High ER stress in β-cells stimulates intracellular degradation of misfolded insulin

Allen, Jenny R.; Nguyen, Linh X.; Sargent, Karen E.; Lipson, Kathryn L.; Hackett, Anthony; Urano, Fumihiko

doi:10.1016/j.bbrc.2004.09.035

Cited by 85 publications

(67 citation statements)

References 22 publications

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“…Before the onset of hyperglycaemia, Ins2 C95S mutants demonstrated an increased abundance of the chaperone BiP, which increases protein folding activity and prevents protein aggregation, and of P-eIF2α, which plays a role in the prevention of accumulation of unfolded proteins by translational inhibition [20]. These findings are in line with the results of other studies that demonstrated increased ER stress in response to the expression of mutated insulin [4,21,22]. The abundance of the apoptosis markers CHOP and cleaved caspase 3, as well as PCNA, an indicator for cell replication, was unaltered in young Ins2 C95S mutants, which was not unexpected, since islet mass only starts to decline after 100 days of age in untreated mutants (N. Herbach, E. Wolf and R. Wanke, unpublished data).…”

Section: Ins2supporting

confidence: 82%

“…Insulin-treated mutants show strongly and weakly stained beta cells (b) and few nonbeta cells, located at the periphery of the islets (e), whereas placebotreated mutants demonstrate only few, weakly insulin positive islet-cells (c) and non-beta cells are distributed throughout the islet profile (f) intracellular degradation of proinsulin. Likewise, increased intracellular degradation of mutant proinsulin was found in the beta cells of Akita mice, leading to reduced insulin and C-peptide content in the pancreas [22,26,27].…”

Section: Ins2mentioning

confidence: 99%

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Early insulin therapy prevents beta cell loss in a mouse model for permanent neonatal diabetes (Munich Ins2 C95S)

et al. 2011

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Aims Heterozygous male Munich Ins2C95S mutant mice, a model for permanent neonatal diabetes mellitus, demonstrate a progressive diabetic phenotype with severe loss of functional beta cell mass. The aim of this study was to investigate the influence of early insulin treatment on glucose homeostasis and beta cell destruction in male Munich Ins2 C95S mutants. Methods One group of male Ins2 C95S mutants was treated with subcutaneous insulin pellets, as soon as blood glucose levels began to rise; placebo-treated mutants and wild-type mice served as controls. An additional group of mutant mice received a sodium-dependent glucose transporter 2 (SGLT2) inhibitor (AVE2268) via rodent chow.Results Insulin treatment normalised blood glucose concentrations, improved oral glucose tolerance, preserved insulin sensitivity and inhibited oxidative stress of Munich Ins2 C95S mutant mice. Pancreatic C-peptide content, as well as total beta cell and isolated beta cell volumes, of insulin-treated mutant mice were higher than those of placebo-treated mutants. In addition, alpha cell dysfunction and hyperplasia of non-beta cells were completely normalised in insulintreated mutant mice. Treatment with the SGLT2 inhibitor lowered blood glucose, improved glucose tolerance and normalised insulin sensitivity as well as oxidative stress of Ins2 C95S mutants. The abundance of the endoplasmic reticulum (ER) stress markers binding Ig protein (BiP) and phosphorylated eukaryotic translation initiation factor 2 alpha (P-eIF2α) was significantly increased in the islets of mutants, before onset of hyperglycaemia, vs wild-type mice. Conclusions We conclude that early insulin treatment protects Munich Ins2 C95S mutant mice from insulin resistance, alpha cell hyperfunction, beta cell loss and hyperplasia of non-beta cells, some well-known features of human diabetes mellitus. Therefore, insulin treatment may be considered early for human patients harbouring INS mutations.

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Section: Ins2supporting

confidence: 82%

Section: Ins2mentioning

confidence: 99%

Early insulin therapy prevents beta cell loss in a mouse model for permanent neonatal diabetes (Munich Ins2 C95S)

et al. 2011

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“…In previous work we showed that the mutant proinsulin fusion protein is degraded via a proteasome-dependent ERAD mechanism (Hartley et al, 2010), which is also the case for untagged Akita mutant proinsulin (Allen et al, 2004). Given that SDF2L1 associates with the ERAD system we hypothesized that SDF2L1 may play a role in the degradation of misfolded proteins in the ER.…”

Section: Journal Of Cell Sciencementioning

confidence: 85%

Stromal Cell-Derived Factor 2 Like-1 (SDF2L1) Associates with the Endoplasmic Reticulum-Associated Degradation (ERAD) Machinery and Retards the Degradation of Mutant Proinsulin in Pancreatic β-Cells

Tiwari

Schuiki

Zhang

et al. 2013

Journal of Cell Science

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SummaryStromal cell-derived factor 2-like 1 (SDF2L1) is an endoplasmic reticulum (ER)-localized protein whose function is undefined. Here we show that SDF2L1 protein levels are increased in response to ER stress-inducing compounds, but not other cell stressors that we tested in insulinoma cell lines. SDF2L1 protein levels were also induced by expression of misfolded proinsulin in insulinoma cells and in islets from diabetic mice. Immunoprecipitation and binding assays demonstrated that SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin. Unexpectedly, knockdown of SDF2L1 in INS-1 (insulin 2 C96Y-GFP) cells increased the degradation kinetics of mutant proinsulin, suggesting that SDF2L1 regulates substrate availability for the ERAD system. We suggest that SDF2L1 increases the time that misfolded proteins have to achieve a correctly folded conformation and thus that SDF2L1 can act as a buffer for substrate availability for ERAD in pancreatic b-cells.

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“…In the Akita mouse model of diabetes, aberrations in proinsulin folding resulting from a point mutation in the Ins2 gene (C96Y), can disrupt disulfide bond formation in insulin processing (47). This results in the accumulation of misfolded proteins in the ER and ultimately ␤-cell death (1,33). Although these findings suggest a potential role for ER stress as a causative agent in diabetes associated complications, the physiological relevance of these observations is A subset of cells was pretreated with 20 M DON.…”

Section: Discussionmentioning

confidence: 99%

Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells

Sage¹,

Walter²,

Shi³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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There is increasing evidence that endoplasmic reticulum (ER) stress contributes to the development of atherosclerosis in diabetes mellitus. The purpose of this study was to determine the effects of increased hexosamine biosynthesis pathway (HBP) flux on ER stress levels and the complications of ER stress associated with diabetes and atherosclerosis in hepatic cells. Glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of the HBP, was overexpressed in HepG2 cells by use of an adenoviral expression system. The ER stress response and downstream effects, including activation of lipid and inflammatory pathways, were determined using real-time PCR, immunoblot analysis, and cell staining techniques. GFAT overexpression resulted in increased expression of ER stress markers, including Grp78, Grp94, calreticulin, and GADD153, relative to cells infected with an empty adenoviral vector. In addition, GFAT overexpression promoted lipid, but not cholesterol, accumulation in hepatic cells as well as inflammatory pathway activation. Treatment with 6-diazo-5-oxo-norleucine, a GFAT antagonist, blocked the effects of GFAT overexpression. Consistent with our in vitro data, hyperglycemic mice presented with elevated markers of hepatic ER stress, glucosamine and lipid accumulation. Together, these data suggest that HBP flux-induced ER stress plays a role in the development of hepatic steatosis and atherosclerosis under conditions of hyperglycemia.

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High ER stress in β-cells stimulates intracellular degradation of misfolded insulin

Cited by 85 publications

References 22 publications

Early insulin therapy prevents beta cell loss in a mouse model for permanent neonatal diabetes (Munich Ins2 C95S)

Early insulin therapy prevents beta cell loss in a mouse model for permanent neonatal diabetes (Munich Ins2 C95S)

Stromal Cell-Derived Factor 2 Like-1 (SDF2L1) Associates with the Endoplasmic Reticulum-Associated Degradation (ERAD) Machinery and Retards the Degradation of Mutant Proinsulin in Pancreatic β-Cells

Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells

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