Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1

Abstract

IGF binding protein 1 (IGFBP1) is a member of the binding proteins for the IGF with an important role in glucose homeostasis. Circulating IGFBP1 is derived essentially from the liver where it is mainly regulated negatively by insulin. Carnosine, a natural antioxidant, has been shown to improve metabolic control in different animal models of diabetes but its mechanisms of action are still not completely unraveled. We therefore investigate the effect of carnosine treatment on the IGFBP1 regulation in db/db mice. Db/db mice and heterozygous non-diabetic mice received for 4 weeks regular water or water supplemented with carnosine. Igfbp1 mRNA expression in the liver was evaluated using qPCR and the protein levels in plasma by western blot. Plasma IGF1 and insulin were analyzed using immunoassays. HepG2 cells were used to study the in vitro effect of carnosine on IGFBP1. The modulation of hypoxia inducible factor-1 alpha (HIF-1a) which is the central mediator of hypoxia-induction of IGFBP1 was analyzed using: WB, reporter gene assay and qPCR. Carnosine decreased the circulating IGFBP1 levels and the liver expression Igfbp1, through a complex mechanism acting both directly by suppressing the HIF-1a-mediated IGFBP1 induction and indirectly through increasing circulating insulin level followed by a decrease in the blood glucose levels and increased the plasma levels or IGF1. Reduction of IGFBP1 in diabetes through insulin-dependent and insulin-independent pathways is a novel mechanism by which carnosine contributes to the improvement of the metabolic control in diabetes.

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation

“…CD248 expression was knocked down by RNAi in human in vitro differentiated adipocytes at day 10 of differentiation using 40 nM siRNA oligonucleotides (M-010720-00-0005, Dharmacon) and compared with non-silencing control RNAi (D-001206-13-05). The electroporation of siRNA was combined with 1 μg of plasmids containing the hypoxia response element (HRE) (previously described in [24]) coupled to a luciferase reporter and 0.1 μg Renilla. Cells were electroporated at day 10 of differentiation as previously described [19] and were then incubated in a hypoxic chamber at day 12 and harvested for subsequent analysis at day 13.…”

Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift

“…Development of carnosine derivatives resistant to CN1 hydrolysis has become the subject of emerging interest in recent years 20 . In rodents, no serum CN1 is present and carnosine supplementation of diabetic mice increases serum and tissue carnosine levels and mitigates DN, reduces renal vasculopathy 21 , normalizes vascular permeability 21 , improves wound healing 22 and decreases insulin growth factor binding protein-1 (IGFBP1) production through suppression of HIF-1α, and improves glucose homeostasis 23 . Moreover, in streptozotocin-induced diabetic rats, carnosine prevents apoptosis of glomerular cells, podocyte loss 24 , 25 , and vascular damage 26 .…”

The Role of GSH in Intracellular Iron Trafficking

“…Likewise, a protective role for carnosine has also been reported in diabetes [66,67]. Indeed, carnosine concentrations in the livers of diabetic mice are lower than those in control mice [68]. In this same study, carnosine was reported to decrease the circulating insulin-like growth factor-binding protein (IGFBP) levels, through a mechanism that involved the suppression of HIF-1α-mediated IGFBP induction [68].…”