[Immunology of type-1 diabetes. The initial stages in a causal therapy].
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Biomedical subjects
Publications and source records attributed to E F Pfeiffer.
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The clinical and laboratory findings are described in three patients who ingested large amounts of L-thyroxine (two cases) and L-thyroxine together with L-triiodothyronine and who were treated with propranolol. Serum concentrations of thyroxine (maximum values 75 micrograms/dl, 64 micrograms/dl, and 20 micrograms/dl, respectively; normal range 4-12 micrograms/dl), triiodothyronine (maximum values 837 ng/dl, 453 ng/dl, and 566 ng/dl, resp.; normal range 80-180 ng/dl), reverse triiodothyronine (maximum values 235 ng/dl, 190 ng/dl, and 65 ng/dl, resp.; normal range 10-40 ng/dl) as well as free thyroxine equivalent and free triiodothyronine equivalent were monitored daily until they reached the normal range. Statistical analysis of the kinetics of these parameters indicated that the extreme thyroxine conversion was directed toward reverse triiodothyronine, partly due to the treatment with the beta-adrenergic blocker propranolol. The striking discrepancy between the high concentrations of the active hormones and the moderate clinical symptoms was most likely caused by peripheral effects of propranolol.
Biologically active insulin gold complex was used as an ultrastructural marker to study insulin binding sites, uptake, and internalization in isolated rat adipocytes. The preparation conditions for monodispersed particles, ca. 16 nm in diameter and loaded with approximately 100 insulin molecules, are reported. The complex is stable for at least six weeks. Single particles or small clusters were scattered across the cell membrane. The distribution of unbound receptors seemed to be independent of the extensive system of pre-existing surface connected vesicles in adipocytes. The uptake of particles took place predominantly via non-coated pinocytotic invaginations; clathrin-coated pits did not seem to be important for this process. Lysosome-like structures contained aggregates of 10-15 particles. These data suggest that insulin gold complex is a useful marker for the specific labeling of insulin binding sites.
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Insulin sensitivity was assessed using the euglycaemic clamp technique in eight type I diabetic patients (after overnight blood glucose normalization with an artificial pancreas) and in six healthy subjects. Basal insulin concentrations were higher in diabetic patients (25 +/- 4 microU/ml) than in control subjects (17 +/- 1 microU/ml; P less than 0.05). Insulin infusion of 0.5, 1.0, 2.0 and 5.0 mU/kg per min during subsequent 2-h periods resulted in similar mean steady-state insulin concentrations in both groups. The mean dextrose requirements during the last 40 min of each period were nevertheless decreased in diabetic patients (1.6 +/- 0.5, 3.5 +/- 0.8, 6.5 +/- 0.7, 10.2 +/- 0.7 mg/kg per min) as compared with control subjects (4.7 +/- 0.3, 8.2 +/- 0.9, 10.2 +/- 0.9, 12.4 +/- 0.9 mg/kg per min). At low insulin concentrations dextrose requirements were diminished in all diabetic subjects. At the highest insulin levels, individual dose-response curves from only four patients were within the normal range. Under basal conditions, the monocyte receptor number was significantly reduced in diabetic patients (17,500 +/- 2,800 sites/cell) as compared with control subjects (26,700 +/- 2,500 sites/cell; P less than 0.05), whereas there were no differences regarding empty site affinities. Receptor data did not differ in patients with normal and decreased maximal dextrose requirements. Insulin resistance is apparently a common feature of type I diabetes at serum insulin concentrations of approximately 100 microU/ml. Normalization of the insulin effect by higher insulin concentrations is not possible in all patients. Insulin antibodies at concentrations observed in this study (less than 0.16 mU/ml) do not contribute significantly to insulin resistance; receptor and postreceptor defects are possibly more important.
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The development of the artificial pancreas (AP) was an important contribution to modern diabetology. The practical and theoretical findings obtained by its application in type I diabetic patients gave rise to new forms of treatment, i.e., portable insulin pumps and intensified conventional insulin therapy. Although these therapies lead to better results than conventional insulin administration, there is no doubt that the problems of diabetes therapy can be solved only by an implantable AP or pancreas transplantation.
The present study was designed to compare, in lean and obese nondiabetic subjects, basal and postprandial levels of peripheral venous plasma insulin, glucagon, gastrin, pancreatic polypeptide (PP), glucose, triglycerides, and somatostatin-like immunoreactivity (SLI) during the infusion of synthetic somatostatin-14 or saline. Thirty-five minutes before the ingestion of the test meal, an infusion of synthetic somatostatin-14 was started at a rate of 0.5 ng/kg X min and was increased to 1.0 ng/kg X min 30 min after consumption of the meal and lasted for another 90 min. During the infusion of saline, basal peripheral vein levels of insulin, gastrin, and triglycerides were elevated in obese subjects, whereas basal plasma SLI levels were significantly lower compared with the lean controls. Basal glucagon and PP levels were similar in both groups. After the ingestion of the meal, augmented concentrations of insulin and gastrin were observed in the obese subjects, whereas postprandial SLI and PP levels were reduced. Chromatography of fasting plasma revealed all measurable SLI to be confined to the void volume fractions of a Bio-Gel P-10 column. The rise in SLI after the meal was due to an increase of SLI co-eluting with somatostatin-28 and somatostatin-14. During the infusion of somatostatin, only basal insulin levels were significantly lower in the obese subjects, whereas no change of any basal hormone level was observed in the lean group. During the infusion of somatostatin, SLI levels were elevated by 20-30 pg/ml in both groups compared with the saline controls. During the infusion rate of 0.5 ng/kg X min, only postprandial PP levels were reduced significantly in the obese group, while all the other parameters were unaffected in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
The release of somatostatin from the pancreas and stomach following the ingestion of a meal and its increase in the peripheral circulation elicits an attenuation of postprandial hormone secretion such as insulin, pancreatic polypeptide and gastrin and retards the rate at which nutrients enter the circulation. Reduced tissue somatostatin content and/or an attenuated somatostatin release is associated with hyperinsulinism and obesity in certain animal models. In the obese Zucker rat, however, tissue somatostatin levels are increased and therefore the present study was designed to determine the effect of synthetic somatostatin on basal and postprandial arterial insulin levels in obese and lean Zucker rats. Synthetic somatostatin was infused at doses of 0.25, 0.5, 1 and 5 ng/kg X min before and after the intragastric instillation of a liver extract/sucrose test meal. In the obese rats somatostatin at a dose of 5 ng/kg X min reduced basal plasma insulin levels significantly, whereas no effect of somatostatin was observed on basal insulin levels in the lean animals at all doses employed. The integrated postprandial insulin response was reduced during 0.25, 0.5, 1 and 5 ng/kg X min somatostatin in the obese animals, whereas only 0.5 ng/kg X min and higher doses had an inhibitory effect in the lean rats. The degree of inhibition in relation to the postprandial insulin response during saline infusions was 35-230% in the obese and 30-100% in the lean Zucker rats within the range of somatostatin infusions employed.(ABSTRACT TRUNCATED AT 250 WORDS)
Pulsatile GnRH therapy is indicated for men with inborn hypothalamic hypogonadotropic hypogonadism and those with acquired gonadotropin deficiency due to hypothalamic disfunction. Oligospermia with hypothalamic GnRH deficiency is a rare indication for efficient GnRH therapy. Based on extended own experience and on the experience of numerous other groups, pulsatile GnRH therapy should be administered as follows: Onset of therapy should not start before the 16th year of age with clearly diagnosed delayed pubertal development. Subcutaneous administration of GnRH is preferred. The cannula should be changed every other day. Injection solutions should not contain Heparin. For diagnostic use or for inefficient subcutaneous therapy, continuation of intravenous therapy containing Heparin in the solution is recommended. The dosage should be measured on the increase of testosterone with stepwise increase of GnRH (25-200 ng/kg/pulse; 2.5-20 micrograms/pulse). As a pulse interval, 120 minutes appeared to be the most efficient, however 90 minutes of pulse intervals may also be efficient. The duration of therapy should be at least three months controlled on the testosterone level, the testes' volume and later on the sperm count.
The biological potency of semisynthetic human insulin (Actrapid HM, Novo) and purified pork insulin (Actrapid MC, Novo) was assessed in normal and diabetic subjects. The blood glucose lowering effect and the related counter-regulatory response were initially tested in six healthy subjects who received an i.v. injection of 0.15 U/kg body weight of either insulin preparation. The attained insulin levels were very similar (peak at 15 min: HM 139 +/- 7, MC 129 +/- 7 microU/ml), as well as the resulting blood glucose curves. A prolonged suppression of C-peptide values was observed after injecting both preparations. The evoked counter-regulatory response [glucagon, growth hormone (GH), cortisol and catecholamines] showed minimal differences. Prolactin secretion was almost identical after HM and MC injection. A glucose clamp study was subsequently performed in six insulin-dependent diabetic (IDD) patients. Blood glucose levels were maintained at 80 mg/dl by the artificial pancreas during a 180 min infusion of MC or HM insulin (30 mU/kg/h). The amounts of dextrose infused during the last 60 min of the study were not significantly different (121 +/- 14 vs 137 +/- 11 mg/kg/h for MC and HM, respectively). It is clear from our results that at the dose levels used in this study, the biological potency of i.v. injected HM is very similar to that of MC.
In nine insulin-dependent diabetics postprandial glucose control under closed loop insulin infusion by an artificial endocrine pancreas was compared with that obtained under open loop infusion employing identical infusion profiles which were advanced 20 min by time in the case of open loop infusion. The earlier increase of insulin infusion rates in the latter case resulted in lower postprandial glucose concentrations during the first 90 min after meal intake. Incremental areas under the blood glucose curves during this time were significantly lower when insulin infusion rates rose earlier (4.5 X 10(3) +/- 0.5 X 10(3) vs 2.1 X 10(3) +/- 0.6 X 10(3) mg/dl X min; p less than 0.02). Insulin was administered at maximum rates 45-50 min after the start of the meal during closed loop infusion (196 +/- 38 mU/min) and 25-30 min after the meal during open loop infusion (192 +/- 35 mU/min). Correspondingly, mean free insulin concentrations which are available from six patients rose to 135 +/- 47 (40 min) or 141 +/- 50 muU/ml (20 min). Glucagon levels did not differ between both parts of the study. It is concluded that increases of postprandial insulin infusion rates occurring earlier than increases of blood glucose levels are important for optimizing glucose profiles and possibly reflect physiologic conditions.
A case of juvenile-onset insulin-dependent diabetes mellitus in a 30-year-old male patient is reported. He was admitted to the hospital because of severe diabetic neuropathy, predominantly in the lower extremities. Signs of autonomic neuropathy were not evident but the patient had severe orthostatic hypotension. Circulating catecholamine concentrations were normal; however, the blood pressure response to infused norepinephrine was reduced ten-fold compared to a group of normals. An improvement of the blood pressure response to sympathomimetic drugs was accomplished during the simultaneous administration of propranolol, a beta-receptor blocking agent. The present data suggest a possible defect of the adrenergic receptor system in response to sympathomimetic drugs while the release of catecholamines and the function of the parasympathetic nervous system appears to be intact. Treatment with beta-blocking agents such as propranolol as an adjunct to sympathomimetics seems to be a promising approach which might deserve further consideration in similar cases.