Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

Maedler, Kathrin; Сергеев, П. В.; Ris, Frédéric; Oberholzer, José; Joller‐Jemelka, H. I.; Spinas, Giatgen A.; Kaiser, Nurit; Halban, Philippe A.; Donath, Marc Y.

doi:10.1172/jci15318

Cited by 422 publications

(394 citation statements)

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“…Increases in islet IL-1␤ during the development of diabetes in an animal model have been reported (7). We reported that specific inhibitors of cyclooxygenase-2 and PGE 2 production prevent IL-1␤ from inhibiting glucose-induced insulin secretion in isolated islets (14).…”

Section: Discussionmentioning

confidence: 75%

“…Long term exposure to high glucose conditions inhibits endothelial cells from responding to cytokine exposure with an increase in GCL expression and activity (3). That the pathogenesis of diabetes mellitus involves interactions with IL-1␤ and oxidative stress secondary to chronic hyperglycemia (6,7) raises the questions of whether GCL is normally expressed in the islet and whether overexpression of GCL protects the beta cell from oxidative stress.…”

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confidence: 99%

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Adenoviral Overexpression of the Glutamylcysteine Ligase Catalytic Subunit Protects Pancreatic Islets against Oxidative Stress

Tran

Parker

Leroy

et al. 2004

Journal of Biological Chemistry

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The catalytic subunit of glutamylcysteine ligase (GCLC) primarily regulates de novo synthesis of glutathione (GSH) in mammalian cells and is central to the antioxidant capacity of the cell. However, GCLC expression in pancreatic islets has not been previously examined. We designed experiments to ascertain whether GCLC is normally expressed in islets and whether it is up-regulated by interleukin-1␤ (IL-1␤). GCLC expression levels were intermediate compared with other metabolic tissues (kidney, liver, muscle, fat, and lung). IL-1␤ up-regulated GCLC expression (10 ng/ml IL-1␤, 3.76 ؎ 0.86; 100 ng/ml IL-1␤, 4.22 ؎ 0.68-fold control) via the p38 form of mitogen-activated protein kinase and NF B and also increased reactive oxygen species levels (10 ng/ml IL-1␤, 5.41 ؎ 1.8-fold control). This was accompanied by an increase in intraislet GSH/GSSG ratio (control, 7.1 ؎ 0.1; 10 ng/ml IL-1␤, 8.0 ؎ 0.5; 100 ng/ml IL-1␤, 8.2 ؎ 0.5-fold control; p < 0.05). To determine whether overexpression of GCLC increases the antioxidant capacity of the islet and prevents the adverse effects of IL-1␤ on glucose-induced insulin secretion, islets were infected with an adenovirus encoding GCLC. IL-1␤ significantly decreased glucose-stimulated insulin secretion (control, 123.8 ؎ 17.7; IL-1␤, 40.2 ؎ 3.9 microunits/ml insulin/islet). GCLC overexpression increased intraislet GSH levels and partially prevented the decrease in glucose-stimulated insulin secretion caused by IL-1␤. These data provide the first report of GCLC expression in the islet and demonstrate that adenoviral overexpression of GCLC increases intracellular GSH levels and protects the beta cell from the adverse effects of IL-1␤.Glutamylcysteine ligase (GCL) 1 is the primary and ratelimiting enzyme responsible for de novo synthesis of intracellular glutathione (GSH). This enzyme catalyzes ATP-dependent ligation of L-glutamate and L-cysteine to form ␥-glutamyl-L-cysteine, which undergoes another ATP-dependent ligation with glycine catalyzed by glutathione synthetase to form the final GSH product (1, 2). GCL is a heterodimer, composed of a light regulatory subunit as well as a heavy catalytic subunit. Although both are required for optimal enzyme activity, overexpression of the catalytic subunit GCLC alone is sufficient to increase enzyme activity significantly over control levels (1). The regulation of GCL expression and activity has been studied in many other cell types, including mesangial and endothelial cells, but not the pancreatic islet. Long term exposure to high glucose levels decreases GCL expression in mesangial, retinal Muller, and endothelial cells, which results in a decrease in GSH levels (3-5). Long term exposure to high glucose conditions inhibits endothelial cells from responding to cytokine exposure with an increase in GCL expression and activity (3). That the pathogenesis of diabetes mellitus involves interactions with IL-1␤ and oxidative stress secondary to chronic hyperglycemia (6, 7) raises the questions of whether GCL is normally expressed in the islet and whe...

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Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

Adenoviral Overexpression of the Glutamylcysteine Ligase Catalytic Subunit Protects Pancreatic Islets against Oxidative Stress

Tran

Parker

Leroy

et al. 2004

Journal of Biological Chemistry

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“…Fas (CD95) is a cell surface receptor that plays a central role in the regulation of death in many cell types, including ␤ cells, and may be implicated in the development of type 1 and type 2 diabetes (3)(4)(5). Glucose-induced ␤ cell apoptosis in human islets involves IL-1␤-mediated up-regulation of Fas and subsequent interaction with the constitutively expressed Fas ligand (FasL) on neighboring ␤ cells (3,(6)(7)(8). Fas/FasL interaction leads to cleavage of procaspase-8, the most upstream caspase in the Fas apoptotic pathway.…”

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confidence: 99%

“…Interestingly, in ␤ cells NF-B activation can also be triggered by glucose (6,13). Increasing evidence points to noninflammatory effects of NF-B, including regulation of insulin secretion (14,15).…”

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confidence: 99%

The Fas pathway is involved in pancreatic β cell secretory function

Schumann

Maedler

Franklin³

et al. 2007

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

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Pancreatic ␤ cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in ␤ cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates ␤ cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a ␤ cell-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fasdeficient ␤ cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased ␤ cell mass. Up-regulation of FLIP enhanced NF-B activity via NF-B-inducing kinase and RelB. This led to increased PDX-1 and insulin production independent of changes in cell turnover. The results support a previously undescribed role for the Fas pathway in regulating insulin production and release.diabetes ͉ IL-1 ͉ insulin

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“…Furthermore, it is becoming increasingly apparent that many factors classically deemed type 1 diabetesspecific are also integral to the process of ␤ cell failure in type 2 diabetes patients. These include the effect of IL-1␤, Fas, and nuclear factor-B, endoplasmic reticulum stress, and increased expression of c-Myc (19)(20)(21)(22). Interestingly, polymorphisms in the Fas pathway have been associated recently with type 2 diabetes (23).…”

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confidence: 99%