Abstract
It has been proposed that cellular Ca2+ signals activate hormone secretion. In pancreatic β cells, which produce insulin, Ca2+ signals have been known to contribute to insulin secretion. Prior to this study, we confirmed that insulin-secreting β cells express CaBP-9k, and assumed that CaBP-9k play a role in β cell insulin synthesis or secretion. Using CaBP-9k knock out (KO) mice, we demonstrated that ablation of CaBP-9k causes reducing insulin secretion and increasing serum glucose. To compare the role of CaBP-9k with pathophysiological conditions, we exposed wild-type and CaBP-9k KO mice to hypoxic conditions for 10 days. Hypoxia induced endoplasmic reticulum (ER) stress, increasing both insulin signaling and insulin resistance. By exposing hypoxia, CaBP-9k KO mice showed an increased level of ER stress marker protein relative to wild type mice. Without hypoxic conditions, CaBP-9K ablation regulates calcium channels and causes ER stress in a CaBP-9K specific manner. Ablation of CaBP-9k also showed decreased levels of sulfonylurea receptor1 (SUR1) and inward-rectifier potassium ion channel 6.2 (Kir6.2), which are insulin secretion marker genes. Overall, the results of the present study demonstrated that CaBP-9k regulates synthesis of insulin and is part of the insulin-secreting calcium signaling.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Blood Glucose / analysis*
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Calbindins / deficiency
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Calbindins / genetics*
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Calcium / metabolism
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Disease Models, Animal
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Endoplasmic Reticulum Stress
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Glucose Tolerance Test
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Hypoxia
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Insulin / metabolism*
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Fluorescence
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Pancreas / metabolism*
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Pancreas / pathology
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Potassium Channels, Inwardly Rectifying / genetics
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Potassium Channels, Inwardly Rectifying / metabolism
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Sulfonylurea Receptors / genetics
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Sulfonylurea Receptors / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Blood Glucose
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Calbindins
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Homeodomain Proteins
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Insulin
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Kir6.2 channel
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Neurod1 protein, mouse
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Potassium Channels, Inwardly Rectifying
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Sulfonylurea Receptors
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein
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Calcium
Grants and funding
This work was supported by the National Research Foundation of Korea (NRF) grant of Korean government (MEST) (No. 2013-010514 and 2015R1A6A1A04020885). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.