Hepatocyte Nuclear Factor-4α Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase

Leclerc, Isabelle; Lenzner, Claudia; Gourdon, Laurence; Vaulont, Sophie; Kahn, Axel; Viollet, Benoı̂t

doi:10.2337/diabetes.50.7.1515

Cited by 146 publications

(120 citation statements)

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“…In addition, expression of these receptors was paralleled by expression of the metabolic gene Pklr, a key enzyme of glycolysis. Until now, high glucose concentration has been thought to trigger specific beta cell functions, predominantly insulin secretion and preproinsulin expression [3,27]. Furthermore, distinct roles of IGF-IR and IR signalling on glucosestimulated insulin secretion were previously investigated by Da Silva Xavier et al [11] using an RNA-silencing technique by small-interfering-RNAs in pancreatic MIN6 beta cells.…”

Section: Discussionmentioning

confidence: 99%

“…PKLR, ALDO-B or SLC2A2 are known glucose-and AICAR-regulated genes in beta cells and their respective gene products are involved in glucose transport and metabolism. Expression of these genes is regulated by the transcription factor HNF4α, which is a substrate of AMPK [27]. Phosphorylation of HNF4α by AMPK inhibits the formation of HNF4α homodimers and thus subsequently prevents HNF4α binding to DNA, while gene expression of HNF4α is not strongly regulated by AMPK activation [39].…”

Section: Discussionmentioning

confidence: 99%

“…In pancreatic beta cells, activation of AMPK by low glucose or by AICAR decreased the expression of metabolic genes, including solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2), aldolase B (ALDOB), liver-type pyruvate kinase (PKLR) or preproinsulin (INS) [24,25]. The nuclear transcription factor hepatocyte nuclear factor-4α (HNF4α), but also the newly discovered carbohydrateresponse-element-binding protein, were found to be downstream targets of AMPK [26,27]. Thus AMPK was claimed to have a pivotal role in the regulation of glucose-dependent metabolic genes [28].…”

Section: Introductionmentioning

confidence: 99%

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Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

et al. 2005

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Aims/hypothesis: Glucose and the peptide growth factors insulin, IGF-I and IGF-II strongly regulate beta cell mass. Furthermore, beta cell expression of IGF-I receptor (Igf1r) and insulin receptor (Insr) is mandatory for several steps of insulin secretion. Materials and methods: We hypothesised that glucose concentration might regulate expression of Igf1r, Insr and insulin receptor-related receptor (Insrr) in islets and beta cells. Moreover, since the ratio of ATP:ADP is the most important intracellular mechanism involved in insulin secretion, and since depletion of ATP leads to AMP accumulation, we evaluated the role of AMP-activated protein kinase (AMPK) in glucose-dependent receptor regulation. Results: In rat islets, high glucose exposure (25 mmol/l) increased gene expression of Igf1r, Insr and Insrr but also of the metabolic glycolysis gene liver-type pyruvate kinase (Pklr) compared with intermediate (6.2 mmol/l) or low glucose concentration (1.6 mmol/l) after 24 h. In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels. Igf1r expression was suppressed by both high-and low-glucose concentration. Activation of AMPK by 5-amino-imidazolecarboxamide riboside (AICAR, 0.5 mmol/l) suppressed Pklr expression, but strongly stimulated gene expression of Igf1r, Insr and Insrr. Protein expression of IR and IGF-IR reflected glucose and AICARregulated mRNA expression of both receptors in INS-1E cells. Conclusions/interpretation: We conclude that glucose directly interacts with islet and beta cell expression of growth factor receptors that are mandatory for both beta cell growth and insulin secretion. Stimulation of Igf1r and Insr gene expression by the AMPK-activator AICAR might indicate involvement of AMPK in the regulation of Igf1r, Insr and Insrr expression in beta cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

et al. 2005

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“…Protein content was assayed using a BCA TM protein assay kit (Pierce, Rockford, IL, U.S.A.), against BSA Type V (Sigma) standards. Total protein extracts (20 µg) were resolved by SDS\PAGE (10 %, v\v, bisacrylamide\acrylamide, 37.5 : 1) and transferred to PVDF membranes [36], followed by immunoblotting [37]. Secondary antibodies were revealed using BM Chemiluminescence blotting substrate (Roche Diagnostics).…”

Section: Western (Immuno-) Blotting and Ampk Assaymentioning

confidence: 99%

“…To explore the possibility that the effects of active or inactive AMPK may therefore result in part or in whole from changes in the expression of key glucose-sensing genes (e.g. GLUT2, glucokinase or L-type pyruvate kinase) [10,37] …”

Section: Effects Of Active and Inactive Ampk On Glucose Metabolism Inmentioning

confidence: 99%

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

Xavier

Leclerc

Váradi

et al. 2003

Biochemical Journal

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245

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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.

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AMPK: Central Regulator of Glucose and Lipid Metabolism

Mihaylova

Shaw

2009

The Liver

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Hepatocyte Nuclear Factor-4α Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase

Cited by 146 publications

References 46 publications

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

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

AMPK: Central Regulator of Glucose and Lipid Metabolism

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