Expression of peroxisome proliferator-activated receptor γ (PPARγ) in normal human pancreatic islet cells

Dubois, Mathilde; Pattou, François; Kerr–Conte, Julie; Gmyr, Valéry; Vandewalle, B.; Desreumaux, Pierre; Auwerx, Johan; Schoonjans, Kristina; Lefèbvre, J

doi:10.1007/s001250051508

Cited by 177 publications

(126 citation statements)

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“…The effects of thiazolidinediones on pancreatic beta cell function are not consistent among different reports, mostly because of differences in experimental design [4,13,14,[35][36][37][38][39][40][41][42]. More studies need to be done to substantiate our understanding of the signalling pathway involved in rosiglitazone-induced insulin secretion through regulation of K ATP channel activity by AMPK.…”

Section: Discussionmentioning

confidence: 96%

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

et al. 2009

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Aims/hypothesis Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco-and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K ATP ) channel might serve as a key step in the regulation of insulin secretion. Methods Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K ATP channel conductance with patch clamp techniques and insulin secretion measured by ELISA. Results Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K ATP channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K ATP channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. Conclusions/interpretation Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazonestimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser 385 residue of the Kir6.2 subunit of the K ATP channel by AMPK may play a role in insulin secretion.

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Section: Discussionmentioning

confidence: 96%

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

et al. 2009

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“…Dubois et al (29) suggested that the cause of β-cell dysfunction in Ala allele may be due to chronic exposure to elevated free fatty acids and/or hyperglycemia, which are characteristic for overt type 2 diabetes, leading to alteration or even reversion of the effect of the genetic variant.…”

Section: Doney Et Al (21) and Memisoglu Et Al (22) Alsomentioning

confidence: 99%

Role of Peroxisome Proliferator-Activated Receptor gamma 2 (PPAR-γ2) Gene Polymorphism in Type 2 Diabetes Mellitus

et al. 2009

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Objective: To find out the relation between Pro 12 Ala polymorphism of peroxisome proliferator-activated receptor gamma2 (PPAR-g2) gene with type 2 diabetes mellitus and the possible role of this gene polymorphism as a link between obesity and type 2 diabetes mellitus. Subjects and Methods: Subjects of this study were classified into 3 groups: (15) Apparently healthy lean individuals (Group I), (15) obese non diabetic individuals (group II) and (24) patients with type 2 diabetes mellitus (group III). This group divided into: Diabetic non obese patients (12 patients) (Group IIIa) and: Diabetic obese patients (12 patients) (Group IIIb). The subjects were subjected to clinical examination, serum insulin level and estimation of PPAR-g2 gene polymorphism by Restriction fragment length polymorphism (RFLP) polymerase chain reaction (PCR). Results: Frequency of Pro allele was significant increase in diabetic non obese patients& diabetic non obese patients when compared to control group (P= 0.048 and 0.003, respectively

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“…Whereas PPAR␥1 is present in many mammalian tissues, the expression of PPAR␥2 is confined largely to adipose tissue (48). Both PPAR␥ mRNA and protein have been detected in human (13) and rodent (4,53) pancreatic islets, although the relative levels of the ␥1 and ␥2 isoforms have yet to be established in this tissue.…”

mentioning

confidence: 99%

Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

Parton¹,

Diraison²,

Neill³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. Impact of PPAR␥ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays. Am J Physiol Endocrinol Metab 287: E390 -E404, 2004. First published May 4, 2004 10.1152/ajpendo.00016.2004.-Peroxisome proliferator-activated receptor-␥ (PPAR␥) serves as a target for the thiazolidinedione class of antidiabetic drugs and is an important regulator of adipose tissue differentiation. By contrast, the principal target genes for PPAR␥ in the pancreatic islet and the impact of their induction on insulin secretion are largely undefined. Here, we show that mRNAs encoding both isoforms of rodent PPAR␥, ␥1 and ␥2, are expressed in primary rat islets and are upregulated by overexpresssion of the lipogenic transcription factor sterol response element-binding protein 1c. Unexpectedly, however, oligonucleotide microarray analysis demonstrates that graded activation of PPAR␥ achieved with 1) the thiazolidinedione GW-347845, 2) transduction with adenoviral PPAR␥1, or 3) a combination of both treatments progressively enhances the expression of genes involved in fatty acid oxidation and transport. Moreover, maximal activation of PPAR␥1 reduces islet triglyceride levels and enhances the oxidation of exogenous palmitate while decreasing glucose oxidation, cellular ATP content, and glucose-, but not depolarization-stimulated, insulin secretion. We conclude that, in the context of the pancreatic islet, the principal response to PPAR␥ expression and activation is the activation of genes involved in the disposal, rather than the synthesis, of fatty acids. Although fatty acid oxidation may have beneficial effects on ␤-cell function in the longer term by countering ␤-cell "lipotoxicity," the acute response to this metabolic shift is a marked inhibition of insulin secretion.␤-cell; insulin; secretion; peroxisome proliferator-activated receptor-␥; sterol regulatory element-binding protein-1c; thiazolidinedione; glucolipotoxicity GROWING EVIDENCE SUGGESTS that ␤-cell secretory failure in some forms of type 2 diabetes is correlated with the accumulation of triglyceride (TG) within the pancreatic islet (28). In the Zucker diabetic fatty (ZDF) rat, overabundance of islet lipid is associated with impaired glucose-stimulated insulin secretion and decreased expression of the glucose transporter GLUT2/Slc2a2 (25), as well as enhanced nitric oxide formation (42) and apoptosis (44). Although the mechanisms underlying these changes, collectively termed "lipotoxicity" or "glucolipotoxicity" (36) are not fully elucidated, elevated levels of "lipogenic" transcription factors, such as sterol response element-binding protein-1c (SREBP-1c) (26) and peroxisome proliferator-activated receptor-␥ (PPAR␥) (26, 28), may play a role.PPAR␥, a member of the nuclear hormone receptor family, is translated from an alternately spliced mRNA in humans and rodents, generating three (␥1, ␥2, and ␥3) or two (␥1 and ␥2) isoforms, respectively, in these species (see Fig. 1A) (16,17,45,48). Whereas PPAR␥1 is present in many m...

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Expression of peroxisome proliferator-activated receptor γ (PPARγ) in normal human pancreatic islet cells

Cited by 177 publications

References 7 publications

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

Role of Peroxisome Proliferator-Activated Receptor gamma 2 (PPAR-γ2) Gene Polymorphism in Type 2 Diabetes Mellitus

Impact of PPARγ overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays

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