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Significance We provide evidence of a mechanistic link between ALS and T2DM. Our data show that a subgroup of ALS-T2DM patients have sera that enhance CaV1 channel-mediated Ca2+ influx and exaggerate [Ca2+]i. These effects occur because the sera accommodate cytotoxic IgG autoantibodies that immunocapture CaVα2δ1 subunits. As a consequence, impairments in [Ca2+]i dynamics, mitochondrial function, insulin secretion, and cell viability appear. We could clarify not only the identity of this serum factor but also the molecular mechanisms underlying its effects on the islet cells. Our findings may lay the foundation for a treatment strategy for this complex and severe group of diabetic patients., 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 Ca2+ concentration ([Ca2+]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 Ca2+ (CaV) channel subunit CaVα2δ1 in the plasma membrane enhancing CaV1 channel-mediated Ca2+ influx and [Ca2+]i, resulting in impaired mitochondrial function. Consequently, impairments in [Ca2+]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 CaVα2δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.

Significance We reveal that increased expression of CaV3.1 channels in rat islets selectively impairs first-phase glucose-stimulated insulin secretion. This deterioration is recapitulated in human islets. Its causal role in diabetes development is clearly manifested in an in vivo diabetic model. Mechanistically, this is due to reduction of phosphorylated FoxO1 in the cytoplasm, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III in a CaV3.1 channel- and calcineurin-dependent manner. Our findings suggest that elevated expression of CaV3.1 channels in pancreatic islets drives FoxO1-mediated down-regulation of exocytotic proteins resulting in the diabetic phenotypes of impaired insulin secretion and aberrant glucose homeostasis. This causal connection pinpoints β cell CaV3.1 channels as a potential druggable target for antidiabetes therapy., Voltage-gated calcium 3.1 (CaV3.1) channels are absent in healthy mouse β cells and mediate minor T-type Ca2+ currents in healthy rat and human β cells but become evident under diabetic conditions. Whether more active CaV3.1 channels affect insulin secretion and glucose homeostasis remains enigmatic. We addressed this question by enhancing de novo expression of β cell CaV3.1 channels and exploring the consequent impacts on dynamic insulin secretion and glucose homeostasis as well as underlying molecular mechanisms with a series of in vitro and in vivo approaches. We now demonstrate that a recombinant adenovirus encoding enhanced green fluorescent protein–CaV3.1 subunit (Ad-EGFP-CaV3.1) efficiently transduced rat and human islets as well as dispersed islet cells. The resulting CaV3.1 channels conducted typical T-type Ca2+ currents, leading to an enhanced basal cytosolic-free Ca2+ concentration ([Ca2+]i). Ad-EGFP-CaV3.1-transduced islets released significantly less insulin under both the basal and first phases following glucose stimulation and could no longer normalize hyperglycemia in recipient rats rendered diabetic by streptozotocin treatment. Furthermore, Ad-EGFP-CaV3.1 transduction reduced phosphorylated FoxO1 in the cytoplasm of INS-1E cells, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III. These effects were prevented by inhibiting CaV3.1 channels or the Ca2+-dependent phosphatase calcineurin. Enhanced expression of β cell CaV3.1 channels therefore impairs insulin release and glucose homeostasis by means of initial excessive Ca2+ influx, subsequent activation of calcineurin, consequent dephosphorylation and nuclear retention of FoxO1, and eventual FoxO1-mediated down-regulation of β cell exocytotic proteins. The present work thus suggests an elevated expression of CaV3.1 channels plays a significant role in diabetes pathogenesis.