Decreased Cystathionine-γ- lyase ( CSE) Activity in Livers of Type 1 Diabetic Rats and Peripheral Blood Mononuclear Cells ( PBMC) of Type 1 Diabetic Patients

Background: Mechanism of impaired H2S signaling in diabetes is not clear. Results: Livers from type 1 diabetic (T1D) rats and PBMC isolated from T1D patients have lower cystathionine--lyase activity. High glucose and/or high ketone treatment also decreased cystathionine--lyase activity in U937 monocytes and PBMC of healthy subjects. Conclusion: Uncontrolled glycemia and ketosis down-regulate cystathionine--lyase activity in T1D. Significance: Impaired cystathionine--lyase can dysregulate H2S signaling in diabetes. The liver plays a major role in the formation of H2S, a novel signaling molecule. Diabetes is associated with lower blood levels of H2S. This study investigated the activities of cystathionine--lyase (CSE, the enzyme that catalyzes H2S formation) in livers of type 1 diabetic (T1D) animals and in peripheral blood mononuclear cells (PBMC) isolated from T1D patients. T1D is associated with both hyperketonemia (acetoacetate and -hydroxybutyrate) and hyperglycemia. This study also examined the role of hyperglycemia and hyperketonemia per se in decreased CSE activity using U937 monocytes and PBMC isolated from healthy subjects. Livers from streptozotocin-treated T1D rats demonstrated a significantly higher reactive oxygen species production, lower CSE protein expression and activity, and lower H2S formation compared with those of controls. Studies with T1D patients showed a decrease in CSE protein expression and activity in PBMC compared with those of age-matched normal subjects. Cell culture studies demonstrated that high glucose (25 mm) and/or acetoacetate (4 mm) increased reactive oxygen species, decreased CSE mRNA expression, protein expression, and enzymatic activity, and reduced H2S levels; however, -hydroxybutyrate treatment had no effect. A similar effect, which was also observed in PBMC treated with high glucose alone or along with acetoacetate, was prevented by vitamin D supplementation. Studies with CSE siRNA provide evidence for a relationship between impaired CSE expression and reduced H2S levels. This study demonstrates for the first time that both hyperglycemia and hyperketonemia mediate a reduction in CSE expression and activity, which can contribute to the impaired H2S signaling associated with diabetes.