Abstract
Disclosure: D. Munjwani: None. D. Hill: None. D. Regan: None. D. Lee: None. M. Muehlbauer: None. H. Hohmeier: None. M. Jensen: None. J. Bain: None.
Type 1 diabetes (T1D), a leading cause of mortality in the United States, is associated with heart disease, nephropathy, neuropathy, retinopathy, and stroke. While management of T1D with medications and healthy lifestyle choices is critical, recent research highlights the contributory role of environmental diabetogens in the pathogenesis of T1D. Here, we propose that the furan compound, 5-hydroxymethyl-2-furfural (HMF), which forms when hexoses such as glucose or fructose lose three water molecules during thermal food processing, might be an unrecognized dietary diabetogen. HMF is a suspected mutagen and carcinogen. In a previous experiment in the rat 832/13 beta-cell line, when cultures were shifted from low- (2.5 mM) to high-glucose media (12 mM), we were surprised to see a large increase in intracellular 5-hydroxymethyl-2-furoic acid (Sumiki’s acid), a cellular oxidation product of HMF. This caused us to wonder whether beta cells are able to concentrate HMF from their environment and oxidize it to Sumiki’s acid. In the present study, the transgenic rat beta-cell line, beta-G 49/206, which shares a close common ancestor with 832/13, was exposed to low-glucose (2.5 mM), high-glucose (12 mM), and a high-glucose buffer spiked with HMF (1 mM). Intracellular metabolites were measured by ultrahigh-pressure liquid chromatography / quadrupole, time-of-flight mass spectrometry (UHPLC / QToF MS) on an Agilent 1290 / 6546 system and by gas chromatography (GC) / MS on an Agilent 8890 / 5977B system. Glucose concentrations were measured on a Beckman UniCel DxC 600 Synchron instrument. Mass spectrometry showed that the 49/206 beta cell line took up HMF and oxidized it to Sumiki’s acid. HMF-treated cells showed increased adenine, 6-methyluracil, spermidine, amino acids (lysine, phenylalanine, tyrosine), and lactate, and decreased Krebs cycle intermediates (succinate, fumarate, malate), suggesting a shift toward glycolysis – though that effect size was modest. By deliberately spiking a glucose-secretion buffer with HMF, we confirmed our earlier suspicion that transgenic rat beta-cell lines can take up HMF and oxidize it to Sumiki’s acid. HMF is abundant in ultra-processed foods, notably in high-fructose corn syrup. Given HMF’s known toxicity and our lack of understanding of how Sumiki’s acid might impact beta-cell biology, we think that further work is needed to determine whether physiologic levels of HMF and its oxidation products are potentially diabetogenic in the American diet.
Presentation: Sunday, July 13, 2025