Does Citrulline Sit at the Nexus of Metformin’s Pleotropic Effects on Metabolism and Mediate Its Salutatory Effects in Individuals With Type 2 Diabetes?

We read with interest the recent article by Adam et al. (1) suggesting an action of metformin on citrulline metabolism in patients with type 2 diabetes. This study provides compelling evidence that metformin treatment is associated with a decrease in plasma citrulline in these patients and also in multiple tissues in diabetic mice. The authors speculate that high citrulline may be associated with insulin resistance, and the accompanying commentary (2) questioned whether a metformin-mediated decrease in citrullinemia may be involved in metformin's mechanism of action. We would like to draw attention on some aspects of citrulline's properties.First, in terms of citrulline concentration, the study by Adam et al. (1) raises several questions because the authors did not specify whether the decrease is to a level below normal or just a normalization of citrullinemia. Citrullinemia has been repeatedly shown to be increased and arginine availability to be decreased with insulin resistance, e.g., in experimental models of high-fat feeding (3) as well as in humans (4). Citrullinemia is determined by citrulline's intestinal production from glutamine and arginine and its renal utilization for arginine synthesis (5). The liver does not play any significant role in these interorgan exchanges because liver citrulline is almost exclusively synthesized locally and channeled into the urea cycle. Intestinal citrulline synthesis is preserved in metabolic syndrome (3). Current data thus point to possible modifications in renal citrulline utilization. Indeed, we recently showed in healthy elderly volunteers that citrullinemia was associated positively with waist circumference and negatively with creatinine clearance (6). The modification of kidney citrulline metabolism under metformin treatment thus deserves to be studied.Second, recent works, including ours, demonstrate that citrulline supplementation may be beneficial in situations of insulin resistance. On the one hand, citrulline improves insulin sensitivity at least in part through its effect on the liver and the visceral adipose tissue (7). In our recent studies (reviewed in [7]), we showed that citrulline-induced improvement in insulin sensitivity in nonalcoholic fatty liver disease was associated with 1) decreased hepatic lipid synthesis, 2) decreased visceral fat mass, 3) preserved fat free mass, and 4) decreased inflammatory processes. Among the possible underlying mechanisms, citrulline prevents the alterations in arginine metabolism as shown by normalized plasma arginine-to-(ornithine1citrulline) ratio and arginine-to-lysine ratio, and some of the peripheral effects of citrulline may stem from an improvement in nitric oxide synthesis (7). On the other hand, citrulline improves vascular function also through the arginine/nitric oxide pathway, and citrulline supplementation is associated with a reduction in resting blood pressure (8).Last, metformin and citrulline are both potent antioxidants and their interactions deserve to be studied.The question arises, therefore, whe...

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“…Prasanthi Jegatheesan, 1 Jean-Pascal De Bandt, 2,3 and Luc Cynober 2,3 Diabetes 2017;66:e1-e2 | DOI: 10.2337/db16-1592…”

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Comment on Adam et al. Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues. Diabetes 2016;65:3776–3785

2017

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“…Moreover, most studies have been conducted in animal models, and there are few studies on metabolic effects of citrulline among patient with diabetes; further clinical studies are warranted in this area. In addition, potential interactions between citrulline and other pharmaceutical drugs used for management of insulin resistance, type 2 diabetes, and cardiovascular disorders should be considered in future studies, because there is some evidence indicating that these drugs (eg metformin, insulin) affect citrulline metabolism …”

Section: Discussionmentioning

confidence: 99%

“…In addition, potential interactions between citrulline and other pharmaceutical drugs used for management of insulin resistance, type 2 diabetes, and cardiovascular disorders should be considered in future studies, because there is some evidence indicating that these drugs (eg metformin, insulin) affect citrulline metabolism. [89][90][91] A major mechanism for development of microvascular complications in diabetes is augmented production of advanced glycation end products (AGEs) subsequent to chronic hyperglycaemia. 92,93 Antioxidant compounds have been suggested to be capable of decreasing the production of AGEs.…”

Section: Knowledge Gaps and Future Directionsmentioning

confidence: 99%

Potential roles of Citrulline and watermelon extract on metabolic and inflammatory variables in diabetes mellitus, current evidence and future directions: A systematic review

Azizi

Mahdavi

Vaghef-Mehrabany

et al. 2019

Clin Exp Pharma Physio

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Objective Diabetes mellitus is a prevalent endocrine disorder worldwide. Citrulline is an α‐amino acid, which is abundant in watermelon, and a precursor of arginine and nitric oxide. Decreased bioavailability of nitric oxide is associated with insulin resistance. The present systematic review focused on the existing evidence of citrulline and watermelon extract effects on metabolic and inflammatory parameters in diabetes mellitus. Methods A systematic search of the databases PubMed, Scopus, EMBASE, ProQuest and Google Scholar was conducted for relevant papers published from inception until October 2018. All clinical trials, animal and in vitro studies published in the English language that assessed the role of citrulline and watermelon extract on diabetes mellitus, were eligible. Studies providing inadequate information were excluded. Results Out of 1262 articles we found, only eight articles met the inclusion criteria for analysis. In three studies an increase in the synthesis of nitric oxide was reported with citrulline and watermelon extract supplementation. Four studies showed a significant reduction in blood glucose after supplementation with watermelon extract, and two studies reported a decrease in a number of inflammatory biomarkers following citrulline supplementation. Although citrulline intake caused a significant reduction in HOMA‐IR in one study, inconsistent results were revealed on the effects of citrulline and watermelon extract on insulin levels and lipid profile. Conclusion Citrulline and watermelon extract could improve nitric oxide synthesis, glycaemic status and inflammation in diabetes mellitus. However, further studies are required to shed light on the underlying mechanisms.

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“…After co-treatment with metformin, the alteration of creatinine in both serum and urine might be attributed to renal acidification 13 . Moreover, the reduction of BUN in the Pb + MH group might have been secondary to suppression of urea biosynthesis owing to inhibition of gluconeogenesis by high-dose metformin 35 . These data are consistent with our previous findings that reno-protection of metformin is more predominant in a low dose than a high dose 18 , 19 .…”

Section: Discussionmentioning

confidence: 99%

Metabolic profiling of metformin treatment for low-level Pb-induced nephrotoxicity in rat urine

Huang

Wang

Chen

et al. 2018

Sci Rep

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Chronic kidney disease is a worldwide problem, and Pb contamination is a potential risk factor. Since current biomarkers are not sensitive for the diagnosis of Pb-induced nephrotoxicity, novel biomarkers are needed. Metformin has both hypoglycaemic effects and reno-protection ability. However, its mechanism of action is unknown. We aimed to discover the early biomarkers for the diagnosis of low-level Pb-induced nephrotoxicity and understand the mechanism of reno-protection of metformin. Male Wistar rats were randomly divided into control, Pb, Pb + ML, Pb + MH and MH groups. Pb (250 ppm) was given daily via drinking water. Metformin (50 or 100 mg/kg/d) was orally administered. Urine was analysed by nuclear magnetic resonance (NMR)-based metabolomics coupled with multivariate statistical analysis, and potential biomarkers were subsequently quantified. The results showed that Pb-induced nephrotoxicity was closely correlated with the elevation of 5-aminolevulinic acid, d-lactate and guanidinoacetic acid in urine. After co-treatment with metformin, 5-aminolevulinic acid and d-lactate were decreased. This is the first demonstration that urinary 5-aminolevulinic acid, d-lactate and guanidinoacetic acid could be early biomarkers of low-level Pb-induced nephrotoxicity in rats. The reno-protection of metformin might be attributable to the reduction of d-lactate excretion.

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Does Citrulline Sit at the Nexus of Metformin’s Pleotropic Effects on Metabolism and Mediate Its Salutatory Effects in Individuals With Type 2 Diabetes?

Cited by 11 publications

References 23 publications

Comment on Adam et al. Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues. Diabetes 2016;65:3776–3785

Comment on Adam et al. Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues. Diabetes 2016;65:3776–3785

Potential roles of Citrulline and watermelon extract on metabolic and inflammatory variables in diabetes mellitus, current evidence and future directions: A systematic review

Metabolic profiling of metformin treatment for low-level Pb-induced nephrotoxicity in rat urine

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