Effects of free fatty acids on β-cell functions: A possible involvement of peroxisome proliferator-activated receptors α or pancreatic/duodenal homeobox

Yoshikawa, Haruhisa; Tajiri, Yuji; Sako, Yasuhiro; Hashimoto, Toshihiko; Umeda, Fumio; Nawata, Hajime

doi:10.1053/meta.2001.22565

Cited by 74 publications

(57 citation statements)

References 32 publications

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“…Increased NEFA concentrations induced constant decrease in GSIS but inconstant decrease in insulin content, and had no influence on insulin gene expression, as described in certain studies [35], in contrast to others [17,18]. Those results suggested that NEFA could probably act via pathways not related to betacell exhaustion, by inducing for example overexpression of hormone-sensitive lipase [36] or change in signal recognition not yet clearly understood [37].…”

Section: Discussionmentioning

confidence: 88%

“…These include endocrine-specific genes such as insulin, glucagon, somatostatin and the glucose transporter GLUT2 [9,15,16,17,18]. Glucose and NEFA have also been shown to impair their own intraislet metabolism via changes in expression of genes encoding for key enzymes in glycolytic, lipogenic and fat oxidation pathways [9,16,19,20,21,22,23,24,25,26,27].…”

mentioning

confidence: 99%

“…Glucose and NEFA have also been shown to impair their own intraislet metabolism via changes in expression of genes encoding for key enzymes in glycolytic, lipogenic and fat oxidation pathways [9,16,19,20,21,22,23,24,25,26,27]. The expression of such transcription factors as pancreatic/duodenal homeobox-1 (PDX-1 or insulin promoter factor-1, IPF-1), peroxisome proliferator-activated receptor (PPAR) α and PPARγ, also appear to be modified by glucose and/or NEFA in pancreatic islets [9,15,16,17,18,25,26,28].…”

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confidence: 99%

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Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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Aims/hypothesis. Whether excess glucose (glucotoxicity) and excess non-esterified fatty acids (lipotoxicity) act synergistically or separately to alter beta-cell function on Type 2 diabetes remains controversial. We examined the influence of non-esterified fatty acids, with or without concomitant increased glucose concentrations, on human islet function and on the expression of genes involved in lipid metabolism. Methods. Human islets isolated from non-diabetic and non-obese donors were cultured with 5.5, 16 or 30 mmol/l glucose, and when appropriate with 1 or 2 mmol/l non-esterified fatty acids. After 48 h, glucose-stimulated insulin secretion, insulin content, triglyceride content and expression of different genes were evaluated. Results. Non-esterified fatty acids decreased glucosestimulated insulin secretion, insulin content and increased triglyceride content of human isolated islets, independently from the deleterious effect of glucose. Increased glucose concentrations also decreased glucosestimulated insulin secretion and insulin content, but had no influence on triglyceride content. Glucose-stimulated insulin secretion of islets appeared to be significantly correlated with their triglyceride content. Glucose and non-esterified fatty acids modified the gene expression of carnitine palmitoyltransferase-I, acetyl-CoA carboxylase, acyl-CoA oxidase and uncoupling protein 2. Conclusion/interpretation. In our model of isolated human islets, increased glucose and non-esterified fatty acids separately reproduced the two major beta-cell alterations observed in vivo, i.e. loss of glucose-stimulated insulin secretion and reduction in islet insulin content. Our results also suggest that this deleterious effect was, at least in part, mediated by modifications in lipid metabolism gene expression. [Diabetologia (2004) 47:463-469]

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%

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confidence: 99%

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Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

et al. 2004

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“…We previously speculated that upregulated GLUT-2 expression might be responsible for the acquired sensitivity to streptozotocin accompanying the maturation of the beta cell phenotype [18]. In contrast, exposure to IL-1β resulted in a similar downregulation of GLUT-2 (FC −2.6, beta cell and FC −2.8, pre-beta cell; Panel B, group 2) expression in both phenotypes, which may result in decreased beta cell function, since decreased glucose-metabolism and insulin secretion has been associated with decreased expression of GLUT-2 [36]. GLUT-2 was also downregulated after cytokine exposure of purified beta cells [24].…”

Section: Discussionmentioning

confidence: 93%

Gene expression profiles during beta cell maturation and after IL-1? exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1? sensitivity

et al. 2004

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Aim/hypothesis. Maturation of the beta cells in the islets of Langerhans is dependent upon sequential activation of different transcription factors such as Pdx-1 and Nkx6.1. This maturation is associated with an acquired sensitivity to cytokines and may eventually lead to type 1 diabetes. The aims of this study were to characterise changes in mRNA expression during beta cell maturation as well as after interleukin-1β (IL-1β) exposure. Methods. Transcriptome analyses were performed on two phenotypes characterised as a glucagon-producing pre-beta-cell phenotype (NHI-glu), which matures to an IL-1β-sensitive insulin-producing beta cell phenotype (NHI-ins). Beta cell lines over-expressing Pdx-1 or Nkx6.1, respectively, were used for functional characterisation of acquired IL-1β sensitivity.Results. During beta cell maturation 98 fully annotated mRNAs changed expression levels. Of these, 50 were also changed after 24 h of IL-1β exposure. In addition, 522 and 197 fully annotated mRNAs, not affected by maturation, also changed expression levels following IL-1β exposure of the beta cell and the prebeta-cell phenotype, respectively. Beta cell maturation was associated with an increased expression of Nkx6.1, whereas both Pdx-1 and Nkx6.1 expression were decreased following IL-1β exposure. Over-expression of Nkx6.1 or Pdx-1 in cell lines resulted in a significantly increased sensitivity to IL-1β. Conclusions/interpretation. These results suggest that the final beta cell maturation accompanied by increased IL-1β sensitivity is, in part, dependent upon the expression of genes regulated by Pdx-1 and Nkx6.1. Future classification of the genes regulated by these transcription factors and changed during beta cell maturation should elucidate their role in the acquired sensitivity to IL-1β and may be helpful in identifying new targets for intervention/prevention strategies.

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“…Earlier, Kotliar et al had suggested that an acute insulin stimulation of glucose transport is not solely dependent on the presence of insulin receptor and Glut-4 protein, indicating the presence of some additional proteins [18]. FFA treatment has been well documented to have effects on the expression level of other proteins such as peroxisome proliferator-activated receptor alpha (PPARα), glucokinase, Glut-1, and Glut-2 glucose transporters [19]which is not the focus of our current study.…”

Section: Discussionmentioning

confidence: 99%

Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: Evidence for PKC activation and oxidative stress-activated signaling pathways

Ragheb

Shanab

Medhat

et al. 2009

Biochemical and Biophysical Research Communications

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In the present study, we examined the effects of free fatty acids (FFAs) on insulin sensitivity and signaling cascades in the C2C12 skeletal muscle cell culture system. Our data clearly manifested that the inhibitory effects of PKC on insulin signaling may at least in part be explained by the serine/threonine phosphorylation of IRS-1. Both oleate and palmitate treatment were able to increase the Serine 307 phosphorylation of IRS-1. IRS-1 Serine 307 phosphorylation is inducible which causes the inhibition of IRS-1 tyrosine phosphorylation by either IκB-kinase (IKK) or c-jun N-terminal kinase (JNK) as seen in our proteomic kinases screen. Furthermore, our proteomic data have also manifested that the two FFAs activate the IKKα/β, the stress kinases S6 kinase p70 (p70SK), stress-activated protein kinase (SAPK), JNK, as well as p38 MAP kinase (p38MAPK). On the other hand, the antioxidant, Taurine at 10 mM concentrations was capable of reversing the oleate-induced insulin resistance in myocytes as manifested from the glucose uptake data. Our current data point out the importance of FFA-induced insulin resistance via multiple signaling mechanisms. KeywordsFree fatty acid (FFA); Insulin resistance (IR); Skeletal muscle cell (C2C12); Protein kinase C (PKC); Insulin receptor substrate-1 (IRS-1)

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Effects of free fatty acids on β-cell functions: A possible involvement of peroxisome proliferator-activated receptors α or pancreatic/duodenal homeobox

Cited by 74 publications

References 32 publications

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration

Gene expression profiles during beta cell maturation and after IL-1? exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1? sensitivity

Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: Evidence for PKC activation and oxidative stress-activated signaling pathways

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