Evidence of Impaired Glucose Signaling in Amyotrophic Lateral Sclerosis

In patients with amyotrophic lateral sclerosis (ALS), serum retinol-binding protein 4 (RBP4) concentration is inversely associated with the risk for and prognosis of the disease, which suggests that vitamin A metabolism or impaired glucose signaling might be involved, according to the results of a population-based, case-control cohort study conducted in Germany and published in JAMA Neurology.

The investigators sought to examine the relationship between the onset and prognosis of ALS and serum RBP4 level as a biomarker for insulin resistance and vitamin A metabolism. This study, in which control patients were selected randomly, was established according to the ALS Registry Swabia, located in southern Germany. For each case (n=289), there were 2 age- and sex-matched control patients (n=504) randomly chosen from the general population. The response rates were 64.8% among the cases and 18.7% among the control individuals. The analysis was performed between April 2016 and May 2017.

Among the 289 patients with ALS who were evaluated, 59.5% were men and the mean age was 65.7±10.5 years. In the control participants, 59.3% of individuals were men and the mean age was 66.3±9.8 years. Most of the patients with ALS had lumbar (33.6%), bulbar (31.5%), or cervical (25/3%) onset. Compared with control patients, patients with ALS were characterized by lower body mass index, less educational attainment, smoking, light occupational work intensity, and self-reported diabetes (9.3% of ALS patients vs 11.0% of control patients for the latter).

Median serum RBP4 level was lower among patients with ALS vs control patients (54.0 vs 59.5 mg/L, respectively). Serum RBP4 concentration was inversely and significantly associated with a risk for ALS (odds ratio [OR], 0.40; 95% CI, 0.26-0.62; P for trend <.001). After adjustment for educational attainment, smoking, occupational work intensity, and family history of ALS, this inverse association remained (OR, 0.44; 95% CI, 0.28-0.68; P for trend <.001). After further adjustment for body mass index, self-reported diabetes, and renal function, these estimates did not change considerably (OR, 0.36; 95% CI, 0.22-0.59; P for trend <.001).

During a median follow-up of 14.5 months, 104 of 279 patients with ALS died (mean age, 68,9±10.3 years; 53.9% men). In the ALS group, there was an inverse association between serum RBP4 level as a continuous measure and survival.

The investigators concluded that additional research on this relationship is warranted, including use of a prospective design and other biologic markers, to clarify the role played by insulin resistance in the pathogenesis of ALS, and thus help identify a potential target for therapeutic intervention.

Reference

Rosenbohm A, Nagel G, Peter RS, et al; ALS Registry Study Group. Association of serum retinol-binding protein 4 concentration with risk for and prognosis of amyotrophic lateral sclerosis [published online February 26, 2018]. JAMA Neurol. doi: 10.1001/jamaneurol.2017.5129