Role of Peroxisome Proliferator-Activated Receptor-γ in the Glucose-Sensing Apparatus of Liver and β-Cells

Kim, Hail; Ahn, Yong-Ho

doi:10.2337/diabetes.53.2007.s60

Cited by 173 publications

(134 citation statements)

References 55 publications

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“…In addition, functional PPAR response elements have been identified in the promoters of GLUT2 and glucokinase in the liver. Given that modulation of these genes in liver has been shown to directly affect both glycolysis and glycogen synthesis (39,40), it is very plausible to suggest that the increased hepatic PPAR␥ expression observed in the PPAR␥ adiposeKO mice may responsible for the improved insulin sensitivity that we have described.…”

Section: Discussionmentioning

confidence: 96%

Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance

Jones

Barrick

Kim

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

444

328

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) plays a crucial role in adipocyte differentiation, glucose metabolism, and other physiological processes. To further explore the role of PPAR␥ in adipose tissues, we used a Cre͞loxP strategy to generate adipose-specific PPAR␥ knockout mice. These animals exhibited marked abnormalities in the formation and function of both brown and white adipose tissues. When fed a high-fat diet, adiposespecific PPAR␥ knockout mice displayed diminished weight gain despite hyperphagia, had diminished serum concentrations of both leptin and adiponectin, and did not develop glucose intolerance or insulin resistance. Characterization of in vivo glucose dynamics pointed to improved hepatic glucose metabolism as the basis for preventing high-fat diet-induced insulin resistance. Our findings further illustrate the essential role for PPAR␥ in the development of adipose tissues and suggest that a compensatory induction of hepatic PPAR␥ may stimulate an increase in glucose disposal by the liver.body weight regulation ͉ diabetes ͉ knockout mouse ͉ Cre recombinase

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Section: Discussionmentioning

confidence: 96%

Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance

Jones

Barrick

Kim

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

444

328

View full text Add to dashboard Cite

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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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“…Another mechanism involves direct actions on pancreatic beta cells [44]. Recent reports have demonstrated that thiazolidinediones directly improve beta cell function [45], ameliorate lipotoxicity [46] and prevent beta cell apoptosis [47,48]. In Wfs1 −/− A y /a mice, direct protective effects, as well as indirect effects, are likely to be exerted.…”

Section: Discussionmentioning

confidence: 99%

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

et al. 2009

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Aims/hypothesis The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. Methods We studied the effect of breeding Wfs1 −/− mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A y /a). We also treated the mice with pioglitazone.

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Role of Peroxisome Proliferator-Activated Receptor-γ in the Glucose-Sensing Apparatus of Liver and β-Cells

Cited by 173 publications

References 55 publications

Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance

Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance

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

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

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