PhD Co-tutelle thesis - Dr. Christian Carpéné

PhD co-tutelle thesis obtained on february 15th 2010 at Semmelweis University, Budapest and at Paul Sabatier University, Toulouse.

Prepared by: Zsuzsa Iffiú-Soltész

Department of Pharmacodynamics, Semmelweis University, Budapest
INSERM U858, Paul Sabatier University, Toulouse

Supervisors: Prof. Dr. Éva Szökő and Dr. Christian Carpéné

Summary: Obesity and diabetes are serious problems in the developed countries and considerable efforts are put in the development of drugs improving impaired carbohydrate metabolism. Semicarbazide sensitive amine oxidase (SSAO) may be a possible target. The enzyme catalyzes the oxidation of primary amines. SSAO is highly expressed in adipocytes and in the vasculature. It has been found an independent cardiovascular risk factor in diabetes, although the administration of its exogenous substrates has been shown to reduce hyperglycemia in diabetic animals. The hydrogen peroxide formed during the enzyme reaction has been proved responsible for such effect. However, this ROS may contribute to vascular complications of obesity and diabetes, as well.
Our aim was to explore the implication of SSAO substrates in diabetes and obesity. We investigated the influence of white adipose tissue (WAT) extension (obesity and fasting) on SSAO activity in WAT. We analysed the insulin-like actions of benzylamine (BzA), an exogenous substrate of SSAO, in vitro and in vivo. Furthermore, being aware of the dual action of SSAO in diabetes, we also investigated the effect of long-term BzA treatment on vascular complications. We also tested SSAO substrate candidates in human adipocytes.
SSAO activity was increased in SCWAT of obese mice. BzA injection was effective alone to improve glucose homeostasis in type 1 and type 2 diabetic animals. Chronic BzA injection also improved endothelial function of diabetic rats when vanadate was simultaneously administered. Chronic oral administration of BzA improved glucose homeostasis in three mouse models of insulin-resistance. In such conditions we did not observe any adverse effects of hydrogen peroxide. Moreover, increased aorta nitrite concentration, indicating NO production accompanied the reduction of plasma glucose.
These results obtained in rodent obesity and diabetes models thus confirmed BzA’s beneficial metabolic action and encouraged us to propose SSAO substrates as possible antidiabetic drugs. In keeping with this, we set up a test system on human adipocytes, which showed a better substrate than BzA among the tested compounds.