Diabetes

Diabetes significantly accelerates fibrotic and inflammatory processes in vital organs, yet current treatments leave a high residual risk of complications. The right biomarkers may offer a way to detect and quantify these underlying changes, particularly in kidney and cardiovascular tissues. By capturing early shifts in tissue dynamics, these biomarkers enable better risk stratification, selection, and evaluation of treatment efficacy—supporting more targeted and effective management of diabetic complications.

Despite the success of novel therapies, the residual risk of outcomes in persons with both type 1 diabetes (T1D) and type 2 diabetes (T2D) remains high. Therefore, novel biomarkers are needed to predict complications before clinical manifestations. There are currently no approved antifibrotic drugs capable of halting and/or reversing progression of kidney and/or cardiac fibrosis.

As novel antifibrotic therapies enter clinical development in early phases of chronic kidney disease (CKD), diabetic kidney disease (DKD), and cardiovascular disease (CVD), specific markers for selecting individuals and evaluating efficacy of treatment are needed.

There is a significant separation between healthy people and individuals with T2D based on serum levels of extracellular matrix (ECM) remodeling biomarkers. Across all eight biomarkers, individuals with T2D show consistently elevated median levels compared to age-and gender matched healthy controls, indicating upregulated fibrotic activity and matrix turnover characteristic of diabetic tissue pathology. Data are median (IQR); T2D (n = 267); healthy subjects (n = 79).

NordicPRO-C3™ and nordicPRO-C6™, markers of collagen type III and VI formation respectively, are markedly higher in T2D, pointing to increased fibrogenesis and pro-fibrotic signaling—particularly through Endotrophin in the case of nordicPRO-C6™. The nordicPRO-C3™/C3M ratio, which captures the imbalance between collagen III synthesis and degradation, is also significantly elevated, suggesting a shift toward net matrix accumulation.

Markers of degradation—C1M (collagen I), C3M (collagen III), and C4M (collagen IV)—are elevated in T2D as well, though the increase in formation markers is generally more pronounced. TUM (tumstatin, a fragment of collagen IV cleaved by MMP-2 and MMP-9) and TIM (titin fragment from MMP-12-mediated breakdown) further reinforce a systemic increase in MMP-driven proteolysis within diabetic individuals.

This biomarker profile reflects dysregulated ECM turnover in T2D, integrating increased collagen deposition with enhanced matrix degradation, a fibrotic phenotype consistent with known vascular and organ complications. The clear separation from healthy subjects across all markers supports the use of these ECM metrics for stratifying disease burden and evaluating therapeutic interventions targeting tissue remodeling in metabolic disease.

Longitudinal plasma nordicPRO-C6™ levels in individuals with T2D over a 5-year period (from the DC-ren study), compared the effects of renin-angiotensin system inhibitor (RASi) monotherapy versus combination therapy with RASi and a sodium-glucose cotransporter 2 inhibitor (SGLT2i).

Participants on RASi monotherapy exhibited an upward trajectory in nordicPRO-C6™ concentrations, indicating persistent or increasing pro-fibrotic signaling over time. In contrast, those receiving combined RASi + SGLT2i therapy show a downward trend in plasma nordicPRO-C6™ levels, with a statistically significant difference in slope (p = 0.002), suggesting that combination therapy actively suppresses fibrogenic processes.

Given that nordicPRO-C6™ reflects collagen type VI formation and endotrophin-mediated fibrosis, this decline aligns with the observed kidney benefit—specifically a slower decline in eGFR—among individuals on dual therapy.

Diabetic kidney disease (DKD) and diabetic cardiomyopathy are initiated by systemic changes, triggering metabolic, hemodynamic, inflammatory, and fibrotic processes contributing to disease progression.

Metabolic disturbances lead to the accumulation of advanced glycation end products, generation of reactive oxygen species, and increased oxidative stress, which induce the production of pro-fibrotic and pro-inflammatory factors and lead to altered metabolism, inflammation, and ECM remodeling.

An imbalance in the formation and/or degradation of ECM components is highly linked with the development of fibrosis. Together these changes mediate cellular hypertrophy and proliferation, inflammation, and fibrosis, ultimately resulting in organ failure (MR, mineralcorticoid receptor; TGF-β, transforming growth factor-β; PAI-1, plasminogen activator inhibitor-1; CTGF, connective tissue growth factor; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; MMP-9, matrix metalloproteinase-9).