Protein Kinase Cζ Activation Mediates Glucagon-Like Peptide-1–Induced Pancreatic β-Cell Proliferation

Buteau, Jean; Foisy, Sylvain; Rhodes, Christopher J.; Carpenter, Lee; Biden, Trevor J.; Prentki, Marc

doi:10.2337/diabetes.50.10.2237

Cited by 238 publications

(183 citation statements)

References 59 publications

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“…This was done in a humidified (5% CO 2 , 95% air) atmosphere at 37°C. The next day, intact islets were either directly used and treated with the different substances to be tested or dispersed in single cells and small clusters of cells by trypsinisation, attached on poly-ornithine glass coverslips as previously described [39] and subsequently incubated under various experimental conditions. Apoptosis was studied by three different methods measuring chromatin condensation, DNA fragmentation and release of histone-associated mono-and oligonucleosomes according to the protocols described below.…”

Section: Methodsmentioning

confidence: 99%

“…Dispersed human islet cells and INS832/13 cells were plated on poly-ornithine-treated glass coverslips at 80% confluency in 6-well plates as described before [39]. Following a preincubation in complete medium for 24 h, cells were washed with PBS and incubated for 24 h at glucose concentrations of 5 or 25 mmol/l in RPMI containing 1% FCS (referred to below as incubation medium).…”

Section: Methodsmentioning

confidence: 99%

“…Dominant-negative (DN) PKB and constitutively active PKB [18] overexpression was conducted as described for other adenoviral constructs [39]. INS832/13 cells were seeded 2 days before use in 6-well plates and cultured in regular RPMI as described above.…”

Section: Methodsmentioning

confidence: 99%

“…PKB has been identified as an important component of pro-survival signalling pathways [47] and more relevantly, a constitutively active PKB construct has been shown to prevent lipotoxicity induced by oleate in INS-1 cells [18]. As we and others previously showed that GLP-1 increases PKB activity in beta cells [39,48], we therefore tested a possible implication of PKB in GLP-1's anti-apoptotic action on beta cell glucolipotoxicity. The following values of PKB activity were observed in the absence or presence of GLP-1 (10 nmol/l), following a 15-min incubation period: basal (3 mmol/l glucose): 100±7%; GLP-1: 176±37%; p<0.02 (as evaluated using a PKB/Akt kinase assay kit [Cell Signaling, Beverly, Mass., USA]).…”

Section: The Anti-apoptotic Action Of Glp-1 On Beta Cell Glucolipotoxmentioning

confidence: 98%

“…GLP-1 mobilises intracellular Ca 2+ [35,36] via cyclic AMP guanine nucleotide exchange factor 2 (Epac) [37], an effect that may contribute to the insulinotropic action of the peptide. Moreover, this gluco-incretin hormone increases islet mass in mouse pancreas in vivo [31,38] and causes in vitro beta cell proliferation via transactivation of the epidermal growth factor receptor and subsequent activation of the phosphatidylinositol-3 kinase (PI-3K) and protein kinase C-ζ (PKC-ζ) signalling pathway in beta-(INS-1)-cells [30,39,40]. Finally, GLP-1 has recently been shown to delay beta cell apoptosis in Zucker diabetic rats, an animal model of diabetes [38], as well as in streptozotocin-treated mice and cytokinetreated rat islets in vitro [41].…”

Section: Introductionmentioning

confidence: 99%

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Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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Aims/hypothesis. We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. Methods. Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay. Results. In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagonlike peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two antiapoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. Conclusions/interpretation. The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo-and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: The Anti-apoptotic Action Of Glp-1 On Beta Cell Glucolipotoxmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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Development and Life Cycle of a β‐Cell

Serup¹,

Nielsen

2003

International Textbook of Diabetes Mellitus

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The understanding of the molecular biology of the pancreas β‐cell began 25 years ago with the cloning of the insulin cDNA, followed by the determination of the genomic organization and the identification of multiple cis ‐ and trans ‐acting elements in the 5′‐flanking region. The developmental biology of the pancreas started earlier but was put on hold until the molecular biological technology allowed approaching the questions raised some 30 years ago. A major breakthrough happened 8 years ago when disruption of the gene for an insulin gene transcription factor was found to ablate the development of the pancreas. This has greatly stimulated the search for new transcription factors and their regulation by growth and differentiation factors in order to understand the basal molecular mechanisms involved in the formation of the pancreas β‐cell and the perspectives for prevention, treatment, and cure of diabetes. The maintenance of an appropriate β‐cell mass depends on neogenesis from progenitor cells, proliferation of existing β‐cells, and β‐cell death. The balance between these processes is regulated by a complex interaction of metabolites, hormones, and growth factors. Under normal conditions there appears to be a close correspondence between insulin demand and the functional β‐cell mass. The function of the β‐cell is not only under acute regulation by nutrients following a meal but is also subject to regulation by chronic changes in the insulin demand as in pregnancy or obesity, which result in adjustment of the β‐cell number.

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Islet Amyloid Polypeptide/GLP‐1/Exendin

Baggio

Drucker

2003

International Textbook of Diabetes Mellitus

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Gastrointestinal peptides exert important physiological roles in the control of feeding behavior, gut motility, nutrient absorption, and energy assimilation. Islet amyloid polypeptide is secreted from islet β‐cells, and exerts inhibitory actions on appetite, gastric motility, and glucagon secretion. Glucagon‐like peptide 1 (GLP‐1) is released from enteroendocrine cells and regulates food intake, gastric emptying, insulin and glucagon secretion, and β‐cell proliferation and apoptosis. Exendin‐4, a lizard‐derived peptide, is a potent and stable GLP‐1R agonist that exerts GLP‐1‐like actions in vivo . The overlapping glucose‐lowering properties of these peptides have fostered considerable interest in their development as new therapeutic agents for the treatment of diabetes mellitus.

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Protein Kinase Cζ Activation Mediates Glucagon-Like Peptide-1–Induced Pancreatic β-Cell Proliferation

Cited by 238 publications

References 59 publications

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Development and Life Cycle of a β‐Cell

Islet Amyloid Polypeptide/GLP‐1/Exendin

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