Insulin-like growth factors prevent cytokine-mediated cell death in isolated islets of Langerhans from pre-diabetic non-obese diabetic mice

Abstract

Interleukin-1 (IL-1 ), tumour necrosis factor-(TNF-) and interferon-(IFN-) contribute to the initial stages of the autoimmune destruction of pancreatic cells. IL-1 is released by activated macrophages resident within islets, and its cytotoxic actions include a stimulation of nitric oxide (NO) production and the initiation of apoptosis. Insulin-like growth factors (IGFs)-I and -II prevent apoptosis in non-islet tissues. This study investigated whether IGFs are cytoprotective for isolated islets of Langerhans from non-obese diabetic mice (NOD) mice exposed to cytokines. Pancreatic islets isolated from 5-6-week-old, pre-diabetic female NOD mice were cultured for 48 h before exposure to IL-1 (1 ng/ml), TNF-(5 ng/ml), IFN-(5 ng/ml) or IGF-I or -II (100 ng/ml) for a further 48 h. The incidence of islet cell apoptosis was increased in the presence of each cytokine, but this was significantly reversed in the presence of IGF-I or -II (IL-1 control 3·5 1·6%, IL-1 1 ng/ml 27·1 5·8%, IL-1 +IGF-I 100 ng/ml 4·4 2·3%, P<0·05). The majority of apoptotic cells demonstrated immunoreactive glucose transporter 2 (GLUT-2), suggesting that they were cells. Islet cell viability was also assessed by trypan blue exclusion. Results suggested that apoptosis was the predominant cause of cell death following exposure to each of the cytokines. Co-incubation with either IGF-I or -II was protective against the cytotoxic effects of IL-1 and TNF-, but less so against the effect of IFN-. Exposure to cytokines also reduced insulin release, and this was not reversed by incubation with IGFs. Immunohistochemistry showed that IGF-I was present in vivo in islets from pre-diabetic NOD mice which did not demonstrate insulitis, but not in islets with extensive immune infiltration. Similar results were seen for IGF-binding proteins (IGFBPs). These results suggest that IGFs protect prediabetic NOD mouse islets from the cytotoxic actions of IL-1 , TNF-and IFN-by mechanisms which include a reduction in apoptosis.

Growth hormone prevents the development of autoimmune diabetes

“…There is considerable evidence for distinct GH effects on pancreatic β-cells (16), some direct and others through its main mediator, IGF1 (42). Exogenous GH in rat islet cultures thus stimulates DNA synthesis and insulin production (43); IGF1 and GH signaling have mitogenic effects on INS-1 cells (44).…”

Ghrelin treatment protects lactotrophs from apoptosis in the pituitary of diabetic rats

“…Both circulating and locally produced IGF-I have cell-proliferative and anti-apoptotic properties (Kooijman, 2006;Kurmasheva and Houghton, 2006) by acting directly through its receptor, which is present in most organs and tissues (Werner and LeRoith, 2000), or indirectly by inhibiting inflammatory mediators such as TNF-α or nitric oxide (Hijikawa et al, 2008;Hill et al, 1999). Accordingly, it has been recently reported that IGF-I treatment prevents liver injury through the inhibition of TNF-α and iNOS induction in D-galactosamine and LPS-treated rats (Hijikawa et al, 2008) and that GHRP-2 treatment, a ghrelin analogue, prevents LPSinduced liver injury by increasing hepatic IGF-I and decreasing nitric oxide concentrations and TNF-α gene expression (Granado et al, 2008).…”

Repression of Malignant Tumor Progression upon Pharmacologic IGF1R Blockade in a Mouse Model of Insulinoma

“…In the developing pancreas, IGF-1 and IGF-2 are produced by cells of the islets of Langerhans where they exert paracrine and autocrine functions critical for islet differentiation (9) and islet cell growth (10,11). IGF-2 supports fibroblast growth factor (FGF)-2-mediated islet growth (12), whereas IGF-1 has been shown to directly protect b-cells from apoptosis (13,14). However, several reports challenge a critical role of the IGF-1/IGF1R system for islet proliferation or protection.…”