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Patients with amyotrophic lateral sclerosis (ALS) often show hallmarks of type 2 diabetes mellitus (T2DM). However, the causal link between ALS and T2DM has remained a mystery. We now demonstrate that 60% of ALS patients with T2DM (ALS-T2DM) have sera that exaggerated K + -induced increases in cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) in mouse islet cells. The effect was attributed to the presence of pathogenic immunoglobulin Gs (IgGs) in ALS-T2DM sera. The pathogenic IgGs immunocaptured the voltage-dependent Ca 2+ (Ca V ) channel subunit Ca V α 2 δ1 in the plasma membrane enhancing Ca V 1 channel-mediated Ca 2+ influx and [Ca 2+ ] i , resulting in impaired mitochondrial function. Consequently, impairments in [Ca 2+ ] i dynamics, insulin secretion, and cell viability occurred. These data reveal that patients with ALS-T2DM carry cytotoxic ALS-T2DM-IgG autoantibodies that serve as a causal link between ALS and T2DM by immunoattacking Ca V α 2 δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.

proceedings of the national academy of sciences of the united states of america

IgGs from patients with amyotrophic lateral sclerosis and diabetes target Ca <sub>V</sub> α <sub>2</sub> δ1 subunits impairing islet cell function and survival

IgGs from patients with amyotrophic lateral sclerosis and diabetes target Ca V α 2 δ1 subunits impairing islet cell function and survival

IgGs from patients with amyotrophic lateral sclerosis and diabetes target Ca _V α ₂ δ1 subunits impairing islet cell function and survival