Non-Nutritive Sweetener Consumption and Glucose Homeostasis in Older Adults With Prediabetes

Non-Nutritive Sweetener Consumption (Aspartame and Sucralose) and Glucose Homeostasis in Older Adults With Prediabetes

Animal and observational research in humans suggest that specific types of non-nutritive sweeteners (NNS) may impair glycemic control. However, 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.

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 oral glucose tolerance test (OGTT), 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.

Controlled feeding study. Dosage of aspartame will follow 50% of the acceptable daily intake (equivalent to 25 mg/kg for aspartame). This amount represents 1,500 mg/day of aspartame for a 60 kg adult.

Controlled feeding study. Dosage of sucralose will follow 50% of the acceptable daily intake (equivalent to 2.5 mg/kg for sucralose). This amount represents 150 mg/day of sucralose for a 60 kg adult.

Provision of either aspartame, sucralose, or control with no non-nutritive sweeteners to a controlled feeding study to determine impacts on glucose homeostasis.

The area under the curve (AUC) glucose concentrations, mg/dl from the continuous glucose monitoring at baseline and follow-up will be used

Oral glucose tolerance in response to 75 g glucose load; levels of glucose mg/dl will be determined 2 hrs after consuming a 75 glucose load

Insulin uU/mL concentrations from the oral glucose tolerance test at baseline and follow-up will be used

Inflammatory cytokine: Tumor Necrosis Factor alpha pg/mL concentrations will be measured at baseline and follow-up

Inflammatory cytokine: Monocyte chemoattractant protein-1 pg/mL concentrations will be measured at baseline and follow-up

Inclusion Criteria: Age 50+ years Prediabetic (fasting glucose concentration of 100-125 mg/dL, 2-hour oral glucose tolerance test glucose concentration of 140-199 mg/dL, or a HbA1c value of 5.7% to 6.4%) Weight stable for previous 6 months (±2 kg) BMI <40 kg/m2 Sedentary to recreationally active No plans to gain/lose weight or change physical activity level Willing to pick up food daily and consume foods provided for an 8-week period Verbal and written informed consent Approval by Medical Director Consume less than one serving of non-nutritive sweetener per week Exclusion Criteria: BMI >40 kg/m2 Diabetes or diabetes medication Antibiotic, prebiotic or prebiotic use in prior 3 months Uncontrolled hypertension (blood pressure (BP) > 159/99 mmHg) Diagnosed inflammatory bowel disease Past or current heart diseases, stroke, respiratory disease, endocrine or metabolic disease, or hematological-oncological disease Vegetarian or vegan Pregnant or plans to become pregnant Breastfeeding Food allergies or aversions, Phenylketonuria (PKU) Estrogen or testosterone usage

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