Diabetes mellitus is associated with elevated urinary pyrrole markers of i 3-diketones known to cause axonal neuropathy

Introduction Progressive distal symmetrical axonal neuropathy, a complication of diabetes mellitus (DM), has an unknown cause. Normal physiological metabolism and diabetic dysmetabolism are associated with the generation of i 3-diketones. i 3-Diketones form pyrroles with protein amines, notably with axonal proteins required for the maintenance of nerve fiber integrity, especially elongate, large-diameter peripheral nerve fibers innervating the extremities. We tested the hypothesis that neuropathy-associated i 3-diketone pyrroles are elevated in DM. Research design and methods We measured the urinary concentration of i 3-diketone pyrroles in age-matched and gender-matched elderly (60-84 years) persons with (n=267) or without (n=267) indicators of DM based in a community population (9411 community older adults aged ≥60 years) in Shenzhen city, Guangdong, China. We used statistical methods, including a generalized linear model, multivariate logistic regression analysis and restricted cubic splines, to assess linear and nonlinear relationships between urinary i 3-diketone pyrroles and indicators of DM. Results Compared with healthy controls, those with DM had significantly higher levels of fasting blood glucose, glycated hemoglobin A1c, urinary ketone bodies and urinary i 3-diketone pyrroles. The median concentration of urinary i 3-diketone pyrrole adducts was significantly higher (p<0.0001) in individuals with DM (7.5 (5.4) μM) compared with healthy controls (5.9 (4.3) μM). Both linear and non-linear relations were found between urinary i 3-diketone pyrroles and indicators of DM. Conclusions Diabetic dysmetabolism includes increased generation and excretion of neuropathy-associated i 3-diketone pyrroles. These findings form the foundation for studies to test whether i 3-diketone pyrrole concentration correlates with quantitative sensory (vibration and temperature) and electrodiagnostic testing.