Effects of Chronic Artificial Sweetener Consumption on Type 1 Diabetes Susceptibility
Authors: Hoffmann Brian R. , Haspula Dhanush , Roethle Mark , Cabrera Susanne , Moosreiner Andrea , Hessner Martin 
Published: April 2020

As the diabetes epidemic grows worldwide, there is a heightened awareness of how modern day diets may contribute to the increased incidence of disease. To combat the dietary intake of sugar, there has been a drastic increase in the daily consumption of non‐caloric artificial sweeteners (NCAS). However, a number of studies suggest that NCAS cause counterintuitive metabolic derangements that may contribute to negative health outcomes. Conversely, there are limited duration studies focused on weight management suggesting the opposite, thus creating controversy. The impact of chronic NCAS consumption in type 1 diabetes (T1D) patients or those with a high genetic susceptibility for T1D is also unknown. T1D has a strong genetic basis; however, environmental factors likely underlie the rapid increase in T1D incidence in the past few decades. Children with T1D frequently consume NCAS as a way of managing postprandial hyperglycemia and insulin doses. Increased availability of NCAS within the home likely also translates to more NCAS consumption by non‐diabetic siblings with a higher risk to develop T1D. Our study aimed to test the effects of chronic consumption of NCAS subtypes on high T1D susceptibility backgrounds. To test this, we supplemented the diet of T1D susceptible BioBreeding DR+/+ rats with aspartame (metabolized) and acesulfame potassium (Ace‐K+, not metabolized) for three weeks in their drinking water. DR+/+ rats consuming NCAS water had a significant increase in blood glucose versus normal water controls. Metabolomics analysis of plasma from these rats revealed alterations in lipid and energy metabolism, with a greater effect resulting from Ace‐K+. Using a novel mass spectrometry‐based quantification assay we developed, we found that Ace‐K+ also accumulated in the plasma these DR+/+ rats (21+10 μM; N=6) following chronic consumption. Further follow‐up was performed in vitro using rat cardiac microvascular endothelial cells (RCMVECs) to measure cardiometabolic effects. The RCMVECs were treated with an Ace‐K+ dose‐response for three weeks and they exhibited impairment during in vitro tube formation and cell viability tests (p<0.05; N=3). Gene expression analysis of the RCMVECs displayed significant differences in insulin signaling, glucose metabolism, and inflammatory regulation (p<0.05; N=4). In further tests, we also observed that chronic Ace‐K+ consumption accelerated the rate of type 1 diabetes onset in DRlyp/lyp rats. Overall, these results suggest that the accumulation of absorbed intact NCAS subtypes, like Ace‐K+, have the potential to lead to metabolic flux that may be important in pre‐ and post‐onset T1D, whereas the metabolized aspartame caused less fluctuation. We are now focused on translating these studies to a pediatric T1D population and are implementing a novel NCAS food frequency questionnaire and plasma quantification test to better measure consumption clinically.Support or Funding InformationSupport for this project was provided by the Medical College of Wisconsin Clinical and Translational Science Institute, the Mayo Clinic Metabolomics Resource Core (pilot award provided by the U24DK100469 grant to BRH), and the Children’s Research Institute (CRI19301 to MH).