The following study was conducted by Scientists from Karolinska Institutet, Stockholm, Sweden; Jilin Academy of Traditional Chinese Medicine, China; Northeast Normal University, China; AstraZeneca, Gothenburg, Sweden; West China Hospital of Sichuan University, Chengdu, China. Study is published in Proceedings of the National Academy of Sciences Journal as detailed below.
Proceedings of the National Academy of Sciences (2020); 117(1): 448-453
Enhanced Expression of β cell CaV3.1 Channels Impairs Insulin Release and Glucose Homeostasis
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.
Abstract
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.
Source:
Proceedings of the National Academy of Sciences
URL: https://www.pnas.org/content/117/1/448
Citation:
Yu, J., Y. Shi, et al. (2020). “Enhanced expression of β cell CaV3.1 channels impairs insulin release and glucose homeostasis.” Proceedings of the National Academy of Sciences 117(1): 448-453.
