Transhepatic absorption and biliary excretion of insulin.

The application of insulin to the liver in rats is followed by an increase of the insulin concentration in the bile. The pathway of insulin from the liver surface to the bile may include a secretory process by the hepatic cells, or it may bypass the hepatic cells, using direct anatomical pathways from blood and lymph to bile. The concentration of insulin in arterial and venous blood, in lymph, and in bile was measured following application of insulin to the liver surface and following peritoneal or intravenous administration. The results confirm that insulin is absorbed from the surface of the liver, but the glucose modulating effect was less effective than after intravenous administration. The insulin concentration in bile was increased after insulin administration by all routes, with the highest and most prolonged increases found after intraperitoneal administration. The results suggest that following transhepatic and intravenous administration, insulin reaches the bile without passing through the liver cells.

Studies on transhepatic insulin absorption.

The intraperitoneal administration of insulin has been recommended because it was found to effectively control the plasma glucose level. Several authors have suggested that intraperitoneal insulin administration may be more "physiological" and therefore preferable because the insulin is absorbed into the portal venous system without, however, identifying the exact pathways. The possibility that insulin is absorbed through the surface of the liver was investigated in rats. The results show that insulin is absorbed rapidly by this route, but the effect on glucose modulation is similar to that of insulin given by other routes. In contrast, the effect on glucose modulation was delayed following insulin administration into the lower peritoneal cavity with exclusion of the liver.

Computer-assisted insulin dosage adjustment.

We report our first experience with a new microprocessor device for assisting individuals with diabetes in the adjustment of insulin therapy. The computer weighs 200 g and can receive, store, and analyze patient-entered capillary blood glucose (CBG) data on an ongoing basis. Changes in the injected mixtures of short- and intermediate-acting insulins are recommended according to algorithms designed to bring the premeal CBG levels to any desired target value set by the physician. Throughout the present study, the premeal target glucose level was set to 110 mg/dl. Seven (type I) insulin-dependent diabetic individuals ranging in age from 11 to 43 yr were selected to participate in the first use of a BCMC (Better Control Medical Computers, Inc., Toronto, Ontario, Canada) computer on an outpatient basis. All subjects were concerned about diabetes control and were fully informed about as well as thoroughly practiced in the use of manual insulin dosage adjustment schemes, based on approximately equal to 4 times daily CBG estimation, as currently taught in our diabetes clinics. During the last 7 days of the control period of self-adjustment, their mean +/- SEM CBG levels (measured before breakfast, lunch, dinner, and bedtime snack) were, respectively, 178 +/- 20, 187 +/- 35, 208 +/- 22, and 207 +/- 13 mg/dl. Immediately after the control period they were given the device and were instructed in the procedure for entering glycemic data and following manufacturer's recommendations in regard to insulin dosages. This experimental period lasted 8 wk and the outcome was assessed as before. Thus, 8 wk after starting daily use of the instrument, all glycemic values measured as before had fallen significantly (P less than 0.005-0.05) closer to normal: 116 +/- 9, 110 +/- 6, 148 +/- 15, and 135 +/- 9 mg/dl, respectively. Concurrently there was also a significant (P less than 0.01) reduction in the variability of glycemia measured before the main meals.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of platelet adhesion by antiplatelet drugs helps prevent cardiovascular complications of diabetes mellitus.

If it could be shown that: The abnormal platelet function in diabetes contributes to the development of cardiovascular complications of diabetes, the abnormal platelet function is a consequence of the diabetic state, the level of blood sugar control or insulin administration, antiplatelet drugs improve the abnormal platelet function independent of the diabetic state and its treatment, the altered platelet function induced by antiplatelet drugs diminishes the evolution of cardiovascular complications, the addition of antiplatelet drugs to the management of diabetes may be reasonable. Specifically designed animal experiments are necessary to provide the scientific basis for designing appropriate clinical trials.

Insulin, glucagon, and amino acids during glycemic control by the artificial pancreas in diabetic man.

The artificial endocrine pancreas (AEP) can normalize glycemia at rest and with meals. To determine whether insulin, glucagon, and amino acid profiles are also normalized, nine diabetics on subcutaneous insulin (S/C) and AEP control were compared to ten normal controls (NC). Glycemia was monitored continuously over 10 hr during which meals were consumed. Insulin infusion rate, and the levels of immunoreactive insulin (IRI) (in NC), free insulin (in S/C and AEP), C-peptide, glucagon, and amino acids are reported. Glycemia in AEP started at somewhat higher levels than in NC, but with breakfast and thereafter, it was identical. In S/C, hyperglycemia prevailed throughout, with no systematic change in free IRI. In AEP, both basal and peak free insulin levels, measured in four patients, were significantly higher than in NC. C-peptide values were significantly lower in diabetics and did not change with meals. Basal glucagon values were not different in the three groups and changes with meals were of small magnitude. Branched chain amino acids were higher in S/C and did not increase as in NC. In AEP, levels were lower than NC after the first two meals. Similarly, lysine and threonine were lower in AEP than in NC at the same times. Alanine, though similar at the onset, was lower 2 hr postbreakfast and higher 2 hrs postsupper in AEP and S/C compared to NC. These studies demonstrate that glycemic control with AEP is accompanied by hyperinsulinemia, which could account for the amino acid responses and the small alterations in immunoreactive glucagon (IRG) patterns. Further refinement is needed to obtain full normalization of metabolic profiles.

Blood glucose regulation using an open-loop insulin delivery system in pancreatectomized dogs given glucose infusions. I. Portal square waves.

This study characterizes the glycaemic and insulin responses of a group of 5 anaesthetized dogs to a portal glucose infusion of 10 mg/kg/min before and after pancreatectomy. Insulin was administered intraportally to the pancreatectomized dogs according to a simple preprogrammed waveform composed of a constant basal rate of 0.35 +/- 0.02 mU/kg/min which was increased to 2.00 mU/kg/min at the time of the 60 minute glucose challenge. When this square waveform was applied the glycaemic response was similar to that seen in the normal controls in the baseline and challenge periods. Blood glucose concentration differed significantly (p less than 0.05) only from 20 to 100 minutes after the end of the challenge when it was higher by 20 +/- 1 mg/dl. Insulin levels were not significantly different from controls. It may be concluded that normoglycaemia and normoinsulinaemia can be maintained by a simple constant rate of portal insulin delivery while the blood glucose response to a glucose infusion can be ostensibly normalized without hyperinsulinaemia simply by enhancing insulin delivery during the challenge. The feasibility of this approach implies that with further development of the preprogrammed waveforms and with a greater understanding of their characteristics portable insulin delivery systems may be realized which accomodate more physiological challenges. The portal route for insulin delivery may however be necessary if peripheral hyperinsulinism is inappropriate.

An improved technique for the rapid continuous measurement of whole blood glucose, suitable for clinical application in an artificial endocrine pancreas.

An improved bedside technique for the continuous monitoring of glycemia is described. A linear relationship results between whole blood glucose concentration and plasma glucose levels, and allows the calibration of the system in terms of plasma glucose levels. In operation venous blood is withdrawn at a steady rate using a double-lumen catheter and directed to a continuous-flow laboratory analyzer, where glucose analysis is carried out using a modified glucose oxidase-peroxidase methodology. The improvements in this technique include: i) a reduction in the delay of the analyzer to 90 s, making it suitable for application in a system for blood glucose regulation, ii) a minimal blood requirement of 3 ml/h, permitting long-term monitoring, iii) elimination of the need for systemic anticoagulation, iv) an excellent correlation (r = 0.993) between the measured whole blood glucose and the actual plasma glucose concentration, v) an average baseline drift of +0.5 mg%/h, vi) a sensitivity loss of less than 0.1%/h, and vii) a reasonable operating cost. This technique was implemented as part of a clinical apparatus known as an artificial endocrine pancreas which has been reliably applied in clinical and animal studies.

Normalization of glycemia in diabetics during meals with insulin and glucagon delivery by the artificial pancreas.

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.

Studies with an artificial endocrine pancreas.

Short-term studies with an artificial endocrine pancreas have provided insights into the pathophysiology of diabetes and demonstrated the ability of such a system to restore and maintain glucose homeostasis in human subjects given either their usual diet, a 50 gm oral glucose tolerance test, or a moderate level of physical exercise. Animals were used to demonstrate that a peripheral route of insulin delivery by the artificial pancreas is equivalent to the portal route.

The metabolic response to moderate exercise in diabetic man receiving intravenous and subcutaneous insulin.

The responses to moderate exercise of circulating energy fuels and endocrine pancreatic hormones were examined in insulin-dependent diabetics receiving insulin either sc or by continuous iv infusion. Eight subjects received one-third of their usual daily insulin doses sc in the thigh 1 h prior to exercise. Seven subjects exercised during infusion (iv) of insulin at 8-20 mU"min, started 12-14 h earlier. Exercise was on a bicycle ergometer for 45 min at 50% maximum oxygen consumption. The diabetics receiving sc insulin showed a sharp decline in glycemia from elevated resting levels (227 +/- 16 mg/dl), in contrast to the control subjects whose glycemia did not change. The control subjects insulin (IRI) fell, and glucagon (IRG) remained unchanged. In the sc-insulin diabetics, exercise induced a further rise in IRG from elevated levels (296 +/- 76 pg/ml). Resting lactate, pyruvate and alanine were normal and increased as in controls. Though FFA, glycerol and ketone body levels were normal at rest, FFA failed to rise with exercise as in the controls and glycerol and ketone body increments were smaller. RQ increased and remained elevated in contrast to the later fall in controls during exercise. These results are consistent with selective insulin deficiency at rest, and increased insulin effect during exercise. This resulted in greater carbohydrate utilization during exercise, but without the normal shift back toward utilization of fat-derived fuels with continuation of exercise. Diabetics receiving insulin by infusion showed no glycemic change with exercise. Exercise caused greater increases in lactate and pyruvate levels (4-fold), although alanine levels increased only during recovery. The significantly elevated resting FFA levels showed a rise which was sustained at higher than control values during recovery; glycerol and ketone body increments also tended to be greater than in controls. Intravenous insulin sustained euglycemia in exercise, obviating the fall in glycemia with sc insulin. The responses of other metabolite levels were abnormal, and consistent with a subtle degree of underinsulinization.