Characterization of proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) in human lung fibroblasts

Abstract

Insulin has been approved for inhaled application, but safety concerns remain, because of un-physiologically high insulin concentrations in the lung. Since insulin may act as growth factor, possible proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) on human lung fibroblasts were studied. As measure of proliferation [(3)H]-thymidine incorporation was studied in HEL-299, MRC-5, IMR-90 and primary human lung fibroblasts. In all cells, mRNA encoding IGF-1 receptors and two variants of insulin receptors was detected. Insulin and IGF-1 stimulated [(3)H]-thymidine incorporation in all cells. Comparison of the concentration-dependent effects in HEL-299 cells showed that IGF-1 and insulin glargine were more potent (EC(50), 3 and 6 nM) and more effective (maximum increase, by 135-150%) than insulin and insulin detemir (EC(50), 22 and 110 nM; maximum increase: by 80%). Proliferative effects of IGF-1 and insulin were inhibited to the same extent by an antibody (1H7) directed against the IGF-1 receptor α-subunit. Insulin-induced stimulation of [(3)H]-thymidine incorporation was reduced by 83% after siRNA-mediated down-regulation of IGF-1 receptor by about 75%, but not affected by a similar down-regulation of the insulin receptor. Insulin and IGF-1 caused rapid up-regulation of the early genes FOS, EGR-1 and EGR-2 as well as of the gene coding for IGF-1. In conclusion, in human lung fibroblasts insulin exerts marked proliferative effects and the pharmacological profile of this response as well as specific receptor knock-down experiments suggest mediation via IGF-1 receptors. The risk of unwanted structural lung alterations by long-term inhalative application of insulin should be considered.

Hyperinsulinemia adversely affects lung structure and function

“…5B). Previous studies have shown that insulin induces proliferation of human lung fibroblasts and bovine tracheal smooth muscle cells (15,40). We found that recombinant human insulin exposure leads to about eightfold increase in human ASM cell number by 72 h (Fig.…”

Critical role of TRPC6 in maintaining the stability of HIF-1α in glioma cells under hypoxia

“…*P<0.05, **P<0.01, ***P<0.0001 [Student's t-test or ANOVA (more than two groups)]. 1R mediates hypoxic effects on TRPC6 activation, we incubated cells with a neutralizing antibody (1H7) directed against the IGF-1R α-subunit to inhibit IGF-1R signaling (Kwon et al, 2009;Warnken et al, 2010) and examined the Ca 2+ elevation. Neutralizing IGF-1 receptors did indeed suppress the hypoxia-induced intracellular Ca 2+ elevation and DNC6 did not further inhibit the Ca 2+ elevation (Fig.…”

Non-small cell lung cancer cell survival crucially depends on functional insulin receptors

“…Various epidemiological studies reveal that T2DM is positively associated with tumorigenesis (Li & Kong 2014). In the population of diabetic patients an increased incidence of liver (El-Serag et al 2006), pancreatic (Everhart & Wright 1995), breast (Wolf et al 2005), substantial reason for insulin's cancer-promoting effects (Cohen 2006, Warnken et al 2010. Relevant structural and functional similarities of the peptides insulin and IGF1, and their receptors, are responsible for this crossreaction binding (De Meyts & Whittaker 2002).…”