Homoarginine supplementation improves blood glucose in diet-induced obese mice
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l-Homoarginine (hArg) is an endogenous amino acid which has emerged as a novel biomarker for stroke and cardiovascular disease. Low circulating hArg levels are associated with increased mortality and vascular events, whereas recent data have revealed positive correlations between circulating hArg and metabolic vascular risk factors like obesity or blood glucose levels. However, it is unclear whether hArg levels are causally linked to metabolic parameters. Therefore, the aim of our study was to investigate whether hArg directly influences body weight, blood glucose, glucose tolerance or insulin sensitivity. Here, we show that hArg supplementation (14 and 28 mg/mL orally per drinking water) ameliorates blood glucose levels in mice on high-fat diet (HFD) by a reduction of 7.3 ± 3.7 or 13.4 ± 3.8 %, respectively. Fasting insulin concentrations were slightly, yet significantly affected (63.8 ± 11.3 or 162.1 ± 39.5 % of control animals, respectively), whereas body weight and glucose tolerance were unaltered. The substantial augmentation of hArg plasma concentrations in supplemented animals (327.5 ± 40.4 or 627.5 ± 60.3 % of control animals, respectively) diminished profoundly after the animals became obese (129.9 ± 16.6 % in control animals after HFD vs. 140.1 ± 8.5 or 206.3 ± 13.6 %, respectively). This hArg-lowering effect may contribute to the discrepancy between the inverse correlation of plasma hArg levels with stroke and cardiovascular outcome, on the one hand, and the direct correlation with cardiovascular risk factors like obesity and blood glucose, on the other hand, that has been observed in human studies. Our results suggest that the glucose-lowering effects of hArg may reflect a compensatory mechanism of blood glucose reduction by hArg upregulation in obese individuals, without directly influencing body weight or glucose tolerance.
KeywordsDiabetes Glucose handling Homoarginine Insulin Obesity
Body mass index
Enzyme-linked immunosorbent assay
High-performance liquid chromatography
Liquid chromatography–tandem mass spectrometry
Nitric oxide synthase
This work was supported by an Else-Kröner Memorial Stipendium from the Else-Kröner Fresenius Stiftung to C.C. and grants from the Deutsche Forschungsgemeinschaft (DFG) (CH872/1-1 to C.C., A.N. and D.I., and IS63/3-1/2 to D.I.). D.A. received funding from the European Union under a Marie Curie Intra-European Fellowship for Career Development. We wish to thank H. Voss and U. Wolters for expert animal care.
Conflict of interest
The authors declare that they have no conflict of interest.
All experimental procedures were in accordance with institutional guidelines and approved by the local animal Ethics Committee.
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