Journal
ENDOCRINOLOGY
Volume 152, Issue 8, Pages 3040-3048Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2010-1422
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Funding
- Danish Research Council
- Swedish Research Council
- Family Erling-Persson Foundation
- Swedish Diabetes Foundation
- Bert von Kantzow's Foundation
- Barndiabetesfonden
- Novo Nordisk A/S
- Novo Nordisk Fonden [NNF11OC1014706] Funding Source: researchfish
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Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic beta-cells in the absence of inflammatory stress. Here, we investigated the effects of ApoCIII on function, signaling, and viability in intact rat pancreatic islets exposed to proinflammatory cytokines to model the intraislet inflammatory milieu in T1D. In contrast to earlier observations in mouse beta-cells, exposure of rat islets to ApoCIII alone (50 mu g/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1 beta + interferon-gamma, ApoCIII reduced cytokine-mediated islet cell death and impairment of beta-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had no impact on IL-1 beta-induced c-Jun N-terminal kinase activation. However, ApoCIII augmented cytokine-mediated nitric oxide (NO) production and inducible NO synthase expression. Further, ApoCIII caused degradation of the nuclear factor kappa B-inhibitor inhibitor of kappa B and stimulated Ser473-phosphorylation of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces rat pancreatic islet cell apoptosis via Akt. (Endocrinology 152: 3040-3048, 2011)
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