Shinji Sawano

The pharmacokinetics of insulin after continuous subcutaneous infusion or bolus subcutaneous injection in diabetic patients.

Pharmacokinetic models of insulin were examined in order to describe a plasma concentration-time profile after subcutaneous (s.c.) administration of insulin to the patients with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Diabetic subjects were restricted to those with fasting plasma insulin levels around the lowest limit for insulin assay (5 μU/ml). A one-compartment open model with first-order absorption and elimination was appropriate for estimating the plasma concentration-time profile of insulin injected or infused subcutaneously. In the case of continuous s.c. insulin infusion (CSII) for 1 h at the rate of 3 ml/h (2–3 U/ml), the absorption rate constant (Ka), elimination rate constant (Ke), and distribution volume (Vd) were 0.026 ± 0.001 min−1 (mean ± SEM; absorption half-life: 27 min), 0.013 ± 0.005 min−1 (elimination half-life: 53 min), and 1.99 ± 0.49 L/kg body wt, respectively. These values did not differ significantly from those generated by single bolus s.c. injection of undiluted insulin (40 U/ml). The calculated areas under the plasma insulin concentration-time curves from time zero to infinity ([AUC]∞0) did not differ after each mode of administration, while the [AUC] ∞0 after CSII was about 32% of that following intravenous bolus injection (P < 0.01). The following conclusions can be drawn from these results: (1) the plasma concentration-time profile of insulin after CSII or bolus s.c. injection can be analyzed by pharmacokinetic modeling, (2) the absorption kinetics of insulin did ot differ significantly between two modes of s.c. insulin administration in the patients with IDDM or NIDDM, and (3) the insulin after CSII or single bolus s.c. injection seems to be degraded at the s.c. site to the same extent.

Retrospective analysis of long-term surgical results in acromegaly: preoperative and postoperative factors predicting outcome

OBJECTIVE Sixty‐one of 83 patients with acromegaly treated between 1969 and 1993 were analysed retrospectively to clarify which early postoperative factors were significant predictors of a successful long‐term outcome and which preoperative factors significantly influenced the early postoperative results.

Growth hormone-releasing activity in the hypothalamus and plasma of rats subjected to stress.

Summary Experiments were performed in the rat to determine whether the increased secretion of growth hormone (GH) during stress involves augmentation of synthesis and/or release of hypothalamlc GH-releasing factor (GRF). Two different stimuli were used as stress: injection of formalin, which was previously shown to be ineffective in inducing GH release; and cold exposure, which evoked depletion of pituitary GH. Exposure of rats to cold (4°C) for 1 hr resulted in a significant depletion of pituitary GH, which was accompanied by disappearance of hypothalamic GRF and appearance of GRF activity in plasma. Cold exposure for 5 minutes was ineffective. Injection of 10% formalin did not induce pituitary GH depletion, or affect hypothalamic and plasma GRF activity. These results indicate that some stressful stimuli, such as cold exposure, capable of releasing GH, induce this effect via the hypothalamus; other stresses, like formalin injection, which do not release GH, exert little effect on the GH-release mechanism of the hypothalamus.

A Simple Multichannel Perifusion Apparatus of Rat Adenohypophysis and Growth Hormone and Prolactin Responses to Partially Purified Bovine Hypothalamic Extracts

Summary A simple multichannel peri-fusion apparatus for rat adenohypophysis was developed using 2.5-ml disposable syringes as incubation chambers. After placing one or two pituitaries in each chamber, the pituitaries were perifused at a rate of 50-75 μ1/min with KRBG which was gassed with a 95% O2-5% CO2 mixture. The BHE fractions used were collected following Sephadex G-25 gel filtration of bovine hypothalamic extracts. When the pituitaries were perifused for intervals of 20 or 40 min with the BHE fractions, the peak responses of GH and PRL were always achieved within 20 min after initiation of perifusion. The peak values and the amounts of GH and PRL stimulated by BHE were dose related. Both parameters of GH and PRL decreased with repeated pulses of the same dose of BHE. We are indebted to the NIAMDD Rat Pituitary Hormone Program for supplying rat GH and PRL radioimmunoassay kits. We thank Miss Yoshiko Teraoka for her expert technical assistance.

Plasma Immunoreactive Somatostatin Response to Arginine After Glycemic Control With Continuous Subcutaneous Insulin Infusion in Type I Diabetics

The effects of 3 wk of near normoglycemia by continuous subcutaneous insulin infusion (CSII) on plasma immunoreactive somatostatin (IRS) responses to arginine (0.5 g · kg−1 · 30 min−1) in seven patients with insulin-dependent diabetes mellitus (IDDM) were compared with the same patients in poor glycemic control during conventional insulin therapy (CIT) and with seven normal controls. After 3 wk of CSII treatment, mean daily blood glucose and HhA1 decreased to mean (±SE) values of 129 ± 6 mg/dl and 8.0 ± 0.1%, respectively. Plasma free-insulin levels in IDDM patients 30 min before a meal during CSII were significantly higher than those during CIT or in normal controls. Fasting mean plasma IRS levels of the IDDM patients during CSII (7.3 ±1.4 pg/ml) were not different from those during CIT (8.4 ± 1.3 pg/ml) and in normal controls (5.9 ± 0.8 pg/ml). Arginine elicited a rise in plasma IRS during CIT in all seven IDDM patients during CIT and in the normal controls, with peak values of 18.2 ± 4 . 1 and 12.5 ± 1.8 pg/ml, respectively. However, no significant increase in plasma IRS was observed in all seven IDDM patients during CSII. The integrated values of plasma IRS during the arginine-infusion study of the IDDM patients treated with CIT were significantly higher than those of the normal controls. The increased integrated values of plasma immunoreactive glucagon response to arginine observed during CIT became normalized after CSII. These results suggest that glycemic control with CSII in IDDM patients suppresses the increased plasma IRS response to arginine that occurs during CIT. The persistent hyperinsulinemia may be related to the suppressed plasma IRS response observed in IDDM patients during CSII.

Pituitary and plasma growth hormone-like activity after administration of highly purified pig growth hormone-releasing factor.

Summary The effect of administration of highly purified pig GH-releasing factor (GRF) on the depletion of pituitary growth hormone (GH) content in recipient rats and levels of plasma GH-like activity were investigated using the tibia test method. It was demonstrated that GRF induced a significant increase in plasma GH-like activity which was accompanied by a simultaneous decrease in pituitary GH content. The levels of plasma GH-like activity in recipient rats treated with saline were not detectable (less than 1.25 μg/ml). These results seem to confirm that the “depletion” of pituitary GH content in rats caused by GRF indicates the “release” of GH.

Stimulation of release and synthesis of growth hormone (GH) in tissue cultures of anterior pituitaries in response to GH-releasing hormone (GH-RH).

Summary Addition of small amounts of pure or highly purified porcine GH-RH twice daily to rat anterior pituitary tissue, maintained for 5 days in Trowells T8 medium, significantly increased the amounts of GH in the medium and tissues relative to the controls as measured by bioassay. Apparent incorporation of radioactive amino acids into the GH bands on polyacrylamide gels after electrophoresis of medium and tissue was increased also. These results support other findings from this laboratory on the identity and properties of this neurohormone. We are grateful to Mrs. C. Wooderson, Miss Nancy Moreland, and Miss K. Beightol for technical assistance and to the Endocrinology Study Section of the NIH for gifts of GH standard.

Physiological and Biochemical Studies on Some Highly Purified Hypothalamic Releasing Factors

Since our group has been scheduled to deliver the concluding presentation, we would like to mention topics not discussed by previous speakers. For this reason, our presentation had to be improvised in part during the preceding talks, so that it will be composed of many topics.

Idiopathic giant-cell granuloma of the pituitary with unusual clinical and histological features

A surgically treated idiopathic giant-cell granuloma of the pituitary in a 48-year-old man is described. Relative to previously reported cases, this case was unusual both clinically and histologically. Diabetes insipidus was the initial, and a prominent clinical, manifestation. Histological studies showed caseating granuloma or fibrosis in addition to a typical giant-cell granuloma. This is the first published documentation of the association of caseous necrosis in a patient diagnosed as having idiopathic giant-cell granuloma of the pituitary.Endocr Pathol 4:169–173, 1993.

The Immunoreactive-GIF Concentrations in Various Fetal Tissues Measured by Two Different RIA Systems

Since the discovery of the structures of somatostatin (GIF) in 1973 by Brazeau et al, its measurement by the radioimmunoassay (RIA) methods has been reported by Arimura et al (1975), Yanaihara et al (1978) and Sawano et al (1978). As GIF does not contain tyrosine and histidine, which can be radioiodized, analogues of GIF are being used as tracers in its radioimmunoassay. In this study, two different types of tracers(1251-tyr8-GIF and 125I-tyrosyl-GIF) were used in RIA to measure the immunoreactive GIF of fetal tissues, and their results were compared.