Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Yamamoto, Kiyotake; Mizuguchi, Hiroyuki; Tokashiki, Natsumi; Tamaki, Motoyuki; Sato, Youichi; Fukui, Hirokazu; Yamauchi, Aiko

doi:10.2152/jmi.64.122

Cited by 9 publications

(12 citation statements)

References 33 publications

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“…As shown here, activation of PKC resulted in the maturation of pre-alpha cells into glucagon-expressing SC-alpha cells. PKC activation has been reported to enhance glucagon secretion from mouse and human islets through calcium-dependent exocytosis 51,55 . Further, a role for PKC in the transcription and protein expression of glucagon has been reported 56 .…”

Section: Discussionmentioning

confidence: 99%

A method for the generation of human stem cell-derived alpha cells

et al. 2020

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The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate. These pre-alpha cells exhibit a transcriptional profile similar to mature alpha cells and although they produce proinsulin protein, they do not secrete significant amounts of processed insulin. Compound screening identified a protein kinase c activator that promotes maturation of pre-alpha cells into SC-alpha cells. The resulting SC-alpha cells do not express insulin, share an ultrastructure similar to cadaveric alpha cells, express and secrete glucagon in response to glucose and some glucagon secretagogues, and elevate blood glucose upon transplantation in mice.

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Section: Discussionmentioning

confidence: 99%

A method for the generation of human stem cell-derived alpha cells

et al. 2020

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“…Our insulin secretion data suggest that the GPR75 ligand CCL5, the CBR1 receptor agonist ACEA, the GLP1R agonist exendin, and the muscarinic receptor agonist CCh are the most effective receptor-operated ligands in terms of stimulating insulin secretion. In addition, the tumorpromoting protein kinase C activator PMA consistently enhanced insulin secretion, demonstrating the importance of the protein kinase C pathway in the regulation of insulin secretion (18). Although we found that MIN6 pancreatic β-cells express mRNA for the orphan receptor GPR56, we did not have the opportunity to assess the effects of collagen III, which has been reported to be a GPR56 ligand (19); thus, we have not evaluated its effects on insulin secretion in the current study.…”

Section: Genementioning

confidence: 91%

Determining the insulin secretion potential for certain specific G-protein coupled receptors in MIN6 pancreatic beta cells

Gençoğlu¹,

Şahin²,

Jones³

2019

Turk J Med Sci

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Background/aim: The polypeptide hormone insulin is essential for the maintenance of whole-body fuel homeostasis, and defects in insulin secretion and/or action are associated with the development of type 1 and type 2 diabetes. The aim of this study was to assess the role of some G-protein coupled receptors (GPCRs), GPR54, GPR56, and GPR75, and cannabinoid receptors CB1R and CB2R, in the regulation of pancreatic β-cell function. Materials and methods: Insulin secretion from mouse insulinoma β-cell line (MIN6) monolayers was assessed via insulin radioimmunoassay (RIA). Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the expression of some specific GPCRs and the other receptors by MIN6 pancreatic β-cells. Results: The agonists were not found to be toxic for the MIN6 pancreatic β-cells within the range of the doses used in this study, whereas insulin secretion altered depending on the ligands and receptors. In addition, arachidonyl-2'-chloroethylamide (ACEA), carbachol, chemokine (C-C motif) ligand-5 (CCL5), and exendin as well as phorbol myristate acetate (PMA) ligands showed significant increases in the insulin secretion of MIN6 pancreatic β-cells. Conclusion: Understanding the normal β-cell function and identifying the defects in β-cell function that lead to the development of diabetes will generate new therapeutic targets.

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“…Inhibitors of the epidermal growth factor receptor (EGFR) were found to reduce ROS in islets from Goto-Kakizaki rats, and it was postulated that Src may transactivate this receptor [25]. In addition, an increase in glucagon secretion in hyperglycemia is associated with an increased activity of protein kinase C delta (PKC-δ) [27]. Thus, PI3K-Akt, PKC-δ, Src, and EGFR should be important components of the suggested signaling pathway ( Figure 2).…”

Section: Isolated Alpha Cells Exhibit a V-shapedmentioning

confidence: 99%

“…There has been increasing interest in the antidiabetic effects of the flavonoid quercetin, but this has mainly been limited to animal studies [97]. Quercetin has been demonstrated to inhibit glucagon secretion through PKC-δ inhibition [27], and it is also known to be an antioxidant and inhibitor of Src [98]. Further studies of this flavonoid and related phytochemicals in the prevention or management of diabetes are warranted.…”

Section: Antioxidant Antidiabetic Agents Improve Glucagon Hypersecretmentioning

confidence: 99%

“…In normal pancreatic islets, unlike isolated alpha cells, the rise in glucagon secretion at glucose concentrations above 7 mM is suppressed by paracrine action of somatostatin and insulin produced by beta cells and delta cells, respectively, and by gap junction coupling between these cells [ 11 , 83 ]; but, this paracrine suppression is lost in diabetes because of alpha cell insulin and somatostatin resistance [ 18 , 55 ]. Chronic exposure of alpha cells to high glucose upregulates the expression of SGLT-1 [ 9 , 29 ] and overactivates the signaling pathway in Figure 2 , as evidenced by increased activation of PI3K-Akt, PKC- δ , Src, and ROS generation in diabetic islets [ 24 – 27 , 81 ]. Oxidative stress and mitochondrial abnormalities cause reduced ATP production in alpha cells [ 9 , 84 , 85 ].…”

Section: Alpha Cell Insulin Resistance Mitochondrial Abnormalitiementioning

confidence: 99%

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Mechanisms of the Regulation and Dysregulation of Glucagon Secretion

Onyango

2020

Oxidative Medicine and Cellular Longevity

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Glucagon, a hormone secreted by pancreatic alpha cells, contributes to the maintenance of normal blood glucose concentration by inducing hepatic glucose production in response to declining blood glucose. However, glucagon hypersecretion contributes to the pathogenesis of type 2 diabetes. Moreover, diabetes is associated with relative glucagon undersecretion at low blood glucose and oversecretion at normal and high blood glucose. The mechanisms of such alpha cell dysfunctions are not well understood. This article reviews the genesis of alpha cell dysfunctions during the pathogenesis of type 2 diabetes and after the onset of type 1 and type 2 diabetes. It unravels a signaling pathway that contributes to glucose- or hydrogen peroxide-induced glucagon secretion, whose overstimulation contributes to glucagon dysregulation, partly through oxidative stress and reduced ATP synthesis. The signaling pathway involves phosphatidylinositol-3-kinase, protein kinase B, protein kinase C delta, non-receptor tyrosine kinase Src, and phospholipase C gamma-1. This knowledge will be useful in the design of new antidiabetic agents or regimens.

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Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Cited by 9 publications

References 33 publications

A method for the generation of human stem cell-derived alpha cells

A method for the generation of human stem cell-derived alpha cells

Determining the insulin secretion potential for certain specific G-protein coupled receptors in MIN6 pancreatic beta cells

Mechanisms of the Regulation and Dysregulation of Glucagon Secretion

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