ER stress and SREBP-1 activation are implicated in β-cell glucolipotoxicity

Wang, Haiyan; Kouri, Georgia; Wollheim, Claes B.

doi:10.1242/jcs.02513

Cited by 243 publications

(230 citation statements)

References 81 publications

(159 reference statements)

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“…In both cases, a clear induction of adipogenic transformation was observed upon the application of high-glucose culture conditions. The capacity of high glucose to partly activate an adipogenic differentiation program had already been noticed in pancreatic ␤ cells (13,14). In our case, the process consists in a full conversion into adipocytes, as verified by morphological and molecular criteria and the capacity of these cultured cell to form viable and vascularized adipose depots when implanted in vivo.…”

Section: Discussionsupporting

confidence: 78%

High glucose induces adipogenic differentiation of muscle-derived stem cells

Aguiari

Leo

Zavan

et al. 2008

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

255

178

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Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most cases remains elusive in terms of cellular identity and differentiation signals. We here show that primary cell cultures derived from adipose tissue or skeletal muscle differentiate into adipocytes when cultured in high glucose. High glucose induces ROS production and PKC␤ activation. These two events appear crucial steps in this differentiation process that can be directly induced by oxidizing agents and inhibited by PKC␤ siRNA silencing. The differentiated adipocytes, when implanted in vivo, form viable and vascularized adipose tissue. Overall, the data highlight a previously uncharacterized differentiation route triggered by high glucose that drives not only resident stem cells of the adipose tissue but also uncommitted precursors present in muscle cells to form adipose depots. This process may represent a feed-forward cycle between the regional increase in adiposity and insulin resistance that plays a key role in the pathogenesis of diabetes mellitus.adipocyte ͉ hyperglycemia ͉ PKC ͉ ROS

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Section: Discussionsupporting

confidence: 78%

High glucose induces adipogenic differentiation of muscle-derived stem cells

Aguiari

Leo

Zavan

et al. 2008

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

255

178

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“…The mean signal intensity (microarray) and threshold cycle measured in G10 (real-time PCR performed with islet cDNA equivalent to 2 ng total RNA) are shown as rough indicators of gene mRNA levels *p<0.05, **p<0.01 vs islets cultured in G10 (one-way ANOVA and Newman-Keuls test) NA, not affected support of that hypothesis, cholesterol depletion and Srebp1c (also known as Srebf1) gene inactivation significantly altered beta cell function [41,42]. However, the fact that Srebp1c and Srebp2 overexpression are also deleterious to beta cell differentiation and function [43,44] suggests that both excessive and insufficient cholesterol availability is harmful to beta cells. Thus, the cholesterol biosynthesis pathway needs to be tightly regulated for optimal preservation of the beta cell phenotype.…”

Section: Resultsmentioning

confidence: 95%

Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations

et al. 2009

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“…4). Prolonged exposure of beta cells to increased glucose levels can cause ER stress and oxidative stress (oxidative stress may worsen ER stress) [10,48,49]. We and others have previously reported that beta cell defences against oxidative stress are reduced in the case of diabetes [28,50].…”

Section: Discussionmentioning

confidence: 99%

The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

et al. 2007

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Aims/hypothesis Pancreatic beta cells have highly developed endoplasmic reticulum (ER) due to their role in insulin secretion. Since ER stress has been associated with beta cell dysfunction, we studied several features of beta cell ER in human type 2 diabetes. Methods Pancreatic samples and/or isolated islets from non-diabetic controls (ND) and type 2 diabetes patients were evaluated for insulin secretion, apoptosis (electron microscopy and ELISA), morphometric ER assessment (electron microscopy), and expression of ER stress markers in beta cell prepared by laser capture microdissection and in isolated islets.Results Insulin release was lower and beta cell apoptosis higher in type 2 diabetes than ND islets. ER density volume was significantly increased in type 2 diabetes beta cells. Expression of alpha-mannosidase (also known as mannosidase, alpha, class 1A, member 1) and UDP-glucose glycoprotein glucosyl transferase like 2 (UGCGL2), assessed by microarray and/or real-time reverse transcriptase polymerase chain reaction (RT-PCR), differed between ND and type 2 diabetes beta cells. Expression of immunoglobulin heavy chain binding protein (BiP, also known as heat shock 70 kDa protein 5 [glucose-regulated protein, 78 kDa] [HSPA5]), X-box binding protein 1 (XBP-1, also known as XBP1) and C/EBP homologous protein (CHOP, also known as damage-inducible transcript 3 [DDIT3]) was not higher in type 2 diabetes beta cell or isolated islets cultured at 5.5 mmol/l glucose (microarray and real-time RT-PCR) than in ND samples. When islets were cultured for 24 h at 11

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ER stress and SREBP-1 activation are implicated in β-cell glucolipotoxicity

Cited by 243 publications

References 81 publications

High glucose induces adipogenic differentiation of muscle-derived stem cells

High glucose induces adipogenic differentiation of muscle-derived stem cells

Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations

The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

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