The general objectives of the Action were dedicated to the diabetes mellitus of aged people which is a considerable health burden of western societies. No widely established screening method is available to detect the persons who are predisposed in the population and due to the incomplete knowledge on the molecular mechanisms leading to NIDDM there are very few means to influence the onset and development of this diverse disease. Various steps of insulin action were studied starting from the insulin receptor and following insulin action till it reaches the cell nucleus with special emphasis on the investigation of pathological changes of the molecular mechanism of insulin action in insulin resistance, obesity and NIDDM of the aged people. This research activity is thought to lead to the development of new drug-candidates for the curing-easing of the consequences of this diverse disease. The secondary objectives were dedicated to the following steps of insulin action: – Identification of diabetogenes: examination of candidate genes; utilization of various differential screening methods; possible links of diabetes-related genes to insulin signalling; search for diabetes-related obesity genes; age-dependent analysis of critical genes. – Studies on the intracellular mechanism of insulin action in normal and pathological states: mechanism of the interactions between insulin receptor and its substrates, analysis of tissue-specificity of insulin signaling pathways; molecular characterization of glucose transport in normal and insulin-resistant states; molecular analysis of insulin signaling and action during the whole lifespan; interrelationships of insulin resistance and leptin action; development of insulin- and leptin-related signaling molecules as potential drug candidates. The Action made a significant advance in four key areas of the molecular mechanism of diabetes, obesity and aging: 1. Glucose transport mechanism. Key elements of insulin-dependent and -independent glucose transport mechanisms were identified, such as the role of GLUT isoforms, Rabs, SUMO-ylation and kinase cascades. 2. Role of exercise to prevent the metabolic syndrome. Important elements of exercise induced changes of muscle metabolism and signaling have been uncovered, such as the role of kinase cascades, IRS, calcineurin, lipid metabolism, and muscle energetics. 3. Novel understanding of insulin action. Key elements of insulin signaling were discovered, such as the role of SHIP2 in insulin sensitivity, novel insulin receptor substrates, the role of AMP-kinase, and the insulinome in adipocytes. 4. Novel therapeutic approaches. As a scientifically outstanding part of the results detailed in point C, novel insulino-mimetic and insulin analogue have been developed and D36 has been proposed as a diabetic marker.
