Comparative studies on intermediary metabolism and hormonal counterregulation following human insulin (recombinant DNA) and purified pork insulin in man.

Human insulin (recombinant DNA) and purified pork insulin (PPI) were administered intravenously at a dosage of 0.075 U/kg in eight healthy men. Both insulins exerted the same hypoglycemic effect with the same restoration pattern to normal glucose levels at the end of the test. Differences were found with respect to a stronger antilipolytic and antiketogenic effect of human insulin; also the reactive rise of both compounds at the end of the test is less under human insulin in comparison with PPI. In spite of the same glucose nadir, the pattern of hormonal counterregulation is different under human insulin in comparison with PPI. There was less epinephrine and glucagon and practically no prolactin secretion following human insulin. Growth hormone secretion is augmented under human insulin. The clinical significance of these results under long-term treatment with human insulin has to be assessed.

Treatment with human insulin (recombinant DNA) in diabetic subjects pretreated with pork or beef insulin: first results of a multicenter study.

In two double-blind studies 66 insulin-dependent diabetic subjects pretreated with pork insulin were changed to human insulin (recombinant DNA) or a purified pork insulin preparation (regular and NPH insulin). Sixty-five patients previously pretreated with beef insulin were transferred, in a randomized, double-blind fashion, to human insulin and purified beef insulin of the same preparations (regular and NPH insulin). Patients' metabolic control, as demonstrated by fasting and 1-h postprandial blood glucose, HbA1c, and daily insulin dosage, over 4 mo was unchanged in our four groups compared with the values before changing insulin preparation. No severe hypoglycemic attacks or skin reactions were reported.

Heterotransplantation of human fetal pituitaries in nude mice.

The heterotransplantation of minced human fetal pituitaries into adult thymus-aplastic nude mice is described. Development and growth of such grafts were observed in 16 of 21 recipient mice. Histological examinations of the transplants showed typical adenohypophyseal cells. Neurohypophyseal cells could never be detected. The levels of human growth hormone (hGH) varied between 0.8 and 42.0 ng/ml in the plasma of the hosts (mean value 7.2 ng/ml, by radioimmunoassay).

Analgesic effect of the somatostatin analogue octreotide in two acromegalic patients: a double-blind study with long-term follow-up.

Two acromegalic patients with severe headache were treated with the somatostatin analogue, octreotide (Sandostatin). A double-blind study of octreotide versus placebo in which pain intensity was measured using a visual analogue scale (VAS) was performed initially with these patients. A rapid (within 4-15 min) pain relief occurred lasting 2-8.5 h after injection of 100 micrograms of octreotide, an effect that was not reversed by intravenous (i.v.) naloxone. These 2 acromegalic patients then received treatment for 71 and 82 months, respectively, with doses starting at 500 micrograms/day and 1500 micrograms/day, respectively, without evidence of either tolerance or dependence, although the effect of octreotide on headache appears to be selective. No unwanted sedative effect has been observed. A screening procedure with injection of 50 micrograms of subcutaneous (s.c.) octreotide was performed in 11 other patients with chronic severe pain associated with various conditions. Only 3 patients (2 with diabetic polyneuropathy and 1 with bone pain associated with myelodysplastic syndrome) reported more than 50% pain relief. In the insulin-dependent diabetic patients the double-blind check was not performed due to the risk of octreotide-induced hypoglycemia. In the patient with bone pain the same double-blind check as in the acromegalic patients could not confirm the analgesic effect. It may thus be concluded that octreotide appears to be useful for the treatment of both chronic and acute severe painful conditions in acromegalic patients. However, since its analgesic effect in our patients was confined to headaches only, further controlled studies must be carried out in order to determine appropriate target groups.

A randomized cross-over comparison of two low-dose oral contraceptives upon hormonal and metabolic serum parameters: II. Effects upon thyroid function, gastrin, STH, and glucose tolerance.

The effect of a low-dose triphasic oral contraceptive (OC) containing ethinyl estradiol and levonorgestrel (EE/NG) upon thyroid function and some other biochemical serum parameters was compared to that of a preparation containing EE and desogestrel (EE/DG). Blood samples were taken on Day 6, 11, 21, and 28 of a control cycle and of the third cycle of treatment with either the EE/NG or EE/DG preparation (11 volunteers each). After a washout period of 3 months, the contraceptives were changed in a cross-over fashion. Blood samples were again taken on Day 6, 11, 21, and 28 of the third washout cycle and the third treatment cycle. There was a significant increase (13%) in basal glucose level during treatment with both OC, but no change in glucose tolerance. Both the EE/NG and FE/DG preparation elevated serum T4 (40%), FT4 (15-22%), T3 (17-28%), and TBG (20%) significant, whereby the effect was more pronounced during the second treatment period after washing-out. The effective thyroxine ratio (ETR) was slightly (4%) but significantly increased. Contrary to this, the levels of FT3, reverse T3 (rT3), TSH, and gastrin were not altered. STH showed great individual fluctuations, but was significantly elevated by 50% during treatment with both OC. There was no effect of endogenous estradiol upon thyroid or other parameter, even though it was raised considerably in some women under OC. Although the increase in T4 and T3 is probably due to a rise in estrogen-induced TBG production, the data seem to indicate that there is a slight but effective stimulation of thyroid function during treatment with low-dose OC.

Pituitary adenomas: serum hormone levels and immunohistochemical staining for ACTH, GH and prolactin.

In 37 pituitary adenomas obtained by surgery the immunohistochemical staining for ACTH, GH and prolactin and the tumor size were related to the basal serum hormone levels. 5 adenomas were associated with Cushing syndrome, 9 with acromegaly, 17 with hyperprolactinemia and 6 were preoperatively diagnosed as inactive. A rather close correlation between immunoreactivity of tumor tissue and basal serum hormone levels was found for GH and prolactin whereas these two parameters were not significantly correlated in the corticotrophic adenomas examined. Furthermore there was no obvious correlation between serum hormone levels and tumor size. Several non immunoreactive adenomas showed slight hyperprolactinemia; all of them were macroadenomas with extended sellar lesions. This fact may be explained by disturbances in the hypothalamic-hypophyseal regulation of serum prolactin.

Abnormalities in cholesterol metabolism cause peripheral neuropathy and dementia in AIDS--a hypothesis.

The AIDS dementia complex and peripheral neuropathy in AIDS are considered to be direct or indirect manifestations of HIV infection, yet the pathogenesis in unclear. There are parallels between AIDS and Tangier disease clinically and histopathologically and in lipid metabolism. The neurological disorders in AIDS may be caused by dysfunction of cellular cholesterol transport. Substitution of high density lipoprotein is recommended in the treatment of severe polyneuropathy and dementia in AIDS.

Spontaneous platelet aggregation and coagulation parameters as risk factors for arterial occlusions in diabetics. Results of the PARD-study.

PARD is a prospective study sponsored by the German Research Council with the aim to establish whether spontaneously enhanced platelet aggregation or changes of other hemostatic parameters are risk factors for new vascular occlusions in diabetic patients. 363 diabetic patients (aged 45-65, 232 men, 131 women) were observed for 5 years. Of the 232 men, 53 were on diet, 104 on oral antidiabetic drugs and 75 on insulin. Of 131 women 16 were on diet, 46 on oral antidiabetic drugs and 69 on insulin. At entry clinical examination and laboratory tests were performed, covering the known risk factors for cardiovascular complications. Hemostatic tests and clinical examination were performed at 3 months' intervals. The life status was followed for all patients. Endpoints were carefully defined. Until December 31, 1984, 42 patients died, 23 from cardiovascular disease and 19 from other causes. 13 patients suffered a myocardial infarction, 10 a stroke and 53 peripheral arterial occlusions. The occurrence of new vascular occlusions was significantly higher in those men with enhanced spontaneous platelet aggregation measured by PAT III angle alpha above 40 degrees at entry as compared to those with lower values. This was not the case for women. Other hemostatic parameters, which had also some relation to cardiovascular complications, in men were fibrinogen and F. VIII R:Ag. Established risk factors for which a significant relation to cardiovascular complications was observed in this study, were smoking, duration of diabetes, diastolic blood pressure, cholesterol, triglycerides and also HbA1. The results of the PARD-study have verified the hypothesis that spontaneous aggregation is a major risk factor for future vascular occlusions in diabetic men. They also lead to the hypothesis that high levels of F. VIII R:Ag and fibrinogen are further indicators of progressive vascular disease and may be useful as predictors of new vascular occlusions in combination with such established risk factors as smoking, duration of diabetes, diastolic blood pressure, cholesterol, and triglycerides.

[Long-term treatment of acromegaly with the somatostatin analog octreotide (Sandostatin). On the predictive significance of acute tests]. / Langzeitbehandlung der Akromegalie mit dem Somatostatinanalogon Octreotid (Sandostatin). Zur prädiktiven Bedeutung von Akuttests.

Twelve acromegalic patients were treated (mean +/- SD) 26 +/- 15 months with daily doses of 440 +/- 330 micrograms of the somatostatin analogue octreotide acetate (SMS 201-995, Sandostatin). The levels of somatomedin-C (Sm-C) decreased by 63% from 8.1 +/- 7.7 U/ml to 3.0 +/- 1.3 U/ml. Before starting therapy a long oral glucose tolerance test (oGTT) and a TRH test were performed both without and after s.c. injection of 100 micrograms octreotide. Under long-term treatment with octreotide four of twelve patients reached normal Sm-C-values. The GH levels of all of these patients were continuously suppressed to less than 2 ng/dl in an oGTT after a test dose of 100 micrograms octreotide s.c. till the end of the test (5 1/2 hours after octreotide injection). The other eight patients had a relief of acromegalic symptoms and five had a decrease of their Sm-C-levels, but none of them reached normal Sm-C-values. None of these patients had a continuous suppression of GH after a test dose of octreotide in an oGTT. Hyperprolactinemia (n = 4) was observed only in those patients with an insufficient response to octreotide. The GH-response to TRH showed neither without nor after injection of octreotide a correlation with the results of long-term treatment. Thus it is concluded that GH-suppression in a long oGTT after administration of a test dose of 100 micrograms octreotide acetate s.c. allows to identify those acromegalic patients who will benefit from long-term treatment with the somatostatin analogue octreotide acetate.

[The influence of autonomic diabetic neuropathy and human atrial natriuretic peptide on adrenal gland function in postural changes]. / Einfluss der autonomen diabetischen Neuropathie und des humanen atrialen natriuretischen Peptids auf das Verhalten der Nebennierenfunktion bei Anderung der Körperhaltung.

To investigate the influence of postural changes on plasma renin activity (PRA), plasma levels of human atrial natriuretic peptide (hANP) and on aldosterone in diabetes mellitus and autonomic neuropathy, ten patients with diabetes mellitus and autonomic neuropathy and ten patients with diabetes mellitus but without autonomic neuropathy were studied. Ten healthy subjects served as controls. Patients and controls were in supine position for 60 minutes, then changed posture sequentially to sitting (90 minutes) and to upright position (15 minutes). In controls, PRA was increased upon sitting and in the upright position, while hANP was decreased. Patients with autonomic neuropathy differed from controls in impaired renin stimulation, whereas in patients without autonomic neuropathy PRA responses to postural changes were only slightly decreased. In both groups of patients, the normal hANP responsiveness to postural changes was lacking. There were no differences in aldosterone levels between patients and controls. In patients with high basal hANP levels due to elevated systolic blood pressure renin responses to postural changes were decreased in comparison to those patients with low basal hANP levels. Thus, in patients with diabetes mellitus increased hANP levels which are not decreased in response to upright standing may contribute to the development of hyporeninism and its sequelae.

[Somatomedin C level and stimulation of growth hormone and adrenal cortex function by administration of releasing hormones and physical exertion in patients with obesity]. / Somatomedin-C-Spiegel und Stimulation von Wachstumshormon und Nebennierenrindenfunktion durch Gabe von Releasing-Hormonen und körperliche Belastung bei Patienten mit Adipositas.

In a clinical study on potential determinants underlying the impairment of growth hormone stimulation in obese human subjects, we examined in 20 otherwise healthy adult obese subjects (14 females, six males, age 18 to 40 years, body mass index greater than 29 kg/m2) the responses of growth hormone (hGH), adrenocorticotropic hormone (ACTH) and cortisol to releasing hormone stimulation (growth hormone-releasing hormone and corticotropin-releasing hormone) and the responses of hGH, ACTH, cortisol and free fatty acids (FFA) to physical exercise. Subjects with somatomedin-C levels less than or equal to 0.7 U/ml (group 1) were more obese than subjects with somatomedin-C levels greater than 0.7 U/ml (group 2) (p less than 0.01). In group 1, hGH increased by 4.3 +/- 1.2 ng/ml in response to releasing hormone administration and by 0.9 +/- 0.3 ng/ml in response to physical exercise (normal responses, increase by greater than 7 ng/ml), in group 2, hGH increased by 6.7 +/- 1.4, and 2.4 +/- 0.8 ng/ml, respectively (p less than 0.05 vs. group 1). Moreover, FFA stimulation by physical exercise was blunted in group 1 (p less than 0.05 vs. group 2). In contrast, ACTH stimulation was found increased in group 1 in comparison to group 2, particularly in response to physical exercise (p less than 0.01), and resulted in enhanced cortisol stimulation (p less than 0.05). Thus, impaired hGH stimulation in obese human subjects is not explained by an altered relationship between hGH and somatomedin-C levels.(ABSTRACT TRUNCATED AT 250 WORDS)