3,4-DGE is Important for Side Effects in Peritoneal Dialysis What About its Role in Diabetes

Alberto      Ortiz; Anders      Wieslander; Torbjorn      Linden; Beatriz      Santamaria; Ana      Sanz; Pilar      Justo; Maria-Dolores      Sanchez-Nino; Alberto      Benito; Per      Kjellstrand

Abstract

Breakdown of glucose under physiological conditions gives rise to glucose degradation products (GDPs). GDPs are also formed during heat sterilization of glucose-containing peritoneal dialysis fluids (PDfluids). In PD-fluids GDPs have been shown in many different in vitro assays to be responsible for adverse effects such as growth inhibition, and impaired leukocyte function and impaired wound healing of peritoneal mesothelial cells. They have been linked to changes in the peritoneal membrane as well as to the decline in residual renal function of PD-patients. In diabetes one of the GDPs, 3-deoxyglucosone (3-DG), has been proposed as responsible for side-effects rather the glucose itself. 3,4-dideoxyglucosone-3-ene (3,4-DGE) was recently identified as the most bio-reactive GDP in PD-fluids. It exists in equilibrium with a pool of precursors, consisting of 3-DG but also of other hitherto unidentified GDPs. In PD-fluids the concentration of GDPs in this pool is 10-20 times as high as that of 3,4-DGE. In vitro 3,4-DGE induces caspase-dependent apoptosis of neutrophils and peripheral blood mononuclear cells. Such induction may explain immunosuppressive properties of 3,4-DGE and contribute to an impaired peritoneal antibacterial defense. 3,4-DGE also induces renal cell apoptosis. This may explain the better preservation of residual renal function in PD patients not exposed to GDPs. The concentration of 3-DG increases with worsening glycemic control and has been implicated in the genesis of diabetic microangiopathy. As 3,4-DGE is much more bio-reactive than 3-DG and as it may be easily recruited from the pool, it seems probable that 3,4-DGE is the molecule involved in the diabetic lesions rather than 3-DG itself. Thus, 3,4-DGE might contribute to diabetic nephropathy and to the impaired antibacterial defenses in diabetics. Unraveling of the pool dynamics of the GDPs and the molecular mechanisms of GDP-mediated cell injury may provide new therapeutic insights in PD and diabetes.

Keywords: Apoptosis, 3,4-DGE, 3-DG, diabetes, diabetic nephropathy, glucose degradation products, and peritoneal dialysis

« Previous Next »