Decreased cystathionine-{gamma}-lyase (CSE) activity in livers of type 1 diabetic rats and peripheral blood mononuclear cells (PBMC) of type 1 diabetic patients [Molecular Bases of Disease]
March 7th, 2014 by Manna, P., Gungor, N., McVie, R., Jain, S. K.
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-γ-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 β-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 ROS production, lower CSE protein expression and activity, and lower H2S formation compared to those of controls. Studies with T1D patients showed a decrease in CSE protein expression and activity in PBMC compared to those of age-matched normal subjects. Cell culture studies demonstrated that high-glucose (HG, 25 mM) and/or acetoacetate (AA, 4 mM) increased ROS, decreased CSE mRNA expression, protein expression, and enzymatic activity, and reduced H2S levels; however, β-hydroxybutyrate treatment had no effect. A similar effect, which was also observed in PBMC treated with HG alone or along with AA, 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.