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

Abstract

IntroductionProgressive 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 γ-diketones. γ-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 γ-diketone pyrroles are elevated in DM.Research design and methodsWe measured the urinary concentration of γ-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 γ-diketone pyrroles and indicators of DM.ResultsCompared with healthy controls, those with DM had significantly higher levels of fasting blood glucose, glycated hemoglobin A1c, urinary ketone bodies and urinary γ-diketone pyrroles. The median concentration of urinary γ-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 γ-diketone pyrroles and indicators of DM.ConclusionsDiabetic dysmetabolism includes increased generation and excretion of neuropathy-associated γ-diketone pyrroles. These findings form the foundation for studies to test whether γ-diketone pyrrole concentration correlates with quantitative sensory (vibration and temperature) and electrodiagnostic testing.

Protein pyrrole adducts are associated with elevated glucose indices and clinical features of diabetic diffuse neuropathies

“…Figure 1 shows that we drew on a population ( n = 534) of 60–79 year‐old Chinese persons who resided in the Luohu district of Shenzhen City, Guangdong Province, China; these individuals had previously participated in a published case–control study. 11 Eight persons with abnormal kidney function, eight individuals aged >80 years, and two individuals with extreme glucose levels (HbA1c > 15%) were excluded. Among the 516 remaining individuals, 258 with elevated glucose indices (glycated hemoglobin HbA1c ≥ 6.5% and FBG ≥ 7.0 mM) were shortlisted for assessment of DSPN symptom and resting heart rates.…”

The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin

“…Fluctuations typical of a circadian rhythm were not observed for 2,5-hexanedione in blood or urine. Excretion of 2,5-hexanedione was inversely related to age among Chinese subjects [ 99 ], while a comparison of two independent studies suggested that levels of urinary pyrroles were markedly higher in older persons [ 101 , 102 ].…”

“…We assayed the urinary concentration of γ-diketone pyrroles in age- and gender-matched elderly (60–84 years) Chinese persons with and without ( n = 267/group) indicators of diabetes mellitus. Subjects were drawn from a community of 9411 adults aged ≥ 60 years in the city of Shenzhen, Guangdong, China [ 102 ]. Subjects with diabetes mellitus relative to healthy controls had significantly higher levels of fasting blood glucose, glycated hemoglobin A1c, urinary ketone bodies, and urinary γ-diketone pyrroles.…”

“…Studies of very old rats reveal an age-associated axonopathy featured by axonal swelling and distal retrograde degeneration of the gracile tract, similar but less affected cuneate nuclei, spinocerebellar tracts, and corticospinal tracts [ 161 ]. While the etiology of these neuropathological changes is unknown, it is noteworthy that age-related changes are found in levels of 2,5-hexanedione (decrease) and associated pyrroles (increase) in acidified human urine [ 99 , 102 ]. This might indicate age-dependent increased binding of 2,5-hexanedione to target proteins, including neuroproteins responsible for maintenance of axonal integrity.…”

“…The thin black line extended from the thick black bar represents the upper (max) and lower (min) adjacent values of the data. ( Figure 5 A was redrawn from [ 102 ]).…”