French researchers have found that a protein-bound uremic toxin, p-cresyl sulfate (PCS), contributes to the development of insulin resistance in mice, providing a new potential therapeutic target for treating chronic kidney disease (CKD), they say.
"We demonstrate that PCS administered to mice with normal renal function induces insulin resistance and metabolic disturbances mimicking those reported in CKD," remark Christophe Soulage (INSERM, Lyon) and colleagues.
The PCS toxin circulates in the blood as a conjugate of p-cresol, which is produced in the gut by the putrefactive bacteria of the gut microbiota. Interestingly, the team found that reducing p-cresol production with the use of a prebiotic reduced PCS levels and prevented insulin resistance and dyslipidemia in the model.
"Because insulin resistance is an important cardiovascular risk factor, novel therapeutic approaches like prebiotics which could decrease PCS more substantially than with the currently available strategies must be developed, especially since this toxin is not very efficiently removed by dialysis," says the team.
As reported in the Journal of the American Society of Nephrology, 4-week intraperitoneal administration of twice-daily PCS (10 mg/kg) in mice with normal renal function increased fasting plasma glucose levels by a significant 1.5 times more than administration of saline solution did in control mice.
In addition, there was a more than 50% greater increase in plasma cholesterol levels in the PCS mice than in control mice, at a median of 152 versus 98 mg/dL. Cholesterol in the PCS mice reached a similar level to that observed in a subset of mice with CKD.
As the activation of extracellular signal-regulated kinase (ERK1/2) has previously been described to alter insulin signaling pathways, Soulage and team compared ERK activation in the skeletal muscle of the different groups of mice.
Indeed, the phosphorylation level of ERK1/2 was increased by a significant 2.9-fold more in the PCS mice compared with controls.
Although no significant differences in total weight and lean body mass were observed between the PCS and control mice, a significantly greater reduction in white adipose tissue (WAT) accretion was noted in the PCS and CKD mice.
On the other hand, significantly greater increases were found in the ectopic lipid contents of the muscle and livers of the PCS and CKD mice than in the control mice, suggesting that lipotoxicity is a putative cause for insulin resistance, says the team.
On treating the CKD mice with dietary arabino-xylo-oligosaccharides (AXOS) - a prebiotic that promotes the growth of bifidobacteria instead of fermentative bacteria - the team found a 74% greater loss in serum PCS levels than in mice fed a control diet.
The prebiotic also reduced the loss of fat mass in the CKD mice, increasing total WAT by 33% and preventing the ectopic lipid redistribution and rise in glycemia and cholesterol associated with CKD.
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