scholarly journals Decreased Insulin Secretion and Accumulation of Triglyceride in β Cells Overexpressing a Dominant-negative Form of AMP-activated Protein Kinase

2010 ◽  
Vol 57 (2) ◽  
pp. 141-152 ◽  
Author(s):  
Yukiko OKAZAKI ◽  
Kazuhiro ETO ◽  
Tokuyuki YAMASHITA ◽  
Masayuki OKAMOTO ◽  
Mitsuru OHSUGI ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Dominant Negative ◽  
Β Cells ◽  
Dominant Negative Form ◽  
Amp Activated Protein Kinase ◽  
Negative Form

scholarly journals Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

2003 ◽  
Vol 371 (3) ◽  
pp. 761-774 ◽  
Author(s):  
Gabriela da SILVA XAVIER ◽  
Isabelle LECLERC ◽  
Aniko VARADI ◽  
Takashi TSUBOI ◽  
S. Kelly MOULE ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Active Form ◽  
Dominant Negative ◽  
Β Cells ◽  
Dominant Negative Form ◽  
Ampk Activity ◽  
Glucose Stimulated Insulin Secretion ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has recently been implicated in the control of preproinsulin gene expression in pancreatic islet β-cells [da Silva Xavier, Leclerc, Salt, Doiron, Hardie, Kahn and Rutter (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 4023–4028]. Using pharmacological and molecular strategies to regulate AMPK activity in rat islets and clonal MIN6 β-cells, we show here that the effects of AMPK are exerted largely upstream of insulin release. Thus forced increases in AMPK activity achieved pharmacologically with 5-amino-4-imidazolecarboxamide riboside (AICAR), or by adenoviral overexpression of a truncated, constitutively active form of the enzyme (AMPKα1.T172D), blocked glucose-stimulated insulin secretion. In MIN6 cells, activation of AMPK suppressed glucose metabolism, as assessed by changes in total, cytosolic or mitochondrial [ATP] and NAD(P)H, and reduced increases in intracellular [Ca2+] caused by either glucose or tolbutamide. By contrast, inactivation of AMPK by expression of a dominant-negative form of the enzyme mutated in the catalytic site (AMPKα1.D157A) did not affect glucose-stimulated increases in [ATP], NAD(P)H or intracellular [Ca2+], but led to the unregulated release of insulin. These results indicate that inhibition of AMPK by glucose is essential for the activation of insulin secretion by the sugar, and may contribute to the transcriptional stimulation of the preproinsulin gene. Modulation of AMPK activity in the β-cell may thus represent a novel therapeutic strategy for the treatment of type 2 diabetes mellitus.

scholarly journals AMP-activated protein kinase as regulator of P2Y6 receptor-induced insulin secretion in mouse pancreatic β-cells

2013 ◽  
Vol 85 (7) ◽  
pp. 991-998 ◽  
Author(s):  
Ramachandran Balasubramanian ◽  
Hiroshi Maruoka ◽  
P. Suresh Jayasekara ◽  
Zhan-Guo Gao ◽  
Kenneth A. Jacobson
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
P2y6 Receptor ◽  
Amp Activated Protein Kinase

Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion

2004 ◽  
Vol 286 (6) ◽  
pp. E1023-E1031 ◽  
Author(s):  
Isabelle Leclerc ◽  
Wolfram W. Woltersdorf ◽  
Gabriela da Silva Xavier ◽  
Rebecca L. Rowe ◽  
Sarah E. Cross ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Pancreatic Islets ◽  
Human Islets ◽  
Β Cells ◽  
Min6 Cells ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761–774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2–1 mM) activated AMPK in both human islets and MIN6 β-cells in parallel with an inhibition of insulin secretion, whereas leptin (10–100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal β-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.

Activation of phosphatidylinositol 3-kinase is required for transcriptional activity of F-type 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: assessment of the role of protein kinase B and p70 S6 kinase

2000 ◽  
Vol 349 (1) ◽  
pp. 59-65 ◽  
Author(s):  
Silvia FERNÁNDEZ DE MATTOS ◽  
Elisabet DE LOS PINOS ◽  
Manel JOAQUIN ◽  
Albert TAULER
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Transcriptional Activity ◽  
Protein Kinase B ◽  
Dominant Negative ◽  
Phosphatidylinositol 3 Kinase ◽  
S6 Kinase ◽  
Dominant Negative Form ◽  
Negative Form ◽  
Phosphatidylinositol 3

Previous studies have demonstrated that the F isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase(6PF2K/Fru-2,6-BPase) is transcriptionally regulated by growth factors. The aim of this study was to investigate the importance of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway in the regulation of 6PF2K/Fru-2,6-BPase gene expression. We have completed studies using chemical inhibitors and expression vectors for the proteins involved in this signalling cascade. Treatment of cells with LY 294002, an inhibitor of PI 3-kinase, blocked the epidermal growth factor (EGF)-dependent stimulation of 6PF2K/Fru-2,6-BPase gene transcription. Transient transfection of a constitutively active PI 3-kinase was sufficient to activate transcription from the F-type 6PF2K/Fru-2,6-BPase promoter. In contrast, co-transfection with a dominant-negative form of PI 3-kinase completely abrogated the stimulation by EGF, and down-regulated the basal promoter activity. In an attempt to determine downstream proteins that lie between PI 3-kinase and 6PF2K/Fru-2,6-BPase gene expression, the overexpression of a constitutively active form of protein kinase B (PKB) was sufficient to activate 6PF2K/Fru-2,6-BPase gene expression, even in the presence of either a dominant-negative form of PI 3-kinase or LY 294002. The over-expression of p70/p85 ribosomal S6 kinase or the treatment with its inhibitor rapamycin did not affect 6PF2K/Fru-2,6-BPase transcription. We conclude that PI 3-kinase is necessary for the transcriptional activity of F-type 6PF2K/Fru-2,6-BPase, and that PKB is a downstream effector of PI 3-kinase directly involved in the regulation of 6PF2K/Fru-2,6-BPase gene expression.

Imaging Glucose-Regulated Insulin Secretion and Gene Expression in Single Islet β-Cells: Control by AMP-Activated Protein Kinase

2004 ◽  
Vol 40 (3S) ◽  
pp. 179-190 ◽  
Author(s):  
Guy A. Rutter ◽  
Isabelle Leclerc ◽  
Takashi Tsuboi ◽  
Gabriela da Silva Xavier ◽  
Frédérique Diraison ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Β Cells ◽  
Amp Activated Protein Kinase

scholarly journals Activation of the AMP-activated protein kinase enhances glucose-stimulated insulin secretion in mouse β-cells

Islets ◽  
2010 ◽  
Vol 2 (3) ◽  
pp. 156-163 ◽  
Author(s):  
Martina Düfer ◽  
Katja Noack ◽  
Peter Krippeit-Drews ◽  
Gisela Drews
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Β Cells ◽  
Glucose Stimulated Insulin Secretion ◽  
Amp Activated Protein Kinase

Palmitate activates AMP-activated protein kinase and regulates insulin secretion from β cells

2007 ◽  
Vol 352 (2) ◽  
pp. 463-468 ◽  
Author(s):  
Xiao Wang ◽  
Libin Zhou ◽  
Guo Li ◽  
Tianhong Luo ◽  
Yanyun Gu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Β Cells ◽  
Amp Activated Protein Kinase

The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 β cells

2010 ◽  
Vol 24 (12) ◽  
pp. 5080-5091 ◽  
Author(s):  
Luisa Garcia-Haro ◽  
Maria Adelaida Garcia-Gimeno ◽  
Dietbert Neumann ◽  
Monique Beullens ◽  
Mathieu Bollen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Phosphatase ◽  
Β Cells ◽  
Amp Activated Protein Kinase ◽  
Kinase A
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