Type 2 diabetes mellitus (T2DM) is a multifaceted metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction, leading to varying metabolic insults. Grape pomace, a byproduct of the winemaking industry, is under investigation as a potential therapy for T2DM due to its abundant content of bioactive polyphenols and dietary fiber. Within the current backdrop of environmental concerns, the conversion of grape pomace into a safe and applicable form, with the aim of promoting sustainable management of environmental waste, acts as a catalyst for the emergence of viable alternatives. Grape pomace flour (GPF) represents an economical and feasible solution. We hypothesized that dietary supplementation of GPF would improve the glycemic control and the associated risk factors in T2DM-induced animals. In this sense, the present study, approved by CEUA UFPel No 033578/2022-14, aimed to evaluate the effect of the GPF from ‘Arinto’ and ‘Touriga Nacional’ grape varieties on biochemical and histopathological parameters in an animal model of T2DM. To induce T2DM, rats were given a high-fat diet and a Streptozotocin (STZ) injection (35 mg/kg). The rats were divided into five groups: Control (CT), T2DM, T2DM+Metformin (Met) (250 mg/kg), T2DM+'Arinto' GPF 10% (WGPF), and T2DM+'Touriga Nacional' GPF 10% (RGPF). Results showed that Met, WGPF, and RGPF groups had significantly lower blood glucose ( p<0.05, P<0.001, and p<0.01, respectively) and triglyceride levels ( p<0.001) compared to the T2DM group. Also, we observed a significant increase in serum cholesterol levels in the T2DM when compared to the CT ( p<0.01), that was reversed in the treated groups. Additionally, the T2DM+RGPF group had higher levels of high-density lipoprotein (HDL) compared to the control group ( p<0.05). Histopathological analysis revealed structural changes in the pancreas in the T2DM animals, while tissue damage was not observed in the Met and GPF supplementation groups. In conclusion, both 'Arinto' and 'Touriga Nacional' GPF demonstrated protective effects against increased blood glucose, triglycerides, and cholesterol levels in a T2DM animal model. 'Touriga Nacional' GPF also increased HDL levels and showed protective effects on pancreatic cell structure. This suggests that GPF could be a promising dietary option for T2DM and its complications. FCT-Foundation for Science and Technology (UIDB/04567/2020 CBIOS, and UIDP/04567/2020 CBIOS), Pelotas Federal University (UFPel), and Brazil's Federal Government (CNPq). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.