The diverse roles of protein kinase C in pancreatic β-cell function

Biden, Trevor J.; Schmitz‐Peiffer, Carsten; Burchfield, James G.; Gurisik, Ebru; Cantley, James; Mitchell, Christopher J.; Carpenter, Lee

doi:10.1042/bst0360916

Cited by 30 publications

(25 citation statements)

References 53 publications

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“…PKC ␤ was also one of the earliest isoforms recognized in insulin signaling and appears to play dual roles in insulin signaling pathways (17)(18)(19)(20)(21)(22). PKC ␤ does not appear to regulate glucose-induced insulin secretion in vivo ( 23 ), even though it has been reported to undergo translocation to the plasma membrane subsequent to stimulation by glucose in primary islet cells ( 24 ). We recently showed that PKC ␤ is markedly elevated in white adipose tissue (WAT) of leptin-defi cient ( ob/ob ) mice and is signifi cantly induced by intake of high-fat diet (HFD) ( 25,26 ).…”

Section: Western Blot Studiesmentioning

confidence: 99%

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Huang

Bansode

Bal

et al. 2012

Journal of Lipid Research

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Section: Western Blot Studiesmentioning

confidence: 99%

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Huang

Bansode

Bal

et al. 2012

Journal of Lipid Research

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“…Rodent studies have shown that chronically elevated glucose downregulates both GLP-1R and GIP-R gene expression in vivo [16,17]. Glucose is also considered likely to activate PKC isoforms in the β-cell [18], which may be the stimulus for PKC-mediated phosphorylation of the GLP-1R that leads to its downregulation [19–21]. Homologous GLP-1R activation has been shown to downregulate the receptor rapidly [21,22], consistent with a classical negative feedback system that may be mediated via cAMP signaling.…”

Section: Introductionmentioning

confidence: 99%

Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic β-cells via protein kinase A

Rajan

Dickson

Mathew

et al. 2015

Molecular Metabolism

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ObjectiveGlucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determine the mechanistic causes underlying the reduced efficacy of GLP-1R ligands.MethodsUsing primary mouse islets and the β-cell line MIN6, outcomes downstream of the GLP-1R were analyzed: Insulin secretion; phosphorylation of the cAMP-response element binding protein (CREB); cAMP responses. Signaling systems were studied by immunoblotting and qRT-PCR, and PKA activity was assayed. Cell surface localization of the GLP-1R was studied by confocal microscopy using a fluorescein-tagged exendin-4 and GFP-tagged GLP-1R.ResultsRodent β-cells chronically exposed to high glucose had diminished responses to GLP-1R agonists including: diminished insulin secretory response; reduced phosphorylation of (CREB); impaired cAMP response, attributable to chronically increased cAMP levels. GLP-1R signaling systems were affected by hyperglycemia with increased expression of mRNAs encoding the inducible cAMP early repressor (ICER) and adenylyl cyclase 8, reduced PKA activity due to increased expression of the PKA-RIα subunit, reduced GLP-1R mRNA expression and loss of GLP-1R from the cell surface. To specifically examine the loss of GLP-1R from the plasma membrane a GLP-1R-GFP fusion protein was employed to visualize subcellular localization. Under low glucose conditions or when PKA activity was inhibited, GLP-1R-GFP was found at the plasma membrane. Conversely high glucose, expression of a constitutively active PKA subunit, or exposure to exendin-4 or forskolin led to GLP-1R-GFP internalization. Mutation of serine residue 301 of the GLP-1R abolished the glucose-dependent loss of the receptor from the plasma membrane. This was associated with a loss of an interaction between the receptor and the small ubiquitin-related modifier (SUMO), an interaction that was found to be necessary for internalization of the receptor.ConclusionsThese data show that glucose acting, at least in part, via PKA leads to the loss of the GLP-1R from the cell surface and an impairment of GLP-1R signaling, which may underlie the reduced clinical efficacy of GLP-1R based therapies in individuals with poorly controlled hyperglycemia.

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“…PKC proteins regulate cellular granule movement and exocytosis [32][33][34][35][36] that also exists in β cells, constituting the distal stages of GIIS regulation. PKC family proteins, PKCα and PKCε, PKCβII, PKCζ, and PKCδ in this study, were found to exhibit up-regulated protein levels in islets from HFD control mice ( Fig.…”

Section: Mtorc2/pkc Signalling and The Pma-stimulated Insulin Secretimentioning

confidence: 99%

The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

Xie¹,

Cui²,

Nie³

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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The diverse roles of protein kinase C in pancreatic β-cell function

Cited by 30 publications

References 53 publications

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic β-cells via protein kinase A

The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

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