The majority of creatine needed to support short-term energy demands, brain function, and neurological development, especially in neonates, is derived from endogenous synthesis in the kidneys and liver.  Creatine is synthesized from arginine conversion to guanidinoacetic acid (GAA), which is dependent on S-adenosylmethionine and the enzyme guanidinoacetate N-methyltransferase.  Because arginine is derived from citrulline in the kidney, GAA synthesis may be impacted by citrulline levels in the kidney.  Dinesh and colleagues conducted a study to determine the contribution of the kidney, pancreas and gut as sources of GAA to support creatine synthesis.  The results of their study are reported in the March 2020 issue of The Journal of Nutrition.

The experiment was conducted with Yucatan miniature piglets (sow reared, 17-21 days old) that were feed deprived, and randomly assigned to receive intravenous treatments of: 1) arginine and methionine; 2) creatine with arginine and methionine; 3) citrulline and methionine; or 4) alanine.  Suckling piglets served as controls for comparison.

Release of GAA from the kidney was greatest when the piglets received the citrulline and methionine treatment.  When the piglets received either the citrulline and methionine or the arginine and methionine treatments, more GAA was released from the kidneys than from the pancreas or gut.  Treatment with arginine and methionine, or creatine with arginine and methionine led to a net release of creatine from the gut, whereas the citrulline and methionine treatment did not.  Both the gut and pancreas had the highest net release of GAA in response to the creatine with arginine and methionine treatment.  The authors concluded from these observations that citrulline is the better precursor for GAA synthesis in the kidney of neonatal piglets.  They also note the importance of the gut for GAA and creatine when both arginine and methionine are readily available.

In a commentary on this article, Marini notes the importance of the intestinal renal axis in arginine synthesis from gut-derived citrulline.  There have been questions concerning the capacity of this system to produce arginine in the neonate because of low levels of the enzymes at that time of development.  Marini suggests the data obtained by Dinesh and colleagues not only support the capacity to develop arginine from citrulline in neonates, but also document the capacity of the neonatal kidney to use excess citrulline in the production of GAA. 

References Dinesh OC, Brunton JA, Bertolo RF. The kidneys are quantitatively more important than pancreas and gut as a source of guanidinoacetic acid for hepatic creatine synthesis in sow-reared Yucatan miniature piglets.  The Journal of Nutrition, DOI:

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