Kinetics of Native Insulin in Diabetic, Obese, and Aged Men

Abstract

The kinetics of unlabeled porcine insulin were studied in 69 nondiabetic male subjects aged 18–83 yr with obesity indexes of 0.93–1.51 and in 12 maturity-onset diabetics age 46–78 yr with obesity indexes of 0.95–1.56 by using the euglycemic clamp technique. Analysis of the insulin kinetic data by using a mathematical model permitted the determination, for each individual, of steady state distribution masses and degradation rate constants. The individuals were grouped to allow comparison of the results on the basis of age, obesity index, or diabetes. The responses over a period of 120 mm to an infusion and wash out of insulin show some transient as well as steady state differences with age, obesity, or diabetes. Analysis of these data by use of compartmental models leads to the conclusion that in the steady state the ratio of insulin in extravascular spaces to that in plasma (T/P) is decreased in the moderately obese group (26%) and in the diabetic group (17%) but increased in the older group (13%) when each is compared with the appropriate control. Since extravascular insulin includes both insulin bound to receptors and insulin in the interstitial fluid, the observed changes in the extravascular to plasma mass ratio most likely reflect changes in in vivo binding to receptors, although the magnitude of the change would be modified somewhat by changes in the size of the interstitial spaces relative to plasma. In addition, the rate of entry of new insulin into plasma (BSDR) was increased in the diabetic population (45%; P <0.02) as well as in the moderately obese group (27%) but was decreased somewhat in the older group (11%). The following general conclusions can be drawn from the results: The pattern of parameter changes seen with obesity is similar to that seen with maturity-onset diabetes. The decrease in T/P seen with obesity and with maturity-onset diabetes cannot be accounted for solely by changes in fasting plasma insulin levels in these populations. The pattern of changes seen in the older subjects is opposite that seen in the maturity-onset diabetics, which suggests that diabetes is a perturbation distinct from the normal aging process. Finally, the changes in the metabolism of insulin are not large, making it unlikely that they are the sole cause of the major alterations in glucose tolerance seen with aging, obesity, or diabetes.