Comparative Effects of Dimethyl Malate and Dimethyl Fumarate on NF-κB Signaling and Pancreatic β-Cell Function: Implications for Diabetes Treatment

Type 1 and type 2 diabetes are both commonly associated with the reduction in pancreatic β-cell function and/or mass, and pathological inflammation is a critically important contributor to the loss. Dimethyl Malate (DMM) and Dimethyl fumarate (DMF) are two methyl esters of organic acids found in the TCA cycle. Moreover, DMF is currently FDA-approved for multiple sclerosis and appears to have beneficial anti-inflammatory properties. We hypothesized that DMM and DMF could reduce pancreatic β-cell inflammatory signaling and improve β-cell function. Methods: Immortalized 832/13 INS-1 pancreatic β-cells were treated with either DMM (5 or 10mM) or DFM (50 or 100µM). A pro-inflammatory response was initiated using interleukin-1 (IL-1) at 1ng/ml. NF-κB activity was examined using promoter-luciferase reporter constructs, Western blots, mRNA abundance, and protein secretion, and β-cell function was assessed via insulin secretion. Results: DMF and DMM dose-dependently reduced inflammatory signaling in β-cells, with DMF showing greater efficacy in several tests. At the higher concentrations (100 µM), DMF reduced IL-1β-induced NF-κB promoter activity by 48.3%, while DMM (10 mM) achieved an 18.9% reduction. These changes were also observed for several inflammatory genes including CXCL1, CXCL2, CCL2, CCL20, CXCL10, ICAM-1, iNOS, and COX2. DMF reduced the inflammatory genes significantly more than DMM. Gene expression was most notably reduced in CCL2, ICAM-1, and iNOS, with DMF suppressing mRNA abundance by 98.1, 98.5, and 99.5 percent, while DMM showed 49.7, 64.6, and 68.9 percent reduction, respectively. Moreover, under inflammatory exposure, mRNA abundance of NKX6.1, a key gene in maintaining β-cell identity and function, was significantly upregulated by DMF with an increase of 2.64-fold at the higher concentration, while DMM did not improve NKX6.1 under similar conditions. DMF but not DMM also suppressed phosphorylation of IκBα and the p65 subunit of NF-κB and reduced nuclear translocation of the p65 subunit of NF-κB. Finally, DMM and DMF similarly improved high glucose-stimulated insulin secretion (GSIS) with a 2-fold increase over the GSIS control. However, under IL-1β exposure, only DMF maintained elevated GSIS, showing a 1.5-fold increase above non-inflammatory control levels, whereas DMM failed to preserve insulin secretion. Conclusion: Both DMM and DMF demonstrated anti-inflammatory effects in the pancreatic β-cell, but DMF appears to be more effective. DMF substantially reduced inflammatory gene expression, preserved β-cell-specific transcription factors like NKX6.1, and maintained insulin secretion even under inflammatory conditions. These findings suggest that DMF provides a promising therapeutic avenue for diabetes management through inflammation modulation and β-cell preservation. This project was funded by the NIH NM-INBRE Developmental Research Project (DRPP) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.