In order to regulate the blood sugar in the intact depancreatized dog as precisely as that accomplished by its normal pancreas, specific equipment has been devised to deliver insulin or glucose continuously and establish normoglycemia both in the fasting and glucose-loaded states. A minicomputer was programmed to respond to the constantly monitored whole blood glucose by injecting appropriate insulin or glucose intravenously to maintain or restore the normal blood sugar. Standardized glucose challenges consisting of uniform infusions of 10 mg. glucose per kg. min. for sixty minutes were applied to assess the performance of the artificial pancreas. Direct control which relates insulin dosage to the level of the circulating blood sugar results in a response to the challenge resembling mild maturity-onset diabetes both in the abnormally high blood sugar response to glucose loading and in the large amount of insulin required to effect a return to normoglycemia. In contrast, control based on projected (predicted) values of blood sugar not only prevents the abnormal rise but consumes in some cases only 10 per cent of the insulin used for the same glucose load. The performance of the system parallels that of the normal pancreas and lends support to the hypothesis that biphasic insulin responses to glucose challenges are essential for the economy of insulin and the precision of regulation seen in healthy subjects.

The metabolic response to exercise in obese postabsorptive noninsulin-dependent diabetics was compared to that of obese nondiabetics. Exercise consisted of 45 min on a cycle ergometer at 60% maximum oxygen consumption. Six diabetic subjects were studied during oral hypoglycemic therapy and four on diet alone. The sulfonylurea therapy had no effect on the response. Glycemia was elevated at rest in both diabetic subgroups (192 +/- 24 mg/dl for diet alone, 226 +/- 36 mg/dl for sulfonylurea treatment) and a similar fall (35 and 37 mg/dl, respectively) occurred with exercise. In control subjects, glycemia was 86 +/- 4 mg/dl and did not change with exercise. In the diabetics at rest, glucose production was elevated (220 +/- 25 mg/min), whereas the metabolic clearance of glucose was suppressed. During exercise the increase in glucose utilization was similar to that in controls, but glucose production failed to increase significantly, thus accounting for the decline in plasma glucose. At rest, plasma immunoreactive insulin (IRI) was elevated to 0.90 ng/ml in the controls and decreased to 0.65 ng/ml with exercise. In the diabetics IRI was similarly elevated (0.89 ng/ml) but failed to decrease normally with exercise. Lactate, pyruvate, alanine, and free fatty acids increased similarly in diabetics and controls, whereas the increase in 3-hydroxybutyrate during recovery was less in diabetics. The sustained insulinemia, the basal overproduction of glucose, and hyperglycemia itself may all contribute to the observed differences in glucose flux during exercise in noninsulin-dependent diabetics.

An artificial pancreas capable of maintaining blood sugar homeostasis within the physiological range is described in this paper. The blood sugar is continuously monitored and then interpreted by a minicomputer which in turn controls and implements the delivery of insulin (or glucose). The entire system is automatic and by giving insulin according to a projected blood sugar level the pattern of insulin administration is similar to the biphasic response of the normal pancreas. Five parameters for control can be selected and altered at will so that any level of normoglycemia can be maintained. Hypoglycemia is not encountered, and none of the patients experienced any side effects during or after the trials. The clinical trials involved a two-day study. On the first day the blood sugar profiles were monitored throughout the day. The patients were given their usual doses of subcutaneous insulin and ate measured meals and snacks. On the second day, they received no subcutaneous insulin; insulin was administered intravenously in accordance with the moment-to-moment requirements of the patients who were given meals the same as those of the previous day. Graphs plotted on a common time scale compare the blood sugar patterns on the two successive days and show the significant improvement in blood sugar homeostasis achieved by this artificial pancreas.

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Patients with diabetes who accessed the ECM system received timely, cost-effective, and reliable medical intervention. This reduced the incidence of diabetic crises and the need for frequent clinic visits. The ECM empowers case managers to provide safer and superior diabetes care.

Physical exercise is often performed during absorption of meals. We have characterized the metabolic response to 45 min of moderate exercise (approximately 55% of estimated maximal oxygen uptake) beginning 30 min after breakfast in seven healthy controls. Nine insulin-dependent diabetes were studied in an identical manner, with glycemia controlled by a closed-loop "artificial endocrine pancreas" controlled by a closed-loop "artificial endocrine pancreas" (AEP). Responses were compared to those during breakfast without exercise. In the controls, onset of exercise rapidly reversed the rise in both glycemia and insulin (IRI) that occurred with breakfast alone, both returning to fasting levels (glycemia, 80 +/- 3 mg/dl; IRI, 0.38 +/- 0.10 ng/ml). After exercise, small and transient increments occurred (glycemia, 33 +/- 6 mg/dl; IRI, 0.81 +/- 0.15 ng/ml). In the diabetics, prior overnight intravenous insulin normalized fasting glycemia (98 +/- 4 mg/dl), and its postbreakfast excursion was identical to that of controls, as were those of most measured substrates. Similarly, with exercise, glycemia returned rapidly to fasting levels, accompanied by an appropriate decrease in insulin infusion rates. "Free" IRI levels mirrored changes in infusion rates by the AEP, with a decrease in insulin requirement of 30% during exercise as compared to breakfast alone (P less than 0.05). Thus, in both diabetics treated with the AEP and in normals, the responses to postprandial exercise required rapid modulation of insulin delivery. To demonstrate the effect of postprandial exercise on preprogrammed open-loop insulin replacement, four diabetic subjects were studied during breakfast with and without exercise while receiving a fixed open-loop insulin infusion pattern (6.1 +/- 0.7 U over 140 +/- 8 min). The glycemic response to breakfast alone was entirely normalized. However, symptomatic hypoglycemia occurred in all subjects when exercise was initiated 30 min after breakfast. The diabetic responses to closed-loop insulin infusion provide important data in defining the appropriate preprogrammed open-loop insulin infusion pattern for postprandial exercise.

This study was undertaken to determine the different consequences of portal and peripheral routes of insulin administration by the artificial endocrine pancreas. Intraportal glucose was infused (10 mg./min./kg. for 60 minutes) in anesthetized normal and pancreatectomized dogs while blood glucose concentrations were monitored continuously. During computer-controlled insulin administration normal glucose tolerance was restored by both portal and peripheral routes of insulin delivery. There were also no significant differences in (1) glycemic patterns, (2) insulin infusion patterns, (3) peripheral IRI levels, and (4) total insulin requirements between the two routes. It is apparent that the peripheral route, which is more readily accessible than the portal route, may be an appropriate infusion site for an implantable or portable prosthesis for controlling blood glucose concentration.