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Metallothionein 1 inhibits glucose-stimulated insulin secretion and is differentially regulated in conditions of beta cell compensation and failure
- Source :
- Diabetologia : clinical and experimental diabetes and metabolism, Vol. 61, no.Issue 1 supplement, p. 210 (2018)
- Publication Year :
- 2018
- Publisher :
- Springer, 2018.
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Abstract
- Background and aims: The mechanisms responsible for β cell compensation in obesity and for β cell failure in type 2 diabetes (T2D) are poorly defined. Metallothioneins play a role in both Zn2+ homeostasis and the regulation of cellular redox state. The mRNA levels of several metallothionein genes are upregulated in islets from subjects with T2D, but their role in β cells is not clear. Here we examined: 1) the temporal changes of islet Mt1 and Mt2 gene expression in models of β cell compensation and failure, and 2) the role of Mt1 and Mt2 in β cell function and glucose homeostasis. Materials and methods: Mt1 and Mt2 expression was assessed in islets from control lean (chow diet) and diet-induced obese (DIO) mice (8 weeks high fat diet), and pre-diabetic (6-week-old) and diabetic (16-week-old) db/db mice and age-matched db/+ (control) mice. Mt1-Mt2 double knockout (KO) mice, Mt1 overexpressing transgenic mice (Tg-Mt1) and corresponding control mice were studied. Mt1 and Mt2 were inhibited in MIN6 cells by small interfering RNAs. mRNA levels were assessed by real-time RT-PCR, plasma insulin and islet metallothionein levels by ELISA, glucose tolerance by i.p. glucose tolerance tests (ipGTT) and fasting-1h refeeding tests, insulin secretion by RIA, cytosolic free Ca2+ with Fura-2 LR, NAD(P)H by autofluorescence and cytosolic redox state using roGFP1 ratiometric thiol redox probe. Results: Increased plasma insulin levels (β cell compensation) correlated with marked downregulation of Mt1 and Mt2 mRNA levels in islets of DIO mice (Mt1: ~4-fold, p
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Diabetologia : clinical and experimental diabetes and metabolism, Vol. 61, no.Issue 1 supplement, p. 210 (2018)
- Accession number :
- edsair.od......1493..ec1406b0f816e94a03d1629d2a6ad8d1