Long-Term Consumption of Sucralose Induces Hepatic Insulin Resistance through an Extracellular Signal-Regulated Kinase 1/2-Dependent Pathway

Abstract

Sugar substitutes have been recommended to be used for weight and glycemic control. However, numerous studies indicate that consumption of artificial sweeteners exerts adverse effects on glycemic homeostasis. Although sucralose is among the most extensively utilized sweeteners in food products, the effects and detailed mechanisms of sucralose on insulin sensitivity remain ambiguous. In this study, we found that bolus administration of sucralose by oral gavage enhanced insulin secretion to decrease plasma glucose levels in mice. In addition, mice were randomly allocated into three groups, chow diet, high-fat diet (HFD), and HFD supplemented with sucralose (HFSUC), to investigate the effects of long-term consumption of sucralose on glucose homeostasis. In contrast to the effects of sucralose with bolus administration, the supplement of sucralose augmented HFD-induced insulin resistance and glucose intolerance, determined by glucose and insulin tolerance tests. In addition, we found that administration of extracellular signal-regulated kinase (ERK)-1/2 inhibitor reversed the effects of sucralose on glucose intolerance and insulin resistance in mice. Moreover, blockade of taste receptor type 1 member 3 (T1R3) by lactisole or pretreatment of endoplasmic reticulum stress inhibitors diminished sucralose-induced insulin resistance in HepG2 cells. Taken together, sucralose augmented HFD-induced insulin resistance in mice, and interrupted insulin signals through a T1R3-ERK1/2-dependent pathway in the liver.

Sucralose: From Sweet Success to Metabolic Controversies—Unraveling the Global Health Implications of a Pervasive Non-Caloric Artificial Sweetener

“…Similarly, Meng and colleagues analyzed the liver tissue of five mice exposed to a sucralose diet. They observed that mice fed with sucralose exhibited decreased insulin signal transduction in both HepG2 cells and liver tissue compared to mice fed with a standard chow diet [ 72 ]. This diminished insulin signaling subsequently compromised glucose utilization by liver cells, potentially leading to impaired hepatic homeostasis, and triggering anaerobic metabolism with the accumulation of ROS products.…”

Unveiling the profound influence of sucralose on metabolism and its role in shaping obesity trends

“…Sucralose consumption elevated insulin levels and decreased insulin sensitivity, indicating a possible effect on glucose metabolism. Consuming sucralose has been associated with elevated insulin levels and reduced insulin sensitivity ( 117 ). Insulin resistance, characterized by elevated insulin levels and diminished cellular responsiveness to insulin, is a pivotal component in various metabolic disorders.…”