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

Gul SS, Hamilton ARL, Munoz AR, Phupitakphol T, Wei L, Hyoju SK, Economopoulos KP, Morrison S, Hu D, Zhang W, Gharedaghi MH, Huo H, Hamarneh SR, Hodin RA (2016) Applied Physiology, Nutrition, and Metabolism  epub ahead of print, Nov 18 Nrcresearch

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Background: 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.

Objective: We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE’s inhibition of endogenous IAP.

Design: In vitro model: IAP was added to diet and regular soda, and IAP activity was measured. Acute model: A closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. Chronic model: Mice were fed chow or high fat diet (HFD) with/without ASP in the drinking water for 18 weeks.

Results: In vitro study: IAP activity was lower (p<.05) in solutions containing ASP compared to controls. Acute model: endogenous IAP activity was reduced by 50% in the ASP group compared to controls (0.2±0.03 vs 0.4±0.24) (p=.02). Chronic model: Mice in the HFD+ASP group gained more weight compared to HFD+water group (48.1±1.6 vs 42.4±3.1, p=.0001). Significant difference in glucose intolerance between HFD +/- ASP groups (53913±4000.58mg*min/dL vs 42003.75±5331.61mg*min/dL, respectively, p=.02). Fasting glucose and serum TNF-alpha levels were significantly higher in the HFD+ASP group (1.23 and 0.87 fold increases, respectively, p=.006 and p=.01).

Conclusions: Endogenous IAP’s protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of aspartame, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks.