Hypoxia reduces HNF4α/MODY1 protein expression in pancreatic β-cells by activating AMP-activated protein kinase

Chronic hyperglycaemia is detrimental to pancreatic β-cells by causing impaired insulin secretion and diminished β-cell function through glucotoxicity. Understanding the mechanisms underlying β-cell survival is crucial for the prevention of β-cell failure associated with glucotoxicity. Autophagy is a dynamic lysosomal degradation process that protects organisms against metabolic stress. To date, little is known about the physiological function of autophagy in the pathogenesis of diabetes. In the present study, we explored the roles of autophagy in the survival of pancreatic β-cells exposed to high glucose using pharmacological and genetic manipulation of autophagy. We demonstrated that chronic high glucose increases autophagy in rat INS-1 (832/13) cells and pancreatic islets, and that this increase is enhanced by inhibition of 5′-AMP-activated protein kinase. Our results also indicate that stimulation of autophagy rescues pancreatic β-cells from high-glucose-induced cell death and inhibition of autophagy augments caspase-3 activation, suggesting that autophagy plays a protective role in the survival of pancreatic β-cells. Greater knowledge of the molecular mechanisms linking autophagy and β-cell survival may unveil novel therapeutic targets needed to preserve β-cell function.

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Role of AMP-activated protein kinase in the regulation of gene transcription

Biochemical Society Transactions ◽

10.1042/bst0300307 ◽

2002 ◽

Vol 30 (2) ◽

pp. 307-311 ◽

Cited By ~ 13

Author(s):

I. Leclerc ◽

B. Viollet ◽

G. da Silva Xavier ◽

A. Kahn ◽

G. A. Rutter

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Regulation Of Gene Expression ◽

Energy Status ◽

Β Cells ◽

Pancreatic Β Cells ◽

Intermediate Metabolism ◽

Energy Consuming ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a regulator of cellular metabolism in response to changes in the energy status of the cells. AMPK was known to shut down energy-consuming pathways in response to a fall in the ATP/AMP ratio by phosphorylating key enzymes of intermediate metabolism. Here we will discuss the recent evidence implicating AMPK in the regulation of gene expression in mammals, mainly in the liver and in the pancreatic β-cells.

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Withdrawal: Glucose regulates MafA transcription factor abundance and insulin gene expression by inhibiting AMP-activated protein kinase in pancreatic β-cells.

Journal of Biological Chemistry ◽

10.1074/jbc.w118.006474 ◽

2018 ◽

Vol 293 (47) ◽

pp. 18403-18403

Author(s):

Ryo Iwaoka ◽

Kohsuke Kataoka

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Protein Kinase ◽

Insulin Gene ◽

Β Cells ◽

Pancreatic Β Cells ◽

Insulin Gene Expression ◽

Factor Abundance ◽

Amp Activated Protein Kinase

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Glucose regulates MafA transcription factor abundance and insulin gene expression by inhibiting AMP-activated protein kinase in pancreatic β-cells

Journal of Biological Chemistry ◽

10.1074/jbc.m117.817932 ◽

2018 ◽

Vol 293 (10) ◽

pp. 3524-3534 ◽

Cited By ~ 1

Author(s):

Ryo Iwaoka ◽

Kohsuke Kataoka

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Protein Kinase ◽

Insulin Gene ◽

Β Cells ◽

Pancreatic Β Cells ◽

Insulin Gene Expression ◽

Factor Abundance ◽

Amp Activated Protein Kinase

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Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response

Endocrinology ◽

10.1210/en.2015-2003 ◽

2016 ◽

Vol 157 (6) ◽

pp. 2243-2258 ◽

Cited By ~ 14

Author(s):

Annalisa Natalicchio ◽

Giuseppina Biondi ◽

Nicola Marrano ◽

Rossella Labarbuta ◽

Federica Tortosa ◽

...

Keyword(s):

Protein Expression ◽

Insulin Release ◽

Binding Protein ◽

Camp Response Element Binding ◽

Β Cells ◽

Pancreatic Β Cells ◽

Camp Response Element ◽

Element Binding Protein ◽

Viral Oncogene Homolog ◽

Erk Kinase

The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E β-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E β-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on β-cells by reducing PDX-1 and GLP-1 receptor expression and signaling in a SREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate.

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