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.

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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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.

Twenty diabetics with end-stage renal disease who had never previously received dialysis treatment were treated with continuous ambulatory peritoneal dialysis for periods of two to 36 months (average, 14.5). Intraperitoneal administration of insulin achieved good control of blood sugar. Even though creatinine clearance decreased significantly (P = 0.001), control of blood urea nitrogen and serum creatinine was adequate. Hemoglobin and serum albumin levels increased significantly (P = 0.005 and 0.04, respectively). Similarly, there was a significant increase in serum triglycerides and alkaline phosphatase (P = 0.02 and 0.05). Blood pressure became normal without medications in all but one of the patients. Retinopathy, neuropathy, and osteodystrophy remained unchanged. Peritonitis developed once in every 20.6 patient-months--a rate similar to that observed in nondiabetics. The calculated survival rate was 93 per cent at one year; the calculated rate of continuation on ambulatory peritoneal dialysis was 87 per cent. We conclude that continuous ambulatory dialysis with intraperitoneal administration of insulin is a good alternative treatment for diabetics with end-stage renal disease.

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An extracorporeal "closed-loop" system has been employed to maintain glycemia in the normal range during consumption of meals in nine insulin-treated diabetics. This artificial pancreas system incorporated continuous blood glucose monitoring (0.05 ml. per minute, delay time 90 seconds), a computer programed to respond to glycemia, and a hormone delivery system. Intravenous insulin delivery rates were determined by control parameters responsive to both glucose concentration and its rate of change. Because insulin-dependent diabetics often defend themselves poorly against hypoglycemia (in some cases due to inadequate glucagon responses), the instrument was also programed for exogenous glucagon delivery. A priori selection of ideal parameters for insulin and glucagon delivery for each individual is not yet possible. Consequently, when the parameters were used for the first time on each subject, they were varied over a reasonable range. This approach resulted in a corresponding variety of glycemic responses, the average of which characterized a set of initial parameters that is generally applicable. Appropriate control parameters are presented that successfully prevented hypoglycemia. Glucagon delivery directly related to glycemia appeared sufficient for this purpose, thus obviating the need for dextrose administration. This system provides a technique for complete normalization of blood glucose concentration in the types of diabetics tested, during both fed and interprandial periods. It has yielded insights essential to the development of more sophisticated future devices.