Excess Fructose Intake Activates Hyperinsulinemia and Mitogenic MAPK Pathways in Association With Cellular Stress, Inflammation, and Apoptosis in the Pancreas of Rats

Guney C., Alcigir M. E., AKAR F.

Molecular Nutrition and Food Research, 2025 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Publication Date: 2025
  • Doi Number: 10.1002/mnfr.70048
  • Journal Name: Molecular Nutrition and Food Research
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, PASCAL, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database
  • Keywords: apoptosis, cellular stress, dietary fructose, inflammation, pancreatic mitogenesis
  • Gazi University Affiliated: Yes

Abstract

The increase in sugar consumption has been associated with current metabolic disease epidemics. This study aimed to investigate the pancreatic molecular mechanisms involved in cellular stress, inflammation, mitogenesis, and apoptosis in metabolic disease induced by high-fructose diet. Here, we used biochemical, histopathological, Western blot, and immunohistochemistry methods to determine the metabolic and pancreatic alterations in male Wistar rats fed 20% fructose in drinking water for 15 weeks. High-fructose consumption in rats increased the immunopositivity and protein expression of glucose transporter 2 (GLUT2) and insulin in the pancreatic tissue, in association with abdominal adiposity, hyperglycemia, and hypertriglyceridemia. The expressions of cellular stress markers, glucose-regulated protein-78 (GRP78) and PTEN-induced putative kinase 1 (PINK1), were increased in the pancreas. The levels of interleukin (IL)-6, nuclear factor kappa B (NFκB), tumor necrosis factor α (TNFα), and IL-1β and components of the Nod-like receptor protein 3 (NLRP3) inflammasome were elevated. Excess fructose intake stimulated the activation of mitogenic extracellular signal-regulated kinases 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK)1 as well as the apoptotic p53 and Fas pathways in the pancreas of rats. There was also an increase in caspase-8 and caspase-3 cleavage. Our findings revealed that dietary high-fructose in the pancreas causes hyperinsulinemia due to the upregulation of GLUT2 together with cellular stress and inflammatory markers, thereby stimulates mitogenic mitogen-activated protein kinase (MAPK) and apoptosis pathways, resulting in a complex pathological situation.