Carnosine Attenuates the Development of both Type 2 Diabetes and Diabetic Nephropathy in BTBR ob/ob Mice

Abstract

We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman’s capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.

Effect of Oral Carnosine Supplementation on Urinary TGF-β in Diabetic Nephropathy: a Randomized Controlled Trial

“…Reduced urinary TGF-β is a biomarker for CKD progression. [7] It has been shown that carnosine may have a reno-protective effect on ischemia/reperfusion-induced acute kidney injury in animal models [15] and attenuates the development of patients with T2DM and nephropathy [16]. Whereas, we found that oral carnosine supplementation did not reduce urine albumin, which differed from one related study [12].…”

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

“…brain (micromolar to millimolar range) [26,27], but it reaches its maximal concentrations in cardiac and skeletal muscles (up to 20 mM) [28]. Furthermore, strong evidence that carnosine protects against pathologies characterized by oxidative stress and/or inflammation such as diabetes [29], depression [30], cerebral ischemia [31] and Alzheimer's disease (AD) [32] has been proved. In previous studies, we showed that 20 mM carnosine is highly effective to positively regulating macrophage and microglial functions [23,33].…”

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

“…Of note, in a carnosine or beta-alanine supplementation study in rats with diet-induced obesity, it was recently demonstrated that plasma rather than muscle carnosine is involved in ameliorating high-fat diet-induced lipoxidative and inflammatory stress (Stegen et al 2015). Carnosine supplementation studies in murine models demonstrated therapeutic efficacy of carnosine to ameliorate diabetes and DN, as albuminuria and histological lesions were reduced after supplementation (Lee et al 2005;Alhamdani et al 2007;Sauerhöfer et al 2007;Riedl et al 2011;Aldini et al 2011;Nagai et al 2012;Peters et al 2012;Albrecht et al 2017).…”

“…This results in increased carnosine levels after oral carnosine supplementation (Albrecht et al 2017). In contrast, carnosine supplementation in humans leads only to a small increase in circulating carnosine because of its fast degradation by serum CN1 (Everaert et al 2011).…”