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 ¹ H/ ³¹ P 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