The Association Between Hyperketonemia and Reduced Circulating Hydrogen Sulfide in Children with Type 1 Diabetes, and Ketone Inhibition of Cystathionine-γ-Lyase mRNA Expression in Cultured Hepatocytes

Background: Hydrogen sulfide (H2S) is known for its significant anti-inflammatory, antioxidant, and vasculoprotective properties. In diabetic patients, blood levels of H2S are observed to be lower. Type 1 diabetic patients (T1D) often experience both hyperketonemia and hyperglycemia. Cystathionine-γ-lyase (CSE), an enzyme encoded by the CTH gene, is responsible for the biosynthesis of H2S. However, it remains uncertain whether the downregulation of CTH genes by ketones is linked to reduced levels of H2S. Objective: This study aims to test the hypothesis that ketones decrease CTH gene expression in cultured hepatocytes and that hyperketonemia negatively correlates with H2S levels in T1D. Methods: Fasting blood samples were collected from children with T1D (n = 36) and age-matched healthy controls (n = 35), following written informed consent. Plasma levels of H2S, 25(OH)VD, ketones, and inflammatory biomarkers were analyzed. To assess the effects of hyperglycemia and hyperketonemia on CTH gene expression, cultured hepatocytes were exposed to high glucose, acetoacetate, or β-hydroxybutyrate. Results: Blood levels of H2S and 25(OH)VD were significantly lower in T1D patients compared to healthy controls. Plasma H2S concentrations showed an inverse association with total ketones, BHB, acetoacetate, and MMP-9, while they were positively associated with HDL-cholesterol and 25(OH)VD. In cultured hepatocytes, exposure to acetoacetate and high glucose was linked to reduced CTH mRNA expression. Conclusions: Lower circulating H2S concentrations are associated with hyperketonemia and inflammatory/metabolic abnormalities in children and adolescents with T1D. The in vitro findings suggest that high glucose and acetoacetate may affect CTH transcription; however, further studies measuring CSE protein, enzymatic activity, and H2S production are necessary to clarify the underlying mechanism and establish causality.