PPAR-γ overexpression selectively suppresses insulin secretory capacity in isolated pancreatic islets through induction of UCP-2 protein

Ito, Eisuke; Ozawa, Sachihiko; Takahashi, Kazuto; Tanaka, Toshiaki; Katsuta, Hidenori; Yamaguchi, Shinya; Maruyama, Masahiro; Takizawa, Makoto; Katahira, Hiroshi; Yoshimoto, Katsuhiko; Nagamatsu, Shinya; Ishida, Hideyuki

doi:10.1016/j.bbrc.2004.08.238

Cited by 47 publications

(35 citation statements)

References 20 publications

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“…19). Interestingly, PPARg function is also critical for h-cell proliferation and physiology: activation of PPARg is sufficient to inhibit h-cell proliferation and PPARg overexpression significantly compromises glucose-stimulated insulin secretion (48)(49)(50). Conversely, elimination of PPARg in h-cells leads to pancreatic hyperplasia in mice, even if normal glucose homeostasis in these animals indicates compensatory mechanisms in h-cell function (48).…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Is a Zac Target Gene Mediating Zac Antiproliferation

et al. 2006

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Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Is a Zac Target Gene Mediating Zac Antiproliferation

et al. 2006

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“…Exposure of human islets to high glucose increases UCP2 expression, and alters GSIS [13]. Peroxisome proliferator-activated receptor (PPAR)α [14][15][16] and PPARγ [17,18] agonists also increase UCP2 and decrease GSIS, except in a study in which a threefold to fourfold increase in UCP2 level, measured after overexpression of PPARα and RXR (retinoid X receptor), decreased neither the mitochondrial membrane potential nor GSIS [16].…”

Section: Introductionmentioning

confidence: 99%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

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“…In contrast, many studies have assessed isolated islets or clonal ␤-cells after hours to several days of exposure to PPAR-␥ agonists (typically thiazoledinediones), often with PPAR-␥ overexpression. A wide variety of effects are reported, including a reduction (17,(43)(44)(45)(46)(47), no change (16,48,49), and increases in glucose-induced insulin secretion (50,51), which may reflect the imperfect specificity for PPAR-␥ of these agents. This may also account for our failure to see an effect of 3 days' exposure to troglitazone on glucose-induced insulin secretion in INS-1 cells.…”

Section: Ppar-␥ Is Expressed In Isletmentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptor-γ Regulates Expression of PDX-1 and NKX6.1 in INS-1 Cells

et al. 2007

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In the 60% pancreatectomy (Px) rat model of ␤-cell adaptation, normoglycemia is maintained by an initial week of ␤-cell hyperplasia that ceases and is followed by enhanced ␤-cell function. It is unknown how this complex series of events is regulated. We studied isolated islets and pancreas sections from 14-day post-Px versus sham-operated rats and observed a doubling of ␤-cell nuclear peroxisome proliferator-activated receptor (PPAR)-␥ protein, along with a 2-fold increase in nuclear pancreatic duodenal homeobox (Pdx)-1 protein and a 1.4-fold increase in ␤-cell nuclear Nkx6.1 immunostaining. As PPAR-␥ activation is known to both lower proliferation and have prodifferentiation effects in many tissues, we studied PPAR-␥ actions in INS-1 cells. A 3-day incubation with the PPAR-␥ agonist troglitazone reduced proliferation and increased Pdx-1 and Nkx6.1 immunostaining, along with glucokinase and GLUT2. Also, a 75% knockdown of PPAR-␥ using RNA interference lowered the mRNA levels of Pdx-1, glucokinase, GLUT2, and proinsulin II by more than half. Our results show a dual effect of PPAR-␥ in INS-1 cells: to curtail proliferation and promote maturation, the latter via enhanced expression of Pdx-1 and Nkx6.1. Additional studies are needed to determine whether there is a regulatory role for PPAR-␥ signaling in the ␤-cell adaptation following a 60% Px in rats. Diabetes 56:88 -95, 2007

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PPAR-γ overexpression selectively suppresses insulin secretory capacity in isolated pancreatic islets through induction of UCP-2 protein

Cited by 47 publications

References 20 publications

Peroxisome Proliferator-Activated Receptor γ Is a Zac Target Gene Mediating Zac Antiproliferation

Peroxisome Proliferator-Activated Receptor γ Is a Zac Target Gene Mediating Zac Antiproliferation

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Peroxisome Proliferator–Activated Receptor-γ Regulates Expression of PDX-1 and NKX6.1 in INS-1 Cells

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