TOWARD AN INTEGRATED PHENOTYPE IN PRE-NIDDM

The search for the genetic basis of NIDDM has magnified the need for a n efficient representation of the pre-NIDDM phenotype. The overall goa l is to relate specific mutations on the genome to specific changes in physiologic function which lead to NIDDM. Unfortunately, there is sti ll not a clear understanding of the molecular cause of NIDDM in most i ndividuals. Therefore, one must take an alternative approach: to expre ss in quantitative terms the various tissue processes which determine the ability to regulate the blood glucose in fasting and after carbohy drate administration. A minimal list of such processes includes the pr ovision of glucose by the liver, insulin sensitivity, insulin secretio n, and glucose effectiveness. The latter function is the ability of gl ucose per se to enhance glucose disappearance from blood, independent of a dynamic insulin response. Approaches to measuring the list of fun ctions which determine the glucose tolerance are reviewed: they includ e the minimal model method, which quantitates insulin sensitivity (S-I ) and glucose effectiveness (S-G), and a combined model approach, whic h measures insulin secretion. These methods are being developed for la rge populations. Such a development is important for elucidating the c auses of reduced glucose tolerance in populations, and examining the r elation between such causes and outcomes including diabetes and cardio vascular disease. Of particular importance for diabetes development is the characteristic hyperbolic relationship between insulin secretion and insulin action. This relationship, the 'hyperbolic law of glucose tolerance' indicates that insulin secretion can only be assessed in te rms of the ambient degree of insulin sensitivity. By applying this pri nciple, it is clear that latent pancreatic islet-cell dysfunction has been underestimated, and may be significant even in subjects with impa ired glucose tolerance. Finally, new explorations of insulin control o f liver glucose output indicate that this process may be under the con trol of free fatty acids. The latter realization indicates that the in sulin effect on lipolysis is what is critical for determination of glu cose output in the fasting state, and that insulin resistance at the l evel of the adipocyte may determine the extent of fasting hyperglycaem ia, and may be an important factor in the overall phenotype in prediab etic and NIDDM individuals.