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

Abstract

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.

Ameliorative Role of Silymarin Against Aspartame–induced Biochemical Changes, Oxidative Stress, Inflammatory Effect and Genotoxicity in Male Albino Rats

“…These findings were in line with who confirmed that ASP increased serum TNF-α in mice as compared to controls [72]. Silymarin was able to restrict the excessive inflammation caused by stress by acting on a variety of molecular targets.…”

The effect of moderate consumption of non-nutritive sweeteners on glucose tolerance and body composition in rats

“…However, when the glucose load was given by gavage bypassing the oral taste receptors, as in this study, a normal response to the glucose load was observed (Swithers et al 2012). Conversely, glucose AUC was higher in response to an intraperitoneal glucose load in high-fat fed mice (Gul et al 2017) and in mice with dietary-induced obesity (Mitsutomi et al 2014) treated with aspartame. Palmnas et al (2014) found a higher glucose AUC in high fat-fed rats than in chow-fed rats, but no separate effect of aspartame on glucose AUC in either group, however insulin stimulated glucose disposal was impaired in both the aspartame treated groups.…”

“…Possible mechanisms for the metabolic activity of NNS include altered ability to compensate for calories expected by sweet taste (Swithers et al 2009;Davidson et al 2011), alterations in the gut microbiota processing of nutrients (Palmnas et al 2014;Abou-Donia et al 2008;Suez et al 2014) and/or inhibition of intestinal alkaline phosphatase (Gul et al 2017). Neither the area under the glucose response curve nor the area under the insulin response curve was different between aspartame treatment or sucralose treatment compared with control in response to an oral glucose load.…”

“…A hyperglycemic response to an oral glucose load was found when NNS were delivered in the diet (Swithers et al 2012), or drinking water (Suez et al 2014;Palmnas et al 2014;Mitsutomi et al 2014;Gul et al 2017) indicating a disconnect between the sweet taste and the learned response to control energy balance. However, when the glucose load was given by gavage bypassing the oral taste receptors, as in this study, a normal response to the glucose load was observed (Swithers et al 2012).…”

Oral and Post‐Oral Actions of Low‐Calorie Sweeteners: A Tale of Contradictions and Controversies

“…Given the rapid degradation of aspartame in the small intestine, its low (millimolar) concentration in foods and beverages, and the fact that its constituent amino acids occur at substantially higher concentrations in many common foods , it would seem unlikely that it could produce any salient post‐oral responses. Nevertheless, it has been proposed that the phenylalanine produced during aspartame digestion inhibits intestinal alkaline phosphatases, which normally detoxify gut bacteria‐derived endotoxins; the accumulation of these endotoxins could disrupt metabolism .…”