One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.

An adaptation of the double antibody radioimmunoassay for insulin originally presented by Morgan and Lazarow is described. These studies have confirmed the presence of an inhibitor in serum and plasma (heparin) which delays the rate at which the insulin-insulin antibody complex is rendered insoluble by rabbit serum containing antibodies to guinea pig globulin. Serum dilution reduces the effect of the inhibitor but increases dilutional error. Heparin similarly reduces the effect of the inhibitor, but excess heparin produces falsely low values for immunoreactive insulin (IRI). Data are presented for serum which show that if sufficient time (72 hrs.) is allowed to elapse after the addition of the precipitating antibody (rabbit, anti-guinea pig globulin, serum), the precipitating system reaches equilibrium. Employing this modification, additional data are presented, showing excellent recovery of human insulin added to serum, good duplication of respective serum IRI values in repeat assays, and constancy of fasting serum IRI in any one individual on repeated sampling. Normal adults exhibit fasting values of serum IRI from 1 to 20 μU./ml. with a mean of 8.4 μU./ml., and after rapid intravenous glucose, serum IRI usually reaches maximum levels in one to two minutes.

Methods are presented for assessing insulin therapies using a physiologic pharmacokinetic model of glucose homeostasis in man. The model is composed of simultaneous differential equations that represent physiologic compartments and spaces in which glucose and insulin are distributed and undergo metabolic reactions. The model is used to simulate clinical experiments in which blood glucose concentration is controlled by artificial device therapies. Predictions of the theoretical model for responses of normal and diabetic individuals to standard intravenous and oral glucose tolerance tests are compared to clinical data. Reasonable agreement is obtained between predictions of the computer simulations and clinical data for normal individuals. The responses of a diabetic person to oral glucose tolerance tests are simulated by removal of the pancreas from the glucose homeostasis model and introduction of insulin into the model by a prescribed therapy. Model simulations reaffirm expectations concerning the poor blood glucose control attainable by intramuscular insulin injection. Simulations of blood glucose regulation by an artificial pancreas using closed-loop feedback control for controlling insulin delivery rate reveal hyperinsulinemia that results in a net shift in the deposition of a glucose load from liver to peripheral tissues. Simulations of this system in which the time delay for glucose measurement is varied from 1.5 to 30 min show that increases in sensor delay result in progressive loss in glucose regulation, exacerbation of hyperinsulinemia, and increased insulin requirements.

The prevalence of hypertension in various age groups of diabetics and its role as a risk factor in juvenileonset insulin-dependent diabetics followed for 40 yr after diagnosis was evaJuated. The results show clearly that hypertension is more prevalent in diabetics of any age after age 24 yr than in the general population.In this type of diabetes, although death due to renal disease occurs earlier than that due to coronary heart disease, both causes of death are significantly related to hypertension. Those patients with an onset of diabetes 13 yr of age or younger can expect to live longer following the diagnosis of diabetes mellitus than those with an onset after 13 yr of age, perhaps because hypertension appears at about the same age in both groups. Case/control analysis of the data shows that survivors have significantly less hypertension than those dying of renal or cardiac disease. Furthermore, the close temporal relationship between the onset of hypertension and the onset of proteinuria in patients with either renal or coronary deaths suggests that the hypertension in these patients is renal in origin.Two other risk factors, smoking and serum lipids, were evaluated in this population. From the data thus far accumulated, neither smoking nor lipids appear to influence mortality significantly. We conclude that hypertension is the major additive risk factor for mortality in juvenile-onset insulin-dependent diabetics. DIA-BETES 30 (Suppl. 2):90-96, 1981.