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 Endocrine Pancreas

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.

Clinical Control of Diabetes by the Artificial Pancreas

(All are verbatim summaries) Albisser, A. M., Leibel, B. S., Ewart, T. G., Davidovac, Z., Botz, C. K., and Zingg, W. (Dept. of Med. Eng. and Surg. Res., Hosp. for Sick Children, Banting and Best Dept. DIABETES, VOL. 28, NO. 1 81 CLOSED-LOOP AND OPEN-LOOP DEVICES FOR BLOOD GLUCOSE CONTROL of Med. Res., and Inst. of Med. Sci., Univ. of Toronto, and Dept. of Rehab. Med., Wellesley Hosp., Toronto, Canada): An Artificial Endocrine Pancreas. Diabetes23:389,1974. 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. Pfeiffer, E. F., Thum, Ch., and Clemens, A. H. (Dept. of Endocrinol. and Metab., Centr. of Intern. Med. and Pediatr., Univ. of Ulm, Germany, and Life Science Instruments, Miles Lab , Elkhart, Ind.): The Artificial Beta Cell—A Continuous Control of Blood Sugar by External Regulation of Insulin Infusion (Glucose Controlled Insulin Infusion System). Horm. Metab. Res. 6:339,1974.\" Continuous control of blood sugar in diabetics without dietary restriction has been effected by a Glucose Controlled Insulin Infusion System (GCIIS) consisting of an automatic blood glucose determination apparatus, a dedicated microcomputer, allowing the optimal adaptation of the diabetic to the artificial endocrine pancreas, a special insulin pump and an automatic printer. Insulin-dependent juvenile diabetics and diabetic subjects suffering from diabetic coma and ketoacidosis were successfully controlled and corrected for various periods of time, exhibiting completely normal blood glucose values despite unrestricted food intake. Future developments are seen on the one hand in the further improvement of the present apparatus for complete automatic treatment of acute diabetic conditions, e.g. diabetic coma, preand post-operative care of the diabetic subject, including correction of electrolyte and other disturbances. On the other hand, a smaller portable instrument should permit the diabetic subject temporarily after food intake to maintain completely normal blood glucose concentrations, preventing the presently unavoidable excessive blood glucose fluctuations. Kraegen, E. W., Campbell, L. V., Chia, Y. 0., Meier, H., and Lazarus, L. (Garvan Inst. of Med. Res., St. Vincent's Hosp., Sydney, Australia): Control of Blood Glucose in Diabetics Using an Artificial Pancreas. Aust. N. Z. J. Med. 7:280, 1977. Studies have been performed using an on-line computer system programmed for blood glucose control of insulin and dextrose infusion (artificial pancreas). The aim of these studies was to test performance of the artificial pancreas and to suggest directions for future optimisation. Blood glucose stabilisation studies of diabetic volunteers were extended throughout the day and included three main meals and light exercise periods. Monitoring of blood glucose profiles of the same diabetics after depot insulin were performed on a separate occasion for comparison. The presence of insulin antibodies did not impair operation of the artificial pancreas. Most of the insulin infused by the artificial pancreas was to initially correct hyperglycaemia with relatively little required to subsequently maintain euglycaemia. The afternoon intra-meal average infusion rate was 0.9 U/hr. It is suggested that correction of fasting hyperglycaemia and maintenance of euglycaemia in diabetics be treated as separate control problems for the artificial pancreas. The overall ability of the artificial pancreas to control blood glucose to a degree not attainable by conventional insulin therapy is confirmed, in this case under conditions which include patient activity. Slama, G., Hautecouverture, M., Assan, R., and Tchobroutsky, G. (Dept. of Diabetes, Univ. of Paris VI, Hotel-Dieu Hosp., Paris, France): One to Five Days of Continuous Intravenous Insulin Infusion on Seven Diabetic Patients. Diabetes 23:732, 1974.\" Regular insulin was infused from one to five days in seven adult diabetic volunteers previously treated with subcutaneous insulin three times a day. Through a catheter inserted in a peripheral vein, a small pump delivered 66 ± 10 units of insulin per day in a 131.0 ± 4.0 ml. solution at mean rates of 26 ± 4 mU./min. between meals and 373 ± 58 rnU/ min. during meals; 40 per cent of the total daily dose was given during the three meal periods. These rates were precalculated. Patients were ambulatory. Blood glucose was assayed every fifteen minutes for eight hours during the postprandial periods and hourly otherwise. The overall highest mean values were observed ninety minutes after breakfast (138 ± 17 mg./100 ml.) and four hours after dinner (121 ± 18); the lowest were 73 ± 7, 64 ± 7, 72 ± 15 at the end of the three high concentration insulin infusion periods and 56 ± 7 at 6 a.m. During insulin infusions the mean values of blood glucose parameters were as follows: 89 ± 7 mg./100 ml. for the mean blood glucose level; 66 ± 9 for the mean amplitude of glycemic excursion; and 17 ± 5 for the modified Schlichtkrull's M coefficient. Insulin infusions gave significantly lower blood glucose levels during the night and at breakfast than insulin three times a day and higher blood glucose values before lunch. Both technics gave very good control of diabetes. Insulin infusions without blood glucose monitoring are feasible for several days in ambulatory patients. Genuth, S., and Martin, P. (Saltzman Inst. for Clin. Invest, and Div. of Invest. Med., Mount Sinai Hosp. of Cleveland, and Case Western Reserve Univ. Sch. of Med., Cleveland, 82 DIABETES, VOL. 28, NO. 1 JULIO V. SANTIAGO AND ASSOCIATES Ohio): Control of Hyperglycemia in Adult Diabetics by Pulsed Insulin Delivery. Diabetes 26:571, 1977.\" Nine adult diabetic subjects were treated for two weeks by an intravenous insulin-delivery system that provided preprogramed five-hour pulses of insulin with each meal such that a normal diurnal pattern of plasma insulin was attained. Plasma insulin peaked at 800 per cent of basal and at approximately 45 minutes after the onset of each pulse. On day 14, mean plasma glucose (hourly sampling x 22) was 94 mg./100 ml., with a range of 66 to 125 mg./100 ml. Eighty-eight per cent of all values were between 50 and 150 mg./100 ml. The dose of insulin required correlated significantly with the degree of obesity. On the first posttreatment day, hourly plasma glucose remained significantly below pretreatment levels while the endogenous plasma insulin area increased 46 per cent above pretreatment values (p < 0.01). Six of the patients still exhibited slight improvement in glucose tolerance for seven days while on diet but not on insulin treatment. It is concluded that insulin replacement, coordinated with meals in a physiologic manner, can virtually normalize plasma glucose even without feedback control of delivery rates. Definite but transient remission of beta-cell dysfunction may follow. Deckert, T., and Lorup, B. (Steno Mem. Hosp., Gentofte, Denmark): Regulation of Brittle Diabetics By A Preplanned Insulin Infusion Programme. Diabetologia 12: 573, 1976. Eleven brittle diabetics, mean duration 11.5 years, all treated with highly purified porcine NPH insulin twice daily, were placed on highly purified porcine regular insulin 4 times daily for 2 days. Thereafter pre-planned intravenous insulin infusion was started. Insulin in an amount corresponding to the daily insulin requirement was infused by a mobile electric infusion pump at precalculated rates between 30 and 7 ml/hour during 2 days. The patients were ambulatory. Capillary blood glucose was taken every 30 min. after meals and every two hours during the night. After an equilibration period of 7 hours, blood glucose fluctuations were in the physiological range in nearly all patients during the infusion period. [Only 1.3% of the blood samples showed glucose levels lower than 2.5 mmol/l and 2.9% levels exceeding 10.0 mmol/l during the infusion days]. Mean blood glucose (MBG) was 6.0 ± 0.9 mmol/l (mean ± s.d.), the standard deviation of MBG was 1.8 ± 0.5 mmol/l, the mean amplitude of blood glucose excursions (MAGE) 4.7 ± 1.4 mmol/l, and glucosuria 3.1 ± 3.9 g/day. All these data of glucose homeostasis were significantly lower during the infusion days. The incidence of hypoglycaemic attacks was low (0.32/patient/day) and not significantly higher than during NPH treatment. It is concluded that near normal blood glucose fluctuations can be achieved in brittle diabetics by pre-planned insulin infusion without blood glucose monitoring. Marliss, E. B., Murray, F. T., Stokes, E. F., Zinman, B., Nakhooda, A. F., Denoga, A., Leibel, B. S., and Albisser, A. M. (Dept. of Med., Toronto Gen. Hosp., and Res. In

Closed-loop and Open-loop Devices for Blood Glucose Control in Normal and Diabetic Subjects

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.

Comparison of Peripheral and Portal Routes of Insulin Infusion by a Computer-controlled Insulin Infusion System (Artificial Endocrine Pancreas)

By means of a glucose-controlled insulin- and glucose-infusion system (GCIGIS) we examined the effect of somatostatin on insulin and glucose requirements following meals or oral glucose loads in juvenile diabetics. In six of seven patients the insulin requirement with somatostatin was remarkably reduced to between 38 per cent and 79 per cent of that of otherwise identical control experiments. No reduction could be found in the seventh case, fed only 575 kcal. In all cases we observed an increase in dextrose demanded from the GCIGIS ranging between 28 per cent and 192 per cent of the control amounts. In addition, a lowering and smoothing of postprandial blood glucose curves caused by somatostatin application was a general finding. It seems to us most likely that the well-known suppression of the secretion of growth hormone and glucagon, both insulin antagonists, is responsible for the antidiabetic action of somatostatin.

B.S. Leibel

Papers

A Computer Analog of the Endocrine Pancreas