The objective of this study was to characterize 10-year progression patterns of diabetic retinopathy (DR) in type 2 diabetes, focusing on visual, structural and microvascular changes, using ETDRS grading, Optical Coherence Tomography (OCT) and OCT-Angiography (OCTA). The PROGRESS 10 study (NCT04650165) followed annually 222 participants (mean age: 63.1±7.3years; 68% male) with no DR to mild nonproliferative DR (NPDR) (ETDRS 10, 20, 35). Longitudinal changes were quantified for retinal thickness, ganglion cell-inner plexiform layer thickness, skeletonized vessel density (SVD) and perfusion density (PD). Linear mixed-effects models accounted for repeated measures. Of the 222 participants, 115 (62%) completed the 10-year visit, and 24 (11%) developed vision-threatening complications: 7.7% clinically significant macular edema and 3.1% proliferative DR. Over 10 years, 27% worsened, 50% remained stable, and 21% improved on ETDRS grading. Eyes that worsened showed progressive capillary nonperfusion, with significant SVD decreases (-0.186±0.063mm⁻¹/year; p=0.004), while improved eyes showed stable microvascular metrics. At year 10, SVD was lower in worsened eyes compared with stable and improved groups (17.82±2.12vs.18.85±2.08 vs.19.33±2.05; p=0.020). Eyes with no DR to mild NPDR showed different 10-year progression patterns. Capillary nonperfusion, measured by SVD and PD using noninvasive OCTA, differentiated the eyes that worsened or remained stable from those that improved.
ARTICLE HIGHLIGHTS We evaluate the importance of the protein-protein interaction (PPI) between PNPLA3-I148M and its cofactor α/β-hydrolase domain-containing protein 5 (ABHD5) in PNPLA3-I148M-mediated hepatic steatosis. We demonstrate that disrupting the PNPLA3-ABHD5 PPI improves I148M-associated steatosis and markers of liver injury. This work supports the development of therapies targeting the PNPLA3-ABHD5 PPI for the treatment of PNPLA3-I148M-associated metabolic dysfunction-associated steatotic liver disease.
Kidney function can decline in individuals with type 2 diabetes despite normal urinary albumin-to-creatinine ratio (UACR), which may not adequately capture this process. We evaluated whether biomarkers reflecting inflammation, tubular injury, regenerative capacity, and fibrosis improve risk stratification and treatment monitoring beyond UACR in normoalbuminuric individuals with type 2 diabetes. We measured plasma tumor necrosis factor receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1), urinary epidermal growth factor normalized to creatinine (uEGF/Cr), and serum matrix metalloproteinase-7 (MMP-7) at baseline and year one in banked samples from normoalbuminuric participants of the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial. We assessed associations of baseline UACR and biomarkers with a composite kidney outcome (sustained ≥40% decline in kidney function, kidney failure, or renal death) and compared longitudinal trajectories by outcome and treatment (canagliflozin vs. placebo). Of 2573 participants, 53 (2.1%) experienced the composite kidney outcome (28 [3.3%] placebo, 25 [1.5%] canagliflozin). Baseline UACR was not associated with the composite kidney outcome, whereas TNFR-1, TNFR-2, KIM-1, and MMP-7 were each independently associated. Among participants who experienced the composite kidney outcome, TNFR-1, TNFR-2, and KIM-1 increased irrespective of treatment, while uEGF/Cr declined. Canagliflozin attenuated the rise in KIM-1 and the decline in uEGF/Cr, and fully suppressed MMP-7 elevation observed with placebo. In normoalbuminuric individuals with type 2 diabetes, biomarkers reflecting inflammation, tubular injury, regenerative capacity, and fibrosis independently identified individuals at risk of CKD progression and showed divergent trajectories by outcome and treatment, supporting their potential clinical utility for risk stratification and treatment monitoring.
