Author: Anan Chaiya
Review Article
Mechanistic Review of Aspartame-Induced Pancreatic Toxicity Involving ZIPK, STAT3 and Caspase-3 Pathways
Anan Chaiya*
Department of Medicine, Chulalongkorn University, Bangkok, Thailand
Published: 22 November 2021
Abstract
Aspartame, a low-calorie artificial sweetener composed of aspartic acid, phenylalanine, and methanol, is widely used in diet beverages and sugar-free food products. Although approved by regulatory agencies such as the FDA and EFSA, concerns have been raised about its potential adverse health effects, particularly in relation to pancreatic function and glucose metabolism. Emerging evidence suggests that chronic exposure to aspartame may induce cellular stress and toxicity in pancreatic β-cells, ultimately impairing insulin secretion and increasing the risk for metabolic disorders like type 2 diabetes. This review explores the biochemical and molecular mechanisms through which aspartame may contribute to pancreatic cell dysfunction and death. Methanol, one of aspartame’s breakdown products, is metabolized into formaldehyde and formic acid—both of which are known to generate reactive oxygen species (ROS) and induce oxidative stress. Additionally, phenylalanine, in high concentrations, may interfere with neurotransmitter synthesis and hormone signaling, further disrupting β-cell homeostasis. Aspartic acid, an excitatory amino acid, may enhance excitotoxicity, contributing to mitochondrial dysfunction and apoptosis in pancreatic cells.
We discuss how these molecular insults converge to activate pathways such as oxidative stress, ER stress, mitochondrial depolarization, and caspase-mediated apoptosis. Furthermore, we examine animal model studies and in vitro experiments demonstrating dose-dependent reductions in β-cell viability and insulin output after aspartame exposure. These effects are especially concerning given the high consumption of aspartame in modern diets, particularly among individuals aiming to manage weight or blood glucose levels. The review also highlights strategies to mitigate aspartame’s cytotoxic effects, including antioxidant supplementation and dietary modifications. Finally, we identify key gaps in the current literature and propose future research directions, such as long-term cohort studies and mechanistic investigations using human pancreatic organoids. A deeper understanding of aspartame’s cellular impact is critical to reassess its safety profile and inform public health recommendations.
Keywords: Aspartame metabolism; Pancreatic β-cell apoptosis; Oxidative stress; Artificial sweeteners; Insulin secretion; Diabetes risk; Mitochondrial dysfunction
