The purpose of the present study was to elucidate the interrelationship between pancreatic polypeptide (PP) and other pancreatic endocrine hormones. For this purpose, a radioimmunoassay (RIA) system of plasma PP was established and the changes in plasma PP, plasma immunoreactive insulin (IRI), plasma C-peptide reactivity (CPR) and plasma immunoreactive glucagon (IRG) following oral administration of glucose were examined in ten normal subjects and twenty-five patients with liver cirrhosis. Patients with liver cirrhosis were classified into a normal glucose tolerance group (NGT), an impaired glucose tolerance group (IGT), and a diabetes mellitus group (DM) on the basis of the glucose tolerance curves obtained after the oral administration of glucose.
In the IGT and DM groups, fasting plasma PP levels were significantly elevated when compared with those in the control and NGT groups. Also oral administration of 75g glucose elicited an exaggerated rise in plasma PP in the IGT and DM groups when compared with the response in the control and NGT groups. On the other hand, PP response to glucose in the NGT group was similar to that in the control group.
Plasma IRI increased markedly before and after oral administration of glucose in the IGT and DM groups when compared with the control groups. In these patients, plasma levels of CPR almost paralleled those of IRI. No significant difference was noted between the NGT group and the control group with regard to plasma IRI and CPR levels before and after oral glucose loading. Accordingly, insufficient insulin action was considered to exist in the IGT and DM groups. This insufficiency in insulin action was expressed in terms of the indices of increase in plasma IRI and CPR, AIRI/ABS and ACPR/ABS, which corresponded to the elevated blood glucose levels, being significantly lower in the IGT and DM groups than in the control and NGT groups 30 minutes after oral administration of glucose. No significant difference was noticeable between the NGT group and control group with regard to these indices. In the patients with liver cirrhosis, the _??_PP value, obtained by subtracting the plasma PP level during fasting from the PP level 30 minutes after oral glucose loading, was inversely correlated with the values of both _??_IRI/_??_BS and _??_CPR/_??_BS.
Plasma IRG levels on fasting tended to be higher in all patients with liver cirrhosis compared with the control group, especially in the IGT and DM groups in which fasting plasma PP levels were elevated. After oral administration of glucose, on the other hand, plasma IRG levels decreased in all cirrhosis groups, especially in the IGT and DM groups in which the plasma PP response to oral glucose was exaggerated.
In the gel filtration pattern of plasma PP in patients with liver cirrhosis indicating a high plasma PP level, the major peak of PP immunoreactivity corresponded to the radioactive peak of¹²⁵I-BPP and this pattern remained unchanged before as well as after oral administration of glucose.
Each group of patients with liver cirrhosis was similar in age, degree of obesity and renal function. In addition, no correlation was observed between the degree of hepatic dysfunction and the plasma level of PP.
From these results, two principal conclusions can be drawn : first, in patients with liver cirrhosis having abnormal glucose tolerance (IGT and DM groups), hyperinsulinemia is associated with high plasma PP, and although hyperinsulinemia is present in these patients, insulin action is insufficient, and second, plasma glucagon is not correlated to plasma PP. In addition, the Dalton of PP increased in the plasma of cirrhotic patients with impaired glucose tolerance, was found to be generally 4, 200

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To evaluate the role of a circulating inhibitor of extrathyroidal conversion of T₄ to T₃ (IEC) in the causation of low T₃ states in patients with various nonthyroidal illnesses (NTI), we measured the in vitro T₃ production in the presence of ether extract of plasma. Blood samples were obtained from 22 normal subjects and 140 patients with various NTI; liver cirrhosis (LC) 37, diabetes mellitus (DM) 48, respiratory failure (RF) 15, chronic renal failure (CRF) 10 and others 30. The assay procedure of in vitro T₃ production was as follows. Rat liver homogenate was incubated with 2.5μM T₄ in the presence of evaporated ether extract of plasma and the amount of T3 produced was quantified by RIA. In each assay, control plasma extracts taken from the two normal subjects were used. The results were expressed as a percentage of the control value (%T₃ production), and estimated as positive IEC when %T₃ production was under 72.7%, that was 2SD below the mean value of normal controls.
Patients were divided into three groups; Group I (T₃≥80ng/dl), Group II (80<T₃≥50) and Group III (50<T₃). The %T₃ productions were 88.5±22.0 in Group I, 84.9±31.5 in Group II and 78.9±34.0 in Group III respectively. The %T₃ productions of each group were significantly lower than that of normal control, 101.9±14.6. IEC was positive 23.4% in Group I, 41.9% in Group II and 43.8% in Group III.
There were eight nonsurvivors, and they all belonged to Group III, in which both serum T₃ and T₄ were subnormal. In nonsurvivors, serum concentrations of T₃ (20±11ng/dl) and TSH (1.2±1.1μU/ml) were significantly lower than that of survivors in Group III (T₃; 38±10ng/dl p<0.005, TSH; 2.8±1.4μU/ml p<0.05). The %T₃ productions were 83.8±32.1 in survivors and 64.8±37.9 in nonsurvivors, and the incidences of positive IEC were 37.5% in survivors and 62.5% in nonsurvivors.
From the standpoint of the underlying illnesses, serum concentrations of T₃ (mean± SDng/dl) were 49±21 in LC, 64±11 in DM, 40±22 in RF and 63±15 in CRF, and %T₃ productions were 60.6±26.5 in LC, 82.5±25.8 in DM, 109.6±32.1 in RF and 97.6±24.3 in CRF. The incidences of positive IEC were 60.9, 47.6, 16.7 and 16.7% respectively. Three patients of eight nonsurvivors suffered from respiratory failure and their IEC were all negative. But all other five patients died of nonrespiratory diseases showed positive IEC.
In nine patients with diabetes mellitus followed, serum T₃ (ng/dl) concentration increased significantly from 69±27 to 88±35 after insulin therapy, and their %T₃ productions also increased from 67.0±18.4 to 101.3±20.5.
In conclusion, 1) IEC was one of the causative factors in low T₃ state in patients with various NTI, 2) the degree of contribution of IEC to low T₃ state was different among the underlying illnesses and 3) IEC might disappear when clinical course of underlying illnesses improved.

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Cell culture techniques for monolayer islets of 3-week-old rat pancreases and the responsiveness of B cells are described. In this procedure, whole pancreatic tissues from 3-week-old rats were enzymatically dispersed and then cultured in a medium with 5.5mM glucose plus 1mM 2-deoxy-2-fluoroglucose or with 5.5mM glucose following a 3-day exposure to a medium with 5.5mM glucose plus 504 iodoacetic acid. The use of 2-deoxy-2fluoroglucose or iodoacetic acid allowed a selective deletion of fibroblasts, yielding large clusters that consisted mostly of islet cells. The immunocytochemical evaluation of the islet cells in these cultures showed that approximately 70% are B-cells, 20% A-cells, and 10% D-cells. On day 0, the response to 16.7mM glucose included only a small rise in insulin secreted during the first and the second phase, and the response to 10mM of leucine or 2-ketoisocaproate was monophasic. After being cultured for 7 days, all three secretagogues markedly stimulated insulin secretion by B cells cultured in both media, resulting in an enhancement of the biphasic pattern. However, quantitative relationships differed. Thus, the total response from B cells in 2-deoxy-2-fluoroglucose during a 30-min stimulation with glucose and leucine was significantly higher (1.6- and 1.9-fold respectively) than that from B cells in 5.5mM glucose, although there was no significant difference in insulin secretion evoked by 2-ketoisocaproate. Furthermore, in the former B cells, the amount of insulin secreted during the second phase was 84-94% of the total insulin secretion, and in the latter it was 66-76%. Addition of 1mM 3-isobutyl-1-methylxanthine and 10pM forskolin resulted in a significant increase in insulin secretion by B cells in 2-deoxy-2-fluoroglucose, whereas there was no difference in the increase of insulin secretion induced by 16.7mM glucose and 200nM 12-o-tetradecanoyl phorbol-13-acetate. In monolayer cultures that had been maintained in both media for 15 days, the second phase of insulin secretion due to the secretagogues was slightly decreased, but the biphasicity in the response was well preserved.
In conclusion, the present results suggest that B cells of 3-week-old rats may be still immature, and that the medium with 2-deoxy-2-fluoroglucose is beneficial to the continued maturation of the B-cell function in vitro.

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The activities of thyroid-stimulating antibody (TSAb) in serum from patients with Graves' disease were measured by a sensitive assay, using cultured porcine thyroid cells and the precipitation from serum with polyethylene glycol (PEG), and the activities were compared with those of thyrotropin binding inhibitor immunoglobulin (TBII), measured by the commercial assay kit.
Porcine thyroid cells after digestion were cultured for 15-18 hours with TSH of 1-10,000μU/ml or the precipitations of sera from normal subjects and patients with Graves' disease or Hashimoto's thyroiditis, and then the cAMP levels in the culture medium were determined by the commercial RIA assay kit (Yamasa). The precipitation was obtained by adding 0.5ml of 30% PEG solution to 0.5ml serum, and was resuspended with 0.6ml of Hanks' medium without NaCl, containing 1.5% bovine serum albumin, 20mM Hepes and 0.5mM 3-isobutyl-1-methylxanthine. The precipitation contained about 85% of immunoglobulin and 63% of albumin of the original amount of the serum, as well as substantial TSH, when the original serum contained TSH more than 40μU/ml.
When the PEG precipitations from 10 normal subjects were incubated with the thyroid cells of 4 × 10⁵ cells, the cAMP releases into the medium ranged from 83 to 124%, when the mean value was calculated as 100%. Therefore, the cAMP release of more than 130% of the amount released into the culture medium when incubated with normal IgG was judged as positive TSAb activity. The minimum detectable quantities were regarded as about 5μU/ml TSH equivalent.
TSAb and TBII activities were detected in 48 (92%) and 50 (96%) of 52 patients with untreated hyperthyroid Graves' disease, respectively, and either TSAb or TBII activities were detected in 16 (80%) of 20 patients with Graves' disease maintained in a clinically euthyroid state by treatment with antithyroid drugs. TBII was positive in 10 (50%) of these patients. Some patients showed distinct discrepancies in these two activities, although there was a significant positive correlation between TSAb and TBII activities (r=0.53, p<0.01) in patients with untreated Graves' disease. In these patients, TSAb activities showed a significant positive correlation with values for ^99mTc thyroid uptake, determined 30 min after the injection. However, they did not show any significant correlation with serum T₄ or T₃ concentrations. Similarly, TBII showed significant correlations with goiter size and ^99mTc thyroid uptake.
To conclude, the present assay for TSAb is sensitive and reproducible. Although these two activities are not always equally detected in these patients, the TSAb and/or TBII activities are detected in virtually all patients with untreated hyperthyroid Graves' disease, suggesting that these activities are important for the etiology of Graves' disease.

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To evaluate the clinical significance of TBII and TSAb activities in euthyroid and hyperthyroid Graves' disease, these two activities were measured in 8 patients with euthyroid Graves' disease and 29 patients with hyperthyroid Graves' disease during treatment with antithyroid drugs. In 8 patients with euthyroid Graves' disease, TBII activity was detectable only in one patient and TSAb activity detected in 3 patients, these detectabilities being much lower than those in hyperthyroid Graves' disease. However, 2 of 4 patients who had either TSAb or TBII came to have both activities, and one of them became overt hyperthyroid. In patients with hyperthyroid Graves' disease, detectabilities of -these activities became lower as they became euthyroid with antithyroid drug treatment, but TSAb tended to be higher than TBII when they remained euthyroid for more than 4 months. Although the majority of the patients who had TSAb and/or TBII activities were T₃ non-suppressible, patients with no TSAb and TBII activities did not necessarily show remission of the disease. The present results suggest that patients with euthyroid Graves' disease with both TBII and TSAb may be apt to become hyperthyroid, and that TSAb and TBII activities and T₃ suppressibility may not be a definite criteria for the remission of Graves' disease.

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Amiodarone, an antiarrhythmic agent, is known to occasionally induce alterations in thyroid function because of its iodine content and ability to inhibit T₄ 5′-monodeiodination. We herein describe the drug-induced chemical hyperthyroidism in a diabetic patient with ventricular premature beats.
A 46-year-old man with well controlled diabetes mellitus revealed neck swelling during a 4 months' treatment with amiodarone for his frequent occurrence of ventricular premature beats. Physical findings were unremarkable other than grade III diffuse struma. Routine laboratory studies were almost normal. The results of thyroid function studies showed hyperthyroidism, including increases in T₄ and free T₄, slight increases in T₃ and free T₃, a marked increase in reverse T₃ and a decrease in ¹²³I 24-h uptake. TSH was low and did not respond to TRH. Antithyroid antibodies and TSH receptor antibodies were negative. The findings of the thyroid biopsy were unremarkable except for a mild follicular hyperplasia. After cessation of the drug, T₃ and free T₃ were returned to normal within 2 weeks, T₄ and free T₄ within 2 months and reverse T₃ after 6 months.
These data suggest that the struma and chemical hyperthyroidism observed in our patient were induced by amiodarone treatment.

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To assess the changes in thyroid hormone metabolism after the onset of acute myocardial infraction (AMI), serum T₄ and T₃ levels were serially measured for 24 hours after the coronary artery ligation in dogs. The effect of thyroid hormone administration on hemodynamics in these dogs were also studied to clarify the possible usefulness of thyroid hormone therapy in nonthyroidal illness (NTI). Dogs were anesthetized with ketamine using “Micro-Mini” drip administration. Coronary artery ligation was performed in 8 dogs (MI group) Open chest operation was performed in 8 dogs, but their coronary arteries were not ligated and were used as control (cont. group). Blood samples were drawn before and 1, 3, 6, 12, 18 and 24 hours after coronary artery ligation, and serum levels of T₄ and T₃ were measured using the TDX T₄ system and a commercial RIA kit, respectively. Various hemodynamic parameters (heart rate, mean blood pressure, max dp/dt, left ventricular end-diastolic pressure, cardiac output) were measured at the same time mentioned above.
All the hemodynamic parameters remained within normal range for 24 hours in the control group. Serum T₄ and T₃ levels, however, showed slight, but significant decreases due to general anesthesia and open chest operation in the control group. On the other hand, hemodynamic parameters were maintained in the normal ranges only for 12 hours, and gradually deteriorated in the MI group. Moreover, it was remarkable that both T₄ and T₃ levels were decreased immediately after the ligation in this group, T₄ being less than 0.1μg/ dl and T₃ less than 10ng/dl. They continued to show the low values thereafter. When T4₄ (30μg/24 hours), and T₃ (7, 14 or 21 μg/24 hours) were continuously infused intravenously for 24 hours after the coronary artery ligation in 10 dogs, serum T4 levels were maintained in the normal range of the dog (1.5 -3.6μg/dl) and the serum T₃ levels were increased to the low normal range. However, there were no significant differences in hemodynamic indices between the thyroid hormone treated groups and the non-treated group.
These data show that T₄ and T₃ concentrations decrease prior to the deterioration of cardiac function. Moreover, the present findings also suggest that administration of thyroid hormone has no benefit in patients with NTI associated with low T₄ and T₃ levels.

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