Saccharin and Acesulfame Potassium Consumption and Glucose Homeostasis in Older Adults with Prediabetes

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1 Project Summary 2 Observational research has linked intake of non-nutritive sweeteners (NNS), which are consumed 3 daily by ~50% of middle-aged/older U.S. adults, with increased risk of type 2 diabetes (T2D). This risk 4 may be exacerbated by advancing age, which is associated with low-grade chronic inflammation and 5 increased risk of T2D. Current T2D prevention recommendations related to NNS usage are unclear 6 and confusing; use as an alternative to added sugar intake is suggested but long-term NNS use is 7 discouraged despite minimal research to support this recommendation. Animal and observational 8 human studies suggest detrimental effects of some NNS on glucose homeostasis. Longer-term human 9 studies largely demonstrate null findings. Differences in study design and a lack of rigor in existing 10 research contribute to inconclusive findings. In addition, NNS are often studied as a single entity yet 11 types of NNS vary in their absorption and metabolism (e.g., two commonly consumed NNS, saccharin 12 and acesulfame potassium [Ace-K]). Whether NNS consumption impacts glucose homeostasis in 13 middle-aged/older adults with prediabetes is unknown, and potential mechanisms by which this could 14 occur have yet to be identified. The overall objective of this R21 proposal is to establish proof-of- 15 concept for alterations in glucose homeostasis following intake of saccharin, but not Ace-K, in middle- 16 aged/older adults with prediabetes compared to a eucaloric diet with no NNS. We will investigate 17 changes in inflammatory markers as potential mechanisms by which saccharin intake influences 18 glucose homeostasis. Following a 2-week eucaloric lead-in diet, 51 middle-aged/older adults (50+ yrs) 19 with prediabetes will be randomly assigned to 1 of 3 controlled feeding conditions for 6 weeks (17 20 participants per group): saccharin, Ace-K, or a control group (no NNS). Standardized diets will be 21 matched for macronutrients (50% carbohydrate, 35% fat, 15% protein) and other variables to avoid 22 the potential confounds of weight change and dietary factors which may influence study outcomes 23 (e.g., added sugars). All groups will receive identical diets, other than the additional NNS for the two 24 NNS groups. 24-hr glycemic control using continuous glucose monitoring and insulin sensitivity and 25 beta cell function via intravenous glucose tolerance test (IVGTT), serum endotoxin, and inflammatory 26 cytokines, including C-reactive protein, will be measured before and following the 6-week dietary 27 treatment period. This research may have clinical practice and policy implications by informing U.S. 28 dietary guidelines and guidelines for T2D prevention, which devote minimal attention to NNS and 29 provide unclear guidance on NNS use due largely to a lack of rigorously-designed controlled feeding 30 trials.