Evidence of Impaired Glucose Signaling in Amyotrophic Lateral Sclerosis

insulin receptor
insulin receptor
Further research is warranted to clarify the role played by insulin resistance in the pathogenesis of 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).

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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.


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