Journal Article

Hypoglycemia and hyperinsulinemia induced by phenolic uremic toxins in CKD and DKD patients

Kawabe, Chiharu, Miyata, Yui, Ho, Hsin-Jung, Suzuki, Takehiro, Itai, Shun, Abe, Takaaki, Matsumoto, Yotaro, Wada, Jun, Suzuki, Kenshin, Kujirai, Ryota, Tomioka, Yoshihisa, Tongu, Yoshiyasu, Nata, Koji, Kanzaki, Makoto, Tanaka, Tetsuhiro, Akiyama, Yasutoshi, Suzuki, Chitose, Kasahara, Tomoko, Toyohara, Takafumi, Kikuchi, Koichi, Watanabe, Shun

2025

Overview

Patients with end-stage renal disease have lower fasting plasma glucose and HbA1c levels, with significantly higher insulin levels. For a long time, it has been believed that this higher insulin level in renal failure is due to decreased insulin clearance caused by reduced renal function. However, here we reported that accumulation of the gut microbiota-derived uremic toxin, phenyl sulfate (PS) in the renal failure, increased insulin secretion from the pancreas by enhanced glucose-stimulated insulin secretion. Other endogenous sulfides compounds which accumulated as in the renal failure also increased glucose-stimulated insulin secretion from β-cell. With RNA-seq analyses and gene knock down, we demonstrated that insulin secretion evoked by PS was mediated by Ddah2. In addition, we also found that PS increased insulin resistance through lncRNA expression and Erk phosphorylation in the adipocytes. To confirm the relationship between PS and glucose metabolism in human, we recruited 2 clinical cohort studies (DKD and CKD) including 462 patients, and found that there was a weak negative correlation between PS and HbA1c. Because these trials did not measure fasting insulin level, we alternatively used the urinary C-peptide/creatinine ratio (UCPCR) as an indicator of insulin resistance. We found that PS may induce insulin resistance in patients with eGFR < 60 mL/min/1.73 m 2 . These data suggest that the accumulation of uremic toxins modulates glucose metabolism and induced insulin resistance in CKD and DKD patients. Considering HbA1c as a reflection of chronic hyperglycemia and UCPCR as a reflection of chronic hyperinsulinemia, our findings indicate that PS is negatively associated with hyperglycemia independent of CKD, and positively associated with hyperinsulinemia in DKD patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154 / 692/308/575 / 692/4022/1585/104 / Adipocytes / Aged / Blood Glucose - metabolism / CKD / Clinical trials / Creatinine / DKD / End-stage renal disease / Fasting / Female / Glucose / Glucose - metabolism / Glycated Hemoglobin - metabolism / Humanities and Social Sciences / Humans / Hyperglycemia / Hyperinsulinemia / Hyperinsulinism - chemically induced / Hyperinsulinism - etiology / Hyperinsulinism - metabolism / Hypoglycemia / Insulin - metabolism / Insulin Resistance / Insulin Secretion / Insulin-Secreting Cells - drug effects / Insulin-Secreting Cells - metabolism / Intestinal microflora / Kidney diseases / Male / Metabolism / Microbiota / Middle Aged / multidisciplinary / Phenolic compounds / Phenyl sulfate / Phosphorylation / Renal failure / Renal function / Renal Insufficiency, Chronic - complications / Renal Insufficiency, Chronic - metabolism / Science / Science (multidisciplinary) / Toxins / Uremic toxin / Uremic Toxins - adverse effects / Uremic Toxins - metabolism / Uremic Toxins - toxicity