Type II diabetes mellitus (T2DM) accounts for approximately 90% of all diabetes mellitus cases in the world. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased capability to target directly or indirectly six core defects associated with T2DM, while the underlying molecular mechanisms of these pharmacological effects are not fully known. This exploratory study was conducted to analyze the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients. Urine samples of thirty-two T2DM patients from the PROVALID study (“A Prospective Cohort Study in Patients with T2DM for Validation of Biomarkers”) collected pre- and post-treatment with GLP-1R agonist drugs were analyzed by CE-MS. In total, 70 urinary peptides were significantly affected by GLP-1R agonist treatment, generated from 26 different proteins. The downregulation of MMP proteases, based on the concordant downregulation of urinary collagen peptides, was highlighted. Treatment also resulted in the downregulation of peptides from SERPINA1, APOC3, CD99, CPSF6, CRNN, SERPINA6, HBA2, MB, VGF, PIGR, and TTR, many of which were previously found to be associated with increased insulin resistance and inflammation. The findings indicate potential molecular mechanisms of GLP-1R agonists in the context of the management of T2DM and the prevention or delaying of the progression of its associated diseases.

We investigated for the first time the effect of combination therapy of renin–angiotensin system inhibition (RASi) and sodium–glucose co-transporter-2 inhibitors (SGLT2is) on endotrophin (ETP), a pro-fibrotic signaling molecule reflecting collagen type VI formation, measured in the plasma of persons with type 2 diabetes (T2D). ETP was measured using the PRO-C6 ELISA in 294 individuals from the “Drug combinations for rewriting trajectories of renal pathologies in type 2 diabetes” (DC-ren) project. In the DC-ren study, kidney disease progression was defined as a >10% decline in the estimated glomerular filtration rate (eGFR) to an eGFR < 60 mL/min/1.73 m². Among the investigated circulating markers, ETP was the most significant predictor of future eGFR. Combination therapy of RASi and SGLT2is led to a significant reduction in ETP levels compared to RASi monotherapy (p for slope difference = 0.002). Higher levels of baseline plasma ETP were associated with a significantly increased risk of kidney disease progression (p = 0.007). In conclusion, plasma ETP identified individuals at higher risk of kidney disease progression. The observed decreased levels of plasma ETP with combination therapy of RASi and SGLT2is in persons with T2D may reflect a reduced risk of kidney disease progression following treatment with SGLT2is.

Aim Type II Diabetes mellitus (T2DM) accounts for approximately 90% of all DM cases in the world; and is diagnosed with increased levels of blood glucose or hyperglycemia. Glucagon-like peptide-1 receptor (GLP-1R) agonists have established an increased capability to target directly or indirectly six core defects associated with T2DM, while, the underlying molecular mechanisms of these pharmacological effects are not fully known. This exploratory study was conducted to analyze the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients. Material and Methods Urine samples of thirty-two T2DM patients from the PROVALID study (A Prospective Cohort Study in Patients with T2DM for Validation of Biomarkers) were collected at pre- and post-treatment with GLP-1R agonist drugs, and analyzed by capillary electrophoresis coupled to mass spectrometry (CE-MS). Results In total, 329 urinary peptides were identified, of which 70 were significantly affected by the GLP-1R agonist treatment; fragmenting from 26 different proteins. The downregulation of MMP proteases, based on the concordant downregulation of urinary collagen peptides with GLP-1R agonist treatment was highlighted in the study. Treatment also resulted in the downregulation of peptides from SERPINA1, APOC3, CD99, CPSF6, CRNN, SERPINA6, HBA2, MB, VGF, PIGR and TTR, many of which were previously found associated with increased kidney and/or vascular damage, indicating beneficial effect of GLP-1R agonists. Conclusions The novel findings in this study, indicate potential molecular mechanisms of GLP-1R agonists in the context of management of T2DM and prevention or delaying the progression of its associated diseases.