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Published on: April 13, 2021
Protein Kinase C (Pkc)-δ Mediates Arginine-Induced Glucagon Secretion in Pancreatic α-Cells
Norikiyo Honzawa1,2, Kei Fujimoto3, Masaki Kobayashi2
1Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan.
Abstract:
The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.
Insights
Protein kinase C delta (Pkcδ) is crucial for regulating glucagon secretion in pancreatic alpha-cells. This study reveals Pkcδ
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Pathophysiology
Background:
- Type 2 diabetes involves complex dysregulation of insulin and glucagon.
- Protein kinase C delta (Pkcδ) is a serine-threonine kinase implicated in cell death and proliferation.
- The specific role of Pkcδ in pancreatic alpha-cell glucagon secretion is not well understood.
Purpose of the Study:
- To investigate the physiological function of Pkcδ in regulating glucagon secretion from pancreatic alpha-cells.
- To determine if Pkcδ plays a role in amino acid-stimulated glucagon release.
Main Methods:
- Utilized Pkcδ-knockdown InR1G9 cells, a glucagon-secreting cell line.
- Employed pancreatic alpha-cell-specific Pkcδ-knockout (αPkcδKO) mice and their isolated islets.
- Measured glucagon secretion in response to arginine stimulation.
Main Results:
- Knockdown of Pkcδ in InR1G9 cells diminished basal glucagon secretion.
- Arginine stimulation led to increased Pkcδ phosphorylation at Thr505, indicating activation.
- Pkcδ knockdown and knockout significantly reduced arginine-induced glucagon secretion in both cell lines and in vivo models.
Conclusions:
- Pkcδ is essential for mediating arginine-induced glucagon secretion in pancreatic alpha-cells.
- These findings elucidate a key molecular mechanism in amino acid-stimulated glucagon release.
- Targeting Pkcδ presents a potential therapeutic strategy for novel antidiabetic drug development.
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