Systemic Inflammation and Peripheral T Cell Responses Associate With Hepatic Energy Metabolism in Recent-Onset Type 1 Diabetes

People with type 1 diabetes feature lower concentrations of hepatic adenosine-triphosphate (ATP) and inorganic phosphate (Pi), which further decline during the early course of disease. However, it is unknown whether inflammatory pathways are involved in the diabetes-associated alterations of hepatic energy metabolism. Participants (median age 35 years, BMI 21.7 kg/m 2, HbA1c 6.0%) of the German Diabetes Study (GDS) with short type 1 diabetes duration (≤ 5 years) underwent 1H/ 31P magnetic resonance spectroscopy to quantify hepatic lipid content, γATP and Pi concentrations. Inflammatory proteins in serum and in supernatants of stimulated CD4 + and CD8 + T cells were measured by a multiplex assay (OLINK Target 96 Inflammation). Analyses were adjusted for multiple testing with false discovery rate (FDR)-correction. Hepatic γATP concentrations positively correlated with circulating TNFSF14 (r = 0.98, p < 0.001, p FDR  = 0.009) and MMP10 (r = 0.71, p = 0.047). Hepatic Pi was positively associated with circulating MMP10 (r = 0.90, p = 0.002), with CD4 + T cell responses, particularly CCL3 (r = 0.74, p = 0.010) and CCL4 (r = 0.75, p = 0.008), and with CD8 + T cell responses, particularly CCL3 (r = 0.86, p = 0.014), CCL4 (r = 0.96, p < 0.001) and TNFSF14 (r = 0.89, p = 0.007). Hepatic lipid content (median 0.4%) negatively correlated with IL-2, IL4, IL-13 and TNF release from CD8 + T cells (all p FDR < 0.05). Even in lean metabolically well-controlled persons with early type 1 diabetes, measures of hepatic energy metabolism strongly associate with a specific inflammatory profile and T cell responses, suggesting a role of pro-inflammatory mechanisms in the regulation of hepatic metabolism, even in the absence of steatotic liver disease. Trial Registration: ClinicalTrial.gov identifier: NCT01055093.