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