Globular Adiponectin Augments Insulin Secretion from Pancreatic Islet β Cells at High Glucose Concentrations

Gu, Weiqiong; Li, Xiaoying; Liu, Changqin; Yang, Jun; Ye, Lei; Tang, Jingfen; Gu, Yuanjun; Yang, Yumei; Hong, Jing; Zhang, Yifei; Chen, Ming-Dao; Ning, Guang

doi:10.1385/endo:30:2:217

Cited by 52 publications

(46 citation statements)

References 32 publications

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“…Finally, our results are concurrent with previous reports that suggest predominant expression of AdipoR1 in pancreatic islets (14). However, knockdown or overexpression of AdipoRs in pancreatic beta cells did not affect adiponectin-induced changes in Akt or ERK phosphorylation or cleaved caspase-3.…”

Section: Discussionsupporting

confidence: 92%

“…The impact of adiponectin on insulin secretion in vitro has so far been variable in literature. Upon stimulation with adiponectin, no effect was observed in basal or GSIS from human islets; basal secretion was reduced, whereas GSIS was increased in insulin-resistant mice; GSIS was increased in isolated rat islets; and basal and GSIS was increased during sustained glucotoxicity, and fatty acid-induced inhibition of GSIS was reversed in cultured beta cells (14,16,21,22,29). Therefore, with the human islet study as an exception, there appears to be a general trend for adiponectin to increase GSIS, especially under stressed conditions, such as in insulin resistance, lipotoxicity, glucotoxicity, or serum starvation.…”

Section: Discussionmentioning

confidence: 92%

“…3 To whom correspondence should be addressed: Dept. gested that adiponectin increases glucose-stimulated insulin secretion (GSIS) (14,16,(21)(22)(23). Adiponectin was shown to also have both pro-and antiproliferative effects in numerous cell types mediated by such signaling molecules as AMPK, Akt, and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) (24 -28).…”

mentioning

confidence: 99%

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Adiponectin-induced ERK and Akt Phosphorylation Protects against Pancreatic Beta Cell Apoptosis and Increases Insulin Gene Expression and Secretion*

Wijesekara

Krishnamurthy

Bhattacharjee

et al. 2010

Journal of Biological Chemistry

208

142

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The functional impact of adiponectin on pancreatic beta cells is so far poorly understood. Although adiponectin receptors (AdipoR1/2) were identified, their involvement in adiponectininduced signaling and other molecules involved is not clearly defined. Therefore, we investigated the role of adiponectin in beta cells and the signaling mediators involved. MIN6 beta cells and mouse islets were stimulated with globular (2.5 g/ml) or full-length (5 g/ml) adiponectin under serum starvation, and cell viability, proliferation, apoptosis, insulin gene expression, and secretion were measured. Lysates were subjected to Western blot analysis to determine phosphorylation of AMP-activated protein kinase (AMPK), Akt, or ERK. Functional significance of signaling was confirmed using dominant negative mutants or pharmacological inhibitors. Participation of AdipoRs was assessed by overexpression or siRNA. Adiponectin failed to activate AMPK after 10 min or 1-and 24-h stimulation. ERK was significantly phosphorylated after 24-h treatment with adiponectin, whereas Akt was activated at all time points examined. 24-h stimulation with adiponectin significantly increased cell viability by decreasing cellular apoptosis, and this was prevented by dominant negative Akt, wortmannin (PI3K inhibitor), and U0126 (MEK inhibitor). Moreover, adiponectin regulated insulin gene expression and glucose-stimulated insulin secretion, which was also prevented by wortmannin and U0126 treatment. Interestingly, the data also suggest adiponectin-induced changes in Akt and ERK phosphorylation and caspase-3 may occur independent of the level of AdipoR expression. This study demonstrates a lack of AMPK involvement and implicates Akt and ERK in adiponectin signaling, leading to protection against apoptosis and stimulation of insulin gene expression and secretion in pancreatic beta cells.Type 2 diabetes is characterized by both a loss of insulin sensitivity and beta cell dysfunction in the pancreas. Adiponectin is an adipocyte-derived hormone that shows a strong negative correlation with insulin resistance and obesity (1, 2). Studies show that whereas adiponectin knock-out mice develop insulin resistance and glucose intolerance when challenged with a high fat diet, adiponectin-overexpressing mice are highly insulin-sensitive and are resistant to diet-induced diabetes (3-6). Adiponectin is reported to stimulate fatty acid oxidation and glucose uptake and reduce gluconeogenesis in myocytes and hepatocytes, thus increasing peripheral insulin sensitivity (7). Reduced adiponectin levels are also correlated with reduced vascular function and an increase in coronary artery disease (8).Adiponectin forms trimers or higher order complexes including hexamers and oligomers (9). These higher order complexes of full-length adiponectin (fAd) 4 are the primary circulating forms, and localized proteolytic cleavage of fAd has been shown to produce globular adiponectin (gAd) (10). Two proposed homologous adiponectin receptors (AdipoR1 and AdipoR2) were cloned and shown to be wi...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

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Adiponectin-induced ERK and Akt Phosphorylation Protects against Pancreatic Beta Cell Apoptosis and Increases Insulin Gene Expression and Secretion*

Wijesekara

Krishnamurthy

Bhattacharjee

et al. 2010

Journal of Biological Chemistry

208

142

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“…Of interest, leptin stimulates AMPK activity in skeletal muscle (Minokoshi and Kahn, 2003), expressing predominantly the 2 subunit, but neither this adipokine (Leclerc et al, 2004c) nor adiponectin (Okamoto et al, 2008) (GAR, Wheeler, MB unpublished results) was reported to have any effect on AMPK activity in primary β-cells. However, and in contradictory findings, others have reported the activation of AMPK by adiponectin in MIN6 cells (Huypens et al, 2005) and in rat islets (Gu et al, 2006).…”

Section: Ampk Isoform Expression In β-Cellsmentioning

confidence: 97%

The AMP-regulated kinase family: Enigmatic targets for diabetes therapy

Rutter

Leclerc

2009

Molecular and Cellular Endocrinology

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Please cite this article as: Rutter, G.A., Leclerc, I., The AMP-regulated kinase family: enigmatic targets for diabetes therapy, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Pt 1):1-16, 2003). In the subsequent five years, dramatic strides have taken place in our understanding of the role of AMPK in the control of whole body metabolic homeostasis, the regulation of the enzyme by upstream kinases, and its molecular structure.These new studies and earlier work arguably propel AMPK, and perhaps related family members into a "super league" of potential therapeutic targets for maladies including diabetes, cancer, heart disease, and obesity. Here we survey some of these recent advances, focussing on the role of this and related enzymes in the control of pancreatic β-cell function and glucose homeostasis.

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“…The studies exploring AdipoR1 and AdipoR2 expression demonstrated that they are fairly ubiquitously expressed with high levels in metabolically active tissues such as skeletal muscle 48,76,77 liver 48,77,78 , heart [79][80][81] and adipose tissue 82,83 . They are also expressed in other adiponectin responsive cells and tissues such as osteoblasts 84 , pancreas 85,86 , leukocytes 75,87 and the brain 88 .…”

Section: Adiponectin Receptor Expression and Regulationmentioning

confidence: 99%

Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2

Keshvari¹

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The increasing global prevalence of cardiovascular and metabolic diseases necessitates the development of more effective therapeutic strategies that, in turn, require a greater understanding of the regulatory networks involved. Research over the last decade has increased our appreciation of the key role of the adiponectin axis as a major regulator of metabolic, cardiovascular and inflammatory tone, thereby establishing it as a province of therapeutic opportunity. The receptors for adiponectin, AdipoR1 and AdipoR2, are distant relatives of the largest single class of drug targets, the G-protein coupled receptor (GPCR) family. However, unlike GPCRs they have intracellular N-termini and extracellular C-termini and signal via atypical pathways. Our current understanding of AdipoR1 and AdipoR2 is rudimentary, constraining our ability to target these receptors effectively. The aim of this thesis was to characterise molecular features of AdipoR1 and AdipoR2 that facilitate adiponectin signal transduction to advance our understanding and identify strategies to enhance adiponectin's beneficial effects.We have begun to characterise basic properties of AdipoR1 and AdipoR2, focusing on molecular factors that drive cell-surface expression (CSE) of the receptors using a range of C-terminal, epitope-tagged AdipoR1 and AdipoR2 constructs. Surprisingly, under steady-state conditions (no serum starvation) only AdipoR1 was readily detected on the cell-surface (cell-surface ratio of AdipoR1 vs AdipoR2 is 0.6±0.1 vs 0.15±0.1, p<0.05). Generation and characterisation of a series of chimeric and truncated constructs demonstrated that a non-conserved, intracellular, N-terminal region of AdipoR2 (R2 ) restricted its CSE whilst the same region in AdipoR1 (R1 (1-70) ) promoted its CSE. We also confirmed that AdipoR1 and AdipoR2 form heterodimer and that coexpression of these receptors increase the CSE of AdipoR2. Subsequently, we provided evidence that the subcellular localisation of AdipoR1 and AdipoR2 is governed by multiple motifs across their non-conserved and conserved cytoplasmic domains. For instance, two highly conserved motifs, an ER exit motif (FxxxFxxxF) and Di-Leucine motif (DxxxLL), in the conserved Nterminal domain are required for the proper CSE of both AdipoR1 and AdipoR2, whilst different parts of the non-conserved domain of AdipoR2 inhibits its CSE.Moreover, we demonstrated that in HEK-293 cells over-expressing AdipoR1 adiponectin activated downstream signalling networks (AMPK, AKT, ERK & P38MAPK) acutely (peaking at 15 min) whereas signal transduction via AdipoR2 was relatively chronic (peaking at 24 h). This difference was also underpinned by the non-conserved N-terminal domains of AdipoR1 and AdipoR2. We also demonstrated that a number of conserved and non-conserved cysteines in the N-terminal domain of iii AdipoR1 and AdipoR2 are subject to palmitoylation and that palmitoylation of a conserved cysteine, situated in the juxta-membrane region of the N-termini of AdipoR1 and AdipoR2 in a position analogous to t...

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Globular Adiponectin Augments Insulin Secretion from Pancreatic Islet β Cells at High Glucose Concentrations

Cited by 52 publications

References 32 publications

Adiponectin-induced ERK and Akt Phosphorylation Protects against Pancreatic Beta Cell Apoptosis and Increases Insulin Gene Expression and Secretion*

Adiponectin-induced ERK and Akt Phosphorylation Protects against Pancreatic Beta Cell Apoptosis and Increases Insulin Gene Expression and Secretion*

The AMP-regulated kinase family: Enigmatic targets for diabetes therapy

Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2

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