Pathogenesis and prediction of diabetes mellitus: lessons from integrative physiology.

The molecular revolution in biology is providing an exponentially increasing body of data regarding subcellular events in normal and pathological conditions. The task of integrating even a small part of this deluge of information is a formidable challenge. Many integrative regulatory principles are still unknown. The present article argues that important principles may be discovered by the repetitive experimental testing of simple isomorphic computer or mathematical models of biological regulation. The system regulating the blood glucose is used as an example. Implicit in a minimal model, postulated more than 20 years ago, were specific but untested assumptions. These assumptions, which were tested over the ensuing decades, have enriched our understanding of metabolic regulation and the causes of diabetes. Currently accepted concepts emerging from modeling include: (a) the importance of sluggish insulin transport across the capillary endothelium in stimulation of glucose uptake; (b) the single gateway concept, that insulin transport across endothelium of adipose tissue suppresses free fatty acids, which act in turn to reduce endogenous glucose production by the liver; (c) the importance of the single gateway mechanism in the metabolic syndrome, whereby increased fat in the abdominal compartment relates to insulin resistance and risk for type 2 diabetes; and (d) the hyperbolic relationship between insulin action and insulin secretion, which provides an accurate prediction of diabetes risk. It is hoped that the experience with the metabolic system will provide a metaphor for other regulatory systems less subjected to critical quantitative analysis. Such analysis may well lead to analogous conceptual understanding of other important integrated biological systems, and provide approaches for early intervention in the pathogenic process of other chronic and devastating diseases.