There is increasing recognition that sleep-disordered breathing (SDB), which is quite prevalent in obese subjects, can play an independent role in facilitating the development of autonomic and metabolic dysfunction. These abnormalities can lead to the emergence of metabolic syndrome, and subsequently with disease progression, to overt Type 2 diabetes (T2DM). The causal pathways linking SDB to T2DM remain controversial and relatively unexplored. We are developing a large-scale simulation model that would enable competing hypotheses of these causal pathways to be tested at the organ systems level. Our current efforts are based on an integrative model of respiratory, cardiovascular and sleep state control (“PNEUMA�) that was developed by us to characterize the underlying mechanisms that lead to SDB and to determine the effects of SDB on autonomic control of the cardiovascular system and sleep-wake control. We have extended PNEUMA by incorporating a metabolic component, representing the regulation of glucose, insulin, glucagon and free fatty acids using a multi-compartment model. An additional feature is the incorporation of the dynamics of beta-cell regulation. Changes in sympathetic output from the cardiorespiratory portion of PNEUMA, as well as changes in sleep-wake state, lead to changes in epinephrine output and blood flow to the tissues, in turn affecting the metabolism of glucose, insulin and FFA. “Metabolic feedback� takes the form of changes in insulin level, which lead to changes in sympathetic tone through stimulation of the alpha-sympathetic receptors. Consistent with clinical observations, the model predicts that increased severity of sleep apnea, as reflected in an increase in apnea-hypopnea index, leads to higher levels of fasting plasma insulin. Ongoing efforts are aimed at incorporating biological and biochemical processes that occur at the cellular or sub-cellular level, that would enable PNEUMA to simulate disease progression.