Carnosine treatment in combination with ACE inhibition in diabetic rats

Peters, Verena; Riedl, Eva; Braunagel, Margarita; Höger, Simone; Hauske, Sibylle J.; Pfister, Frederick; Zschocke, Johannes; Lanthaler, Barbara; Benck, Urs; Hammes, Hans‐Peter; Krämer, Bernhard K.; Schmitt, Claus Peter; Yard, Benito A.; Köppel, Hannes

doi:10.1016/j.regpep.2014.09.005

Cited by 35 publications

(39 citation statements)

References 27 publications

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“…We therefore provide a new mechanism by which carnosine improves the metabolic control in diabetes and protect against the development of complications in diabetes. Even though carnosine shown protective effect in several animal models for complications of diabetes (Pfister et al 2011, Riedl et al 2011, Ansurudeen et al 2012, Yapislar & Aydogan 2012, Brown et al 2014, Peters et al 2014, Menini et al 2015 and strongly suggested to be relevant for diabetes complications in humans (Ahluwalia et al 2011, Kurashige et al 2013) the exact mechanism of action is still unraveled. Here we suggest a potential mechanism by showing that carnosine complexly modulates IGFBP1 by different mechanisms, i.e.…”

Section: Discussionmentioning

confidence: 99%

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

Forsberg¹,

Botusan²,

Wang³

et al. 2015

Journal of Endocrinology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Forsberg¹,

Botusan²,

Wang³

et al. 2015

Journal of Endocrinology

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“…Angiotensinconverting enzyme inhibitors (ACE-Is) are known to reduce proteinuria and have been the first-line agents in the management of diabetic nephropathy during the last years. 22 Despite protective treatment with ACE-Is and angiotensin receptor blockers (ARBs), many patients progress to end stage renal disease. 23 To the best of our knowledge, no previous studies examined the role of carnosine in pediatric patients with type 1 diabetes in particular diabetic nephropathy and there is insufficient evidence to recommend its supplementation for those patients.…”

Section: Introductionmentioning

confidence: 99%

The effect of 12 weeks carnosine supplementation on renal functional integrity and oxidative stress in pediatric patients with diabetic nephropathy: a randomized placebo‐controlled trial

et al. 2017

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“…In diabetic mice, carnosine supplementation mitigates DN, reduces renal vasculopathy, normalizes vascular permeability (Peters et al 2012), and improves wound-healing (Ansurudeen et al 2012). In streptozotocin-induced diabetic rats, carnosine treatment prevents apoptosis of glomerular cells, podocyte loss (Peters et al 2014;Riedl et al 2011), and vascular damage (Pfister et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Carnosine metabolism in diabetes is altered by reactive metabolites

et al. 2015

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Carnosinase 1 (CN1) contributes to diabetic nephropathy by cleaving histidine-dipeptides which scavenge reactive oxygen and carbonyl species and increase nitric oxide (NO) production. In diabetic mice renal CN1 activity is increased, the regulatory mechanisms are unknown. We therefore analysed the in vitro and in vivo regulation of CN1 activity using recombinant and human CN1, and the db/db mouse model of diabetes. Glucose, leptin and insulin did not modify recombinant and human CN1 activity in vitro, glucose did not alter renal CN1 activity of WT or db/db mice ex vivo. Reactive metabolite methylglyoxal and Fenton reagent carbonylated recombinant CN1 and doubled CN1 efficiency. NO S-nitrosylated CN1 and decreased CN1 efficiency for carnosine by 70 % (p < 0.01), but not for anserine. Both CN1 cysteine residues were nitrosylated, the cysteine at position 102 but not at position 229 regulated CN1 activities. In db/db mice, renal CN1 mRNA and protein levels were similar as in non-diabetic controls, CN1 efficiency 1.9 and 1.6 fold higher for carnosine and anserine. Renal carbonyl stress was strongly increased and NO production halved, CN1 highly carbonylated and less S-nitrosylated compared to WT mice. GSH and NO2/3 concentrations were reduced and inversely related with carnosine degradation rate (r = -0.82/-0.85). Thus, reactive metabolites of diabetes upregulate CN1 activity by post-translational modifications, and thus decrease the availability of reactive metabolite-scavenging histidine dipeptides in the kidney in a positive feedback loop. Interference with this vicious circle may represent a new therapeutic target for mitigation of DN.

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Carnosine treatment in combination with ACE inhibition in diabetic rats

Cited by 35 publications

References 27 publications

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

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

The effect of 12 weeks carnosine supplementation on renal functional integrity and oxidative stress in pediatric patients with diabetic nephropathy: a randomized placebo‐controlled trial

Carnosine metabolism in diabetes is altered by reactive metabolites

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