* This work was supported by the Myronis Foundation (Graduate Research Scholarship), the European Social Fund (75%) and National Resources (25%) $ Operational Program Competitiveness $ General Secretariat for Research and Development (Program ENTER 04), a grant from the Empeirikion Foundation of Greece and the NIH Center Grant No P41$EB001978 to the Biomedical Simulations Resource at the University of Southern California.             Mihalis G. Markakis 1 , Georgios D. Mitsis 2 , George P. Papavassilopoulos 3 & Vasilis Z. Marmarelis 4 1 Massachusetts Institute of Technology, Cambridge, MA, USA 2 University of Cyprus, Nicosia, Cyprus 3 National Technical University of Athens, Athens, Greece 4 University of Southern California, Los Angeles, CA, USA   Diabetes represents a major threat to public health with alarmingly rising trends of incidence and severity in recent years, as it appears to correlate closely with emerging patterns of nutrition/diet and behavior/exercise worldwide. The concentration of blood glucose in healthy human subjects is about 90 mg/dl and defines the state of normoglycemia. Significant and prolonged deviations from this level may give rise to numerous pathologies with serious and extensive clinical impact that is increasingly recognized by current medical practice. When blood glucose concentration falls under 60 mg/dl, we have the acute and very dangerous state of hypoglycemia that may lead to brain damage or even death if prolonged. On the other hand, when blood glucose concentration rises above 120 mg/dl for prolonged periods of time, we are faced with the detrimental state of hyperglycemia that may cause a host of long$term health problems (e.g. neuropathies, kidney failure, loss of vision etc.). The severity of the latter clinical effects is increasingly recognized as medical science advances and diabetes is revealed as a major lurking threat to public health with long$term repercussions. Prolonged hyperglycemia is usually caused by defects in insulin production, insulin action (sensitivity) or both (Carson et al., 1983). Although blood glucose concentration depends also on the action of several other hormones (e.g. epinephrine, norepinephrine, glucagon, cortisol), the exact quantitative nature of this dependence remains poorly understood and the effects of insulin are considered the most important. So traditionally, the scientific community has focused on the study of this causal relationship (with infused insulin being the “input” and blood glucose being the “output” of a system representing this functional relationship), using mathematical modeling as the means of quantifying it. Needless to say, the employed mathematical model plays a critical role in