Search

This prospective study was undertaken to examine whether glycemic normalization could have beneficial on the course of diabetic vascular complications in 6 insulin-dependent diabetics. A significant amelioration of glycemic regulation was achieved by intensive glycemic control with artificial devices and multiple injections for 3 months, which also resulted in an improvement in conduction velocity, a regression in retinovascular permeability and a decrease in urinary total protein excretion. These results indicate that even after short-term treatment, glycemic near-normalization can have a beneficial effect on the early stage of diabetic vascular complications.

An instrument for the control of blood glucose in a closed-loop fashion has been developed. This artificial beta cell consists of 4 subunits: a Glucose Monitor, a Microcomputer, an Insulin Infusion Pump and a Printer. Its internal control algorithm was derived from the modeled dynamics of glucose-induced insulin secretion, and includes the effects of both the proportional and derivative actions of blood glucose concentration, and is expressed as: IIR = Kp . BG + Kd . deltaBG + Kc, where IIR is insulin infusion rate, BG and deltaBG are blood glucose concentration and rate of change in glycemia, respectively. Kp and Kd are individual coefficients and Kc is a constant of basal insulin secretion. The performance of this system was studied with various kinds of glucose challenges on anaesthetized depancreatized dogs. Its notable characteristics were: 1) the insulin infusion rate was such as to maintain physiological insulin levels, and 2) dextrose or glucagon infusions were not required.

A practical method for continuous blood glucose analysis in vivo is described. Using an interference-free enzyme reagent in a modified Auto-Analyzer whole blood glucose concentration can be monitored continuously and interpreted in terms of the actual plasma glucose concentration. The method uses a novel technique for preheating the sample diluent without introducing additional time delays, consumes whole blood at a rate of 0.05 ml/min, and demonstrates a transport delay of 148 s. Other improvements include an average baseline drift of -0.11 mg/dl/h and a mean change in sensitivity of -0.4% after 8.5 h. In vitro glucose recovery studies comparing whole blood to the corresponding plasma samples show the method is precise (101.3 +/- 0.7%), linearly proportional (slope of 1.007 +/- 0.012) and highly correlated (greater than 0.998) over the range of 0 to 500 mg/dl, with reference to a Beckman glucose analyzer. In vivo applications are presented to show that this method is suitable for us in systems such as the 'artificial endocrine pancreas'.

An artificial endocrine pancreas has been developed by adding a glucose infusion system to the artificial beta cell system. In this computer algorithm, glucose is infused on the basis of proportional and derivative actions to blood glucose concentration with the time delay constant between blood withdrawal and initiation of glucose infusion. When glucose was infused on the basis of proportional action with a 20-minute time delay, the prompt restoration to normoglycemia from the hypoglycemic state with a smaller amount of glucose was shown in depancreatized dogs. These results indicate that the artificial endocrine pancreas thus prepared is not only a useful device to safely control blood glucose, but also is an efficient research tool for the analysis of the blood glucose regulatory mechanism.

A dynamic study of scintigraphy of the pancreas using 75Se-selenomethionine in diabetic patients was performed. Patients were selected who complained of abdominal pain or diarrhea or both and whose pancreatic exocrine functions were thought to be disturbed. Selenium-75-selenomethionine (3 muCi/kg body weight) was injected intravenously and radioactivity (cpm) was recorded by a scinticamera for 10 min successively up to 120 min. After 20-30 min the increase of radioactivity in the selected area of the displayed pancreas usually reached a plateau. Pancreozymin (1 Harper unit/kg) and secretin (1 harper unit/kg) were administered intravenously and decrease of radioactivity in the same area was followed for 60 min to examine pancreatic exocrine function. After 75Se-selenomethionine injection, the angle of the initial increase of radioactivity, the height of the plateau, and the reactive decrease of radioactivity after pancreozymin and secretin were analyzed in each case. Radioactivity recorded on data tape was reproduced for each 10-min period on a cathode-ray tube display. Areas of interest were selected for dynamic analyses. To supplement the diagnosis by visual image of a scintigram of the pancreas, the scintigram was quantified in the present study and the dynamic curves of radioactivity in the selected area of the displayed pancreas were studied for a total of 3 hr. Application of the dynamic study of the pancreas scintigraphy and the additional data analyses seemed useful for the early detection of pancreatic exocrine dysfunction in diabetic patients in whom the ordinary laboratory pancreatic exocrine function tests gave uncertain results.

This paper provides some details of a new insulin delivery system which includes a reservoir, a pump and a power pack. The reservoir holds 50 ml and is coupled to a precision peristaltic pump whose delivery can be set to any one of 128 different mean flow rates from 0 to 80 microliter/min (+/- 1.6% over 10 months) using the flow rate controller included in the battery power pack. The system weighs 525 g consuming 60 mW at the maximum pumping rate, proportionately less at lower rates. Ten pumps have undergone bench tests for 30 days. One has been subjected to an extended life test of 11 months while seven complete systems have been used on dogs to demonstrate their capability for precise longterm intravenous insulin therapy. With this system experimental diabetes has been reversed in 4 dogs for periods now extending beyond 6 months. This device now qualifies for long-term studies on hospitalized patients with diabetes mellitus.

Insulin plays a central role in metabolic control after a mixed meal. In the absence of adequate meal insulin release, abnormal circulating concentrations of most meal-derived metabolic substrates can be expected. To quantify these abnormalities in depth, responses of six pancreatectomized dogs on long-term intravenous insulin replacement were compared to those of five normal control dogs. Blood samples were drawn hourly for 24 h via a chronic indwelling catheter, and all animals ate a single mixed meal. To establish whether there were route-related differences, insulin was delivered into either the portal or the peripheral circulation of the diabetic animals at constant rates. These insulin infusion rates resulted in premeal fasting normoglycemia and in normal levels of insulin, glucagon, lactate, pyruvate, 3-hydroxybutyrate, nonesterified fatty acids, and 9 of 13 amino acids. In the absence of enhanced meal insulin infusion, the subsequent responses of glucose, lactate, pyruvate, alanine, and 10 of 13 other blood amino acids were exaggerated in terms of both amplitude and duration. Only minor or transient differences were attributable to the routes of insulin infusion. Remarkably, in spite of these abnormal postmeal responses, basal insulin alone (with constant circulating levels) succeeded in restoring all metabolite and hormonal levels during the postabsorptive period 16-23 h after the meal. Thus, with intravenous insulin infusions, the requirements for fasting metabolic normalization may be considered independently of those for metabolic control following caloric intake. It remains to be shown how prolonged deprivation of the postprandial insulin supplement results in metabolic decompensation under these conditions.

The metabolic and hormonal consequences of long term intravenous insulin replacement were studied in 11 pancreatectomised dogs. Insulin was delivered into the portal circulation of six animals for 164-224 days and into the peripheral circulation of the remainder for 123-365 days. Infusion rates were initially adjusted to achieve normoglycaemia in the fasting (0.37 +/- 0.01 mU Kg-1 min-1 portal; 0.45 +/- 0.03 mU kg-1 min-1 peripheral) and post-prandial states (2.57 +/- 0.07 mU kg-1 min-1 for 7 1/2 h portal; 3.16 +/- 0.18 mU kg-1 min-1 for 7 h peripheral). Animals were fed their usual mixed diet and blood samples were drawn from indwelling catheters at regular intervals for 24 h. A matched group of six normal dogs was similarly studied. Significantly less insulin was needed for glycaemic normalisation with portal (1.05 +/- 0.03 U kg-1 day-1) compared with peripheral (1.27 +/- 0.08 U kg-1 day-1) infusions, but post-prandial insulin levels were not normalised. Glucagon levels were normal and unaffected by the route of insulin infusion. Lactate and pyruvate responses were exaggerated post-prandially in the diabetic compared with the normal dogs. Fasting non-esterified fatty acid levels were suppressed with peripheral but normal with portal insulin infusion. There were only minor differences in the branched chain, essential and other non-essential amino acids except for alanine which was significantly above normal in the diabetic animals. Fasting levels of insulin, lactate, pyruvate and non-esterified fatty acids were normalised only with portal infusion while glucose, glucagon, 3-hydroxybutyrate and most amino acids were normalised regardless of the route of infusion. We conclude that the metabolic regulation achieved with portal insulin replacement is closer to normal than that achieved with peripheral infusion.

Alloxan diabetic rats with fasting blood glucose levels above 300 mg/100 ml were treated with oral administration of water-in-oil-in-water (W/O/W) insulin emulsions at a dose of 50 U/100 g body weight, three times daily for 10 to 14 days. The course of diabetes was followed by determinations of glucose levels in blood and urine. During treatment with oral W/O/W insulin emulsions, daily excretion of urinary glucose decreased by about 30 to 40% (2 to 3 g/day) in all of the five rats studied, and returned to the pre-treatment levels after the treatment being discontinued. During treatment, a significant reduction in fasting blood glucose levels was observed in 4 out of 5 rats, giving the decrease by 18 to 44%. Quantitative estimates suggested that the effectiveness of 50 U/100 g of oral W/O/W insulin emulsions was comparable to that after intramuscular regular insulin at a dose of 0.5 U/100 g. Although oral W/O/W insulin emulsions are still of low efficiency, these results would indicate that diabetes can be controlled by effective oral insulin preparations.