The ratio of levels of insulin signaling system factors and diabetes markers in the blood of patients with non-muscle-invasive bladder cancer in the absence and presence of type 2 diabetes mellitus.

Abstract

e16609 Background: Components of the insulin signaling system (ISS) are involved in oncogenesis, and type 2 diabetes mellitus (T2DM) is known to influence cancer development. However, data on ISS alterations in non-muscle-invasive bladder cancer (NMIBC) are contradictory, and changes associated with the co-occurrence of NMIBC and T2DM remain largely unexplored. This study aimed to investigate the levels of ISS factors and markers of diabetes mellitus in the blood of patients with NMIBC, both with and without comorbid T2DM. Methods: The study included 20 patients with primary NMIBC, 20 patients with NMIBC and comorbid T2DM (age 49-72 years, both sexes), 12 patients with T2DM without cancer, and 10 age- and sex-matched healthy donors. Blood levels of insulin-like growth factors (IGF-1, IGF-2), insulin-like growth factor-binding protein 1 (IGFBP-1), glucose, glycated hemoglobin (HbA1c), insulin, and C-peptide were measured by enzyme-linked immunosorbent assay (ELISA) prior to anticancer treatment. Statistical analysis was performed using the Mann-Whitney test (with Bonferroni correction), coefficient of variation, and Spearman's rank correlation coefficient. Only statistically significant differences (p < 0.05) are reported. Results: Blood levels of ISS factors in patients with NMIBC exhibited high variability (coefficient of variation up to 273%). Despite normal insulin levels, a sharp decrease in C-peptide (3.6–21-fold lower than the minimum donor value) and a 3.5-fold average increase in IGFBP-1 were observed. In patients with comorbid T2DM, these differences from donors were 2–6 times less pronounced. Unlike patients with NMIBC-only or T2DM-only, those with both conditions showed relatively low levels of IGF-1 and IGF-2, similar to donor values. Among patients receiving effective metformin therapy for T2DM, IGF-1 levels were the lowest across all groups. A strong negative correlation between C-peptide and glucose levels was found exclusively in the NMIBC+T2DM group (r = -0.845). In the metformin-treated subgroup of this cohort, a strong positive correlation was observed between IGF-1 and glucose levels (r = +0.803). Conclusions: Blood levels of ISS factors in NMIBC patients are highly variable. The presence of comorbid T2DM shifts the profile toward lower IGF-1 and IGF-2 levels. Normoinsulinemia in NMIBC is accompanied by decreased C-peptide and elevated IGFBP-1, alterations that are attenuated in patients with T2DM. The minimal IGF-1 levels in normoglycemic patients on metformin, coupled with the positive IGF-1/glucose correlation, suggest a potential antitumor mechanism of metformin mediated through IGF-1 suppression.