Introduction Diabetes affects 425 million people worldwide, and is characterized by abnormal carbohydrate metabolism (hyperglycemia). Type 2 diabetes (T2D), characterized by variable degrees of insulin deficiency and resistance and is responsible for > 90% of cases of diabetes in adults. On the other hand, Type 1 diabetes (T1D) is an autoimmune disorder with an absolute deficiency of insulin. Diabetic Ketoacidosis (DKA) is the most common acute cause of morbidity and mortality in youth with T1D. The endoplasmic reticulum (ER) is the major cellular mechanism responsible for protein folding. Several factors such as hyperglycemia can disrupt ER homeostasis, resulting in ER stress and the unfold protein response (UPR). One class of toxic misfolded protein that can occur is soluble protein oligomers (SPOs). Persistent hyperglycemia is one of the main factors responsible for the pathogenesis of T1D and T2D complications. Based on this facts, we have hypothesized that SPOs are increased in the plasma sample from patients with DKA. Further, we wanted to know if soluble oligomers induce ER stress, or ER stress induces oligomers release. Methods By using the dot blotting approach, we measured SPOs in plasma from young (8 - 18 years old) male (n=4) and female (n=6) DKA patients in three different time points: (a) initial 6 -12 hours of treatment; (b) 2-3 weeks post-DKA correction; (c) 3 months post-DKA correction. Mechanistically, we evaluated if vascular smooth muscle cells (VSMCs) from the tibial artery of a 45 year old male with T2D presents with ER stress and/or SPOs in the media. VSMCs was treated with ER stress inhibitor (4-PBA, 2 mmol/L), SPOs inhibitor (K01-162, 10 µmol/L) or vehicle (DMSO) for 48 hours. Results SPOs were present in plasma from male and female patients with DKA at all-time points. Interestingly, SPOs levels increased in a time-dependent manner in females, but not males (Figure 1). On the other hand, SPOs were not detected in the media of VSMCs from a patient with T2D. However, the C/EBP Homologous Protein (CHOP), a marker for ER stress, was expressed in VSMC from this patient, and the treatment with ER stress inhibitor, PBA, but not SPOs inhibitor, K01-162, decreased its expression (A.U.: Vehicle: 55.3 ± 5 vs. PBA: 40.1± 5 * vs. K01-162: 64.3 ± 9; *p=0.04 vs. Vehicle). Conclusion Here we propose that in diabetes, there is an accumulation of toxic misfolded proteins in the form of SPOs that may contribute to the systemic inflammation observed in young patients with DKA. Although VSMC presents ER stress, this tissue may not be the main source of SPOs, at least in vitro or in the absence of hyperglycemia. These data have promising clinical implications as it proposes a novel mechanism that can be exploited as a therapeutic target in diabetes and DKA.