Insulin concentrations and time-action profiles of three different intermediate-acting insulin preparations in nondiabetic volunteers under glucose-controlled glucose infusion technique.

This study describes the pharmacokinetics of three intermediate-acting insulin preparations, NPH porcine insulin, NPH human insulin (recombinant DNA), and "Depot-A" insulin, a mixture of 20% regular and 80% NPH human insulin from Eli Lilly and Company. Metabolic healthy normal weight volunteers were selected for the study. After overnight fasting, each test person received 0.4 U of each insulin per kg body weight injected subcutaneously in the triceps area of the arm. To prevent severe hypoglycemia, the test persons were connected to a "GCIIS Biostator" with blood glucose clamp at the 60 mg/dl level. Peripheral blood was sampled at regular intervals for glucose, insulin, and C-peptide determination. More elevated insulin levels were measured after application of both NPH human insulin and "Depot-A" insulin than after NPH porcine insulin. A more rapid decrease in the blood glucose concentration was observed after injection of both human insulin preparations than after porcine insulin. The dextrose output of the "GCIIS Biostator" was more pronounced in both human insulins than after the porcine preparation. After the injection of NPH human and NPH porcine insulin, significant differences were calculated between the concentrations of these two insulins in the blood, from the 2nd to the 10th hour (P less than 0.05-P less than 0.005) and between the dextrose output of the "GCIIS Biostator" from the 3rd to the 8.5th hour (P less than 0.05). The fall of the C-peptide concentration to the lower detection limit of the assay reflects suppression of the endogenous B-cell secretion and confirms the measure of peripheral insulin concentrations as a result of the exogenously applied insulin. Although all investigations were performed under identical experimental conditions and equal dosages of each insulin were injected, higher insulin concentrations and a stronger biologic effect, shown by larger amount of dextrose delivered, were observed in both human insulins than in porcine insulin. Why this phenomenon occurs is as yet unclear. The clamp technique used with the "GCIIS Biostator" enables establishment of the biologic profile of any insulin, and thus represents a valuable tool in comparative studies.

Pharmacokinetics of biosynthetic human insulin and characteristics of its effect.

In the last 2 years we have developed a new method for determining insulin biologic activity with the help of the glucose-controlled insulin infusion system (GCIIS). Primarily this closed-loop system infuses insulin. But to prevent hypoglycemia, it can in addition, infuse glucose below a certain blood glucose minimum. This effect is used to reproduce insulin biologic activity. After subcutaneous injection of the insulin to be tested in healthy persons (not in insulin-dependent diabetic subjects), the blood glucose level falls, and this is checked by the counterregulatory glucose delivery from the apparatus. The time and intensity of glucose delivery from the GCIIS reflect the insulin effect, so that each insulin manifests its own particular biologic activity.

[Pharmacokinetics of insulin administered intraperitoneal in a bolus form (author's transl)]. / Verhalten der Insulinkonzentration im peripher-venösen Blut nach intraperitonealer Bolusgabe von Insulin.

Although carbohydrate-intake and subcutaneous insulin injection in the insulin dependent diabetics are brought to match with one another, there is often an incongruity between the momentary insulin need and the actual insulin supply, because insulin is resorbed relatively slow from the subcutaneous injection site. While the plasma insulin concentration in healthy persons after carbohydrate-intake reaches its maximum after ca. 45 min, the maximum insulin concentration after subcutaneous application of regular insulin is observed only after ca. 2 h. For this reason, we studied whether a faster rise in the insulin concentration can be obtained by intraperitoneal bolus application of insulin. 5 metabolic healthy volunteers received 20 UI regular insulin diluted in isotonic saline solution injected intraperitoneal. The insulin concentration in the peripherovenous system was examined. In order to prevent severe hypoglycaemia the test persons were connected to a Biostator (so-called artificial Beta-cell), which delivered glucose automatically when the blood glucose concentration fell below the 60 mg/dl - level, and thus avoided a drastic fall of the blood glucose. A rapid increase in the plasma insulin concentration was observed within a few minutes after the intraperitoneal bolus injection of insulin. After ca. 20 min the maximal insulin concentration was reached. Already after ca. 2 h the plasma insulin levels fell off and approached the initial values. Consequently, the changes of insulin concentration after intraperitoneal bolus application of insulin correspond widely to the insulin curve characteristic of metabolic healthy persons after carbohydrate-intake. Thus, the intraperitoneal bolus injection of insulin presents a mode of application, which must be pursued further in the treatment of insulin dependent diabetics.