosphatase intestinale; aspartame; diet-induced insulin resistance; insulin resistance; insulinorésistance; insulinorésistance induite par la diète; intestinal alkaline phosphatase; non-nutritive sweeteners; noncaloric sweeteners; obesity; obésité; édulcorants non caloriques; édulcorants non nutritifs.

MeSH terms

  • Alkaline Phosphatase / antagonists & inhibitors*
  • Alkaline Phosphatase / metabolism
  • Animals
  • Aspartame / adverse effects*
  • Aspartame / metabolism
  • Biomarkers / blood
  • Biotransformation
  • Blood Glucose / analysis
  • Diet, High-Fat / adverse effects
  • Enzyme Inhibitors / metabolism
  • Glucose Intolerance / blood
  • Glucose Intolerance / etiology*
  • Glucose Intolerance / metabolism
  • Insulin Resistance*
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / metabolism
  • Intestine, Small / enzymology
  • Intestine, Small / metabolism
  • Male
  • Metabolic Syndrome / blood
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / metabolism
  • Mice, Inbred C57BL
  • Non-Nutritive Sweeteners / adverse effects*
  • Non-Nutritive Sweeteners / metabolism
  • Obesity / blood
  • Obesity / etiology*
  • Obesity / metabolism
  • Phenylalanine / metabolism
  • Tumor Necrosis Factor-alpha / blood
  • Weight Gain


  • Biomarkers
  • Blood Glucose
  • Enzyme Inhibitors
  • Non-Nutritive Sweeteners
  • Tumor Necrosis Factor-alpha
  • Phenylalanine
  • Alkaline Phosphatase
  • Aspartame