Evaluation of SGLT2 inhibitor therapeutic efficacy and identification of IL-18/IL-18R1 signaling as a predictive biomarker in patients with T2DM
Description
We hypothesised that circulating proteins predict inter-individual variability in the metabolic and cardiorenal benefits obtained from sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapy in type 2 diabetes mellitus (T2DM). To test this, we combined longitudinal clinical phenotyping with plasma proteomics (Olink ® panels) and PBMC RNA-seq in up to 70 adults initiating SGLT2i treatment and followed for six months. What the Data Show - Clinical outcomes: Significant improvements in HbA1c (median −0.9 %), UACR (−26 %), body-weight (−1.8 kg) and related metabolic indices. - Proteomics: Baseline IL-18R1 and its six-month reduction correlated with glycaemic change, fat-mass loss and albuminuria improvement (AUC = 0.75 for overall response). Macrophage-linked proteins (CD163, CHI3L1, CD93) and inflammasome‐related IL-1R2 also declined after therapy. - Transcriptomics: RNA-seq of paired PBMC samples confirmed down-regulation of pro-inflammatory genes (CCR2, TNFAIP8L2, VIP) and up-regulation of reparative markers (SELENBP1, HIF1A), supporting an anti-inflammatory shift.
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Steps to reproduce
After IRB approval (TSGHIRB 2-108-05-052; A202105153), 70 adults with type 2 diabetes were enrolled, clinically phenotyped at baseline, started on SGLT2-inhibitor therapy, and re-assessed six months later. Fasting plasma was collected, stored at −80 °C, and analysed with Olink Target 96 Inflammation and Cardiovascular III panels to generate NPX values. Peripheral blood mononuclear cells were isolated, total RNA prepared with the Illumina Stranded Total RNA Prep + Ribo-Zero kit, and sequenced on an Illumina NovaSeq 6000. Reads were quality-filtered, mapped to GRCh38, and quantified as TPM; differential expression used a negative-binomial GLM (FDR < 0.05). Processed proteomic and transcriptomic matrices, accompanying metadata, and R scripts for preprocessing, statistics, ROC analysis, and figure generation are deposited in Mendeley Data ( 10.17632/gfv8nh5m52.1). Running the scripts in sequence reproduces all results and figures. Raw FASTQ files are available under controlled access in SRA (accession PRJNA1278918).