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Patients with diabetes mellitus (DM) often suffer from various and severe infection. Patients with pancreatic DM have malnutrition due to chronic pancreatitis. Therefore it is believed that patients with pancreatic DM have a lower ability of host defence to infectious diseases than normal subjects. We examined the primpheral lymphocyte subsets (T cell, B cell, NK cell, CD3+ 56+ T) of eighteen patients (males, age = 52.8 +/- 12.7 years old, mean +/- SD) with pancreatic DM by two color flow-cytometry to evaluate the lymphocyte function. Ratios of T cell (T%, 66.9 +/- 9.3%, mean +/- SD). B cell (B%, 13.1 +/- 5.8%) and NK cell (Nk%, 19.3 +/- 8.7%) to total peripheral lymphocytes of patients with pancreatic DM were not significantly different from those (T% = 66.4 +/- 7.8%, B% = 13.5 +/- 6.7%, NK% = 19.9 +/- 9.1%) of thirteen normal subjects (males, age = 51.2 +/- 13.1). CD3+56+ T cell % (4.1 +/- 1.9%) of patients with pancreatic DM was lower than that (6.0 +/- 3.0%) of normal subjects (p < 0.05). CD3+56+ T cells have cytotoxic activity and it is likely that this activity is similar to that of NK cells. These results suggested that a decrease in peripheral CD3+56+ T cell % is a factor showing a weak host defense mechanism to infectious diseases in patients with pancreatic DM.

We examined whether arginine vasopressin (AVP) is involved in the adrenocorticotropin (ACTH) response induced by interleukin (IL)-6 or tumor necrosis factor (TNF)-alpha in the rat. To accomplish this, we employed immunoneutralization of brain AVP by injecting anti-AVP antiserum intracerebroventricularly (i.c.v., 3rd ventricle). For comparison, we also tested the effect of immunoneutralization of corticotropin-releasing hormone (CRH) in the brain. Anti-CRH antibody, anti-AVP antibody, or normal rabbit serum (control) was given i.c.v. 15 min before an i.c.v. administration of human recombinant IL-6 (100 ng) or TNF-alpha (100 ng). Both IL-6 and TNF-alpha significantly elevated plasma ACTH levels. The IL-6-induced ACTH response was significantly suppressed by both anti-CRH and anti-AVP antibodies. On the other hand, the TNF-alpha-induced ACTH response was not significantly affected by anti-AVP antibody, although anti-CRH antibody could suppress the response. These results suggest that the IL-6-induced ACTH response may be mediated by both CRH and AVP, whereas the ACTH response to TNF-alpha is only via CRH.

To investigate possible parameters for the differential diagnosis of steatorrhoea in patients with low fat intakes, faecal specimens were analysed from 15 patients with steatorrhoea due to chronic pancreatitis and seven patients with steatorrhoea due to intestinal malabsorption. The fat intakes of the patients ranged from 30.1 to 60 g, less than the average in American and European patients. The group with pancreatic steatorrhoea showed a significantly lower faecal output than the group with intestinal steatorrhoea but the two groups did not differ significantly in their total faecal fat excretion or concentration. The percentage triglycerides and the molecular ratio of triglycerides to fatty acids in the faeces were significantly higher ( P < 0.01) in the group with pancreatic steatorrhoea than in those with intestinal steatorrhoea. The molecular percentage ratio of triglycerides to fatty acids was 6.8 ± 2.2 for the chronic pancreatitis group and 2.4 ± 1.0 for the intestinal malabsorption group; while the respective faecal hydroxy fatty acid contents were 3.1 ± 3.6% and 10.1 ± 3.3% (means ± SDs). These latter two parameters appeared to be the most valuable for distinguishing the two forms of steatorrhoea.

It is almost generally agreed that prostaglandins (PGs), especially PGE2, may play a significant role in mediating corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) secre

The serum zinc, prealbumin, retinol-binding protein and carotene concentrations and the plasma fatty acid composition were determined to assess the nutritional condition of 24 patients with chronic pancreatitis compared with that of 20 healthy controls. The daily food intake and faecal fat excretion of the two groups were also measured. In the chronic pancreatitis group, the calorie and fat intakes were significantly lower than those of the controls. Serum levels of zinc, prealbumin and carotene were also significantly lower than those of the controls. Percentages of plasma linoleic and arachidonic acids were low, while percentages of palmitoleic acid, eicosapentaenoic acid and docosahexaenoic acid were high. Fish oil intake correlated negatively with plasma linoleic acid concentration ( P < 0.05). The above results indicate that the relatively high intake of fish oil and the relatively low intake of dietary fat in Japanese patients with chronic pancreatitis with a mild degree of steatorrhoea results in an abnormally low plasma level of linoleic acid.

In order to examine the malnutritional condition of outpatients with pancreatitis, a dietary investigation was conducted in Japanese patients with chronic pancreatitis (n = 38) and healthy subjects (n = 35) of the same age for 3-7 consecutive days, and the characteristics of their food intake were examined. The patients with pancreatitis took in less calories, fat, carbohydrate, and protein than the healthy subjects, by 900 kcal, 20 g, 150 g, and 20 g, respectively. On the other hand, the fat energy ratio in the patients was 20%, similar to that in the healthy subjects. Also, when the fat intake was classified according to origin, i.e., animal, marine, or plant, the proportions for animal (g) and plant (g) were low, while marine fat accounted for a significantly higher percentage than in the healthy subjects. The intake of cholesterol and Ca in the patients was significantly smaller than that in the healthy subjects, but no significant difference was observed in the intake per body weight of proteins and Ca. It seems, possible that the low calorie, low protein, low fat, and low carbohydrate intake may be factors in the malnutritional condition of the patients with chronic pancreatitis. Analysis of covariance and principal component analysis showed that the body weight of the patients was closely correlated with decreases of caloric intake and intake of carbohydrate. The above results revealed that low body weight in patients with chronic pancreatitis was closely related to the decrease of calorie and carbohydrate intake, in addition to maldigestion and malabsorption of nutrients.

A determination of caloric consumption based on a dietary survey table, fat and cholesterol intake, and analyses of fecal fatty acids and neutral sterols, and bile acid analysis (gas chromatographic method) were conducted on 33 subjects (including 17 patients with chronic pancreatitis and 16 normal controls). The factors related to hypocholesterolemia in chronic pancreatitis (CP) patients were investigated and the following conclusions were obtained: (1) The total caloric intake and fat consumption by the CP patients were significantly lower with the exception of cholesterol consumption. (2) Significant increases were noted in fecal fat, neutral sterols, and bile acid excretion by the CP patients. (3) A significant positive correlation was noted between the total cholesterol and body mass index (BMI), reaffirming that the cholesterol level can be used as an indicator of nutritional status. (4) A significant negative correlation was noted between the serum total cholesterol and fecal bile acid excretion. These findings indicate that CP patients suffer from neutral sterol malabsorption, in addition to dietary fat maldigestion and bile acid malabsorption. Furthermore, bile acid malabsorption is cited as a factor in the development of hypocholesterolemia in CP patients.

A group of oxygenated sterols has been identified as physiological regulators of hepatic cholesterol biosynthesis. However, the regulatory effects of these oxysterols on cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis, is not clearly elucidated. We administered 0.1% 7-ketocholesterol (15 mg/day), a strong inhibitor of sterol synthesis, to rats orally for 6 days. Then, the levels of accumulated oxysterols in liver microsomes and microsomal 7 alpha-hydroxylase activity were determined. The results were compared to those in the groups of rats treated with either control diet or diets containing 0.1 or 1% cholesterol, 0.1% butylated hydroxytoluene, 3% cholestyramine or 1% taurocholate. 7-Ketocholesterol feeding resulted in significant increase of both 7-ketocholesterol and 7 beta-hydroxycholesterol in microsomal fraction (449.4 +/- 36.8 and 438.2 +/- 46.8 ng/mg protein, respectively; mean +/- S.E.). Hepatic microsomal 7 alpha-hydroxylase activity in the rats fed 7-ketocholesterol was significantly elevated as compared with those of control rats; 44.70 +/- 5.97 vs. 16.57 +/- 2.46 pmol/min per mg protein. Addition of BHT to 7-ketocholesterol reduced the accumulation of 7 beta-hydroxycholesterol, and the stimulatory effect of 7-ketocholesterol on 7 alpha-hydroxylase activity was suppressed. Our results demonstrate that oxysterols do not inhibit but rather stimulate hepatic microsomal 7 alpha-hydroxylase.

The metabolism of cholesterol ester (CE) was studied in peritoneal macrophages taken from rats with streptozocin-induced diabetes. Levels of CE and synthesized [ 14 C]-cholesterol oleate did not differ significantly between the macrophages from diabetic and control rats incubated with low-density lipoprotein (LDL). However, when macrophages were incubated with Cu 2+ -induced oxidized LDL, CE levels were significantly higher in diabetic rats than in control rats (3.03± 0.09 μg/10 6 cells versus 2.66±0.09 μg/10 6 cells; P 14 C]-cholesterol oleate did not differ significantly between the two groups of rats. The findings suggest that CE accumulates in macrophages in the presence of diabetes mellitus and may play a role in the development of atherosclerosis in diabetes mellitus.

The present study was performed to assess the influence of hyperlipidemia on the appearance and development of diabetic nephropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). This was done by comparing the incidence of nephropathy in 35 diabetic patients with heterozygous familial hypercholesterolemia (FH) with the incidence of nephropathy in 165 patients without FH. There was no significant difference in sex, age, body mass index, or mean duration of diabetes between the two groups. Both groups received similar treatment for diabetes. No significant difference in mean hemoglobin A 1c levels or prevalence of hypertension was noted between the two groups. Total serum cholesterol and triglyceride levels were significantly higher ( P P

This study examined the effects of a new oral hypoglycemic drug, CS-045, on glucose tolerance and serum lipids in 10 nonobese patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma glucose levels before and at 2, 3, 4, 6, 8, 10, 15, 20, and 30 minutes after administration of the intravenous glucose tolerance test (IVGTT) were significantly ( P P P P P

It has been demonstrated in several animal species that neuropeptide Y (NPY) exerts a modulatory effect on luteinizing hormone (LH) secretion. However, whether NPY plays a similar role also in humans has yet to be determined. Therefore, in this study we examined the effect of human NPY on the anterior pituitary hormone secretion in 6 normal men. Intravenous bolus injection of 100 micrograms of human NPY alone did not affect the secretion of any anterior pituitary hormone or cortisol. However, when NPY (100 micrograms) was administered simultaneously with LH-releasing hormone (LHRH, 100 micrograms), a significant potentiation was observed for LHRH-induced LH secretion. Similarly, follicle-stimulating hormone (FSH) response to LHRH was slightly potentiated by the coadministration of NPY, although this effect was not statistically significant. This is the first study to demonstrate that NPY can augment the LHRH-induced LH secretion in humans.

The study was designed to investigate whether impaired composition of platelet lipids in untreated diabetic patients improved after diabetic treatment. Fourteen untreated patients with non-insulin-dependent diabetes mellitus (NIDDM) and 15 healthy control subjects were studied. In the diabetic patients, the ratio of free cholesterol to phospholipid (FC/PL) in platelets of 0.33 +/- 0.02 (mean +/- SEM) at pre-treatment, which was statistically (p < 0.05) higher than that of 0.26 +/- 0.02 in control subjects, was significantly decreased to the value of 0.29 +/- 0.02 (p < 0.01) after insulin therapy. Platelet FC level of 9.77 +/- 0.77 micrograms 10(-8) cells pre-treatment was significantly (p < 0.01) reduced to the value of 7.72 +/- 0.38 micrograms 10(-8) cells post-treatment. Platelet PL level showed no significant changes after the treatment. There was a significantly (p < 0.01) positive correlation between the decrease in FC/PL of platelets and that in haemoglobin A1c (HbA1c) after treatment for diabetes (rs = -0.729). These results indicate that the impaired lipid composition in platelets can be improved after an adequate glycaemic control in patients with NIDDM.

Utilizing the push-pull perfusion technique, we examined the effect of an intravenous bolus injection of recombinant human interleukin (IL)-1 beta on the release of prostaglandin E2 (PGE2), CRF, and AVP in several hypothalamic areas of freely moving rats, simultaneously monitoring plasma ACTH levels. Perfused hypothalamic areas were the median eminence (ME), the paraventricular nucleus (PVN), and the medial preoptic area (MPOA). During the period 12:00-15:00 h, perfusates and blood samples were collected every 10 min (between 13:00 and 13:40 h) or 20 min (between 12:00 and 13:00 h, and between 13:40 and 15:00 h). IL-1 beta (1.0 micrograms/rat) or vehicle only (in control groups) was injected at 13:00 h. In both the ME and the PVN but not in the MPOA, the outputs of CRF and AVP were significantly stimulated by IL-1 beta, prior to the rise in plasma ACTH. A significant stimulation of PGE2 by IL-1 beta was observed only in the PVN, and its temporal profile was very similar to those of CRF and AVP in the PVN. These results suggest that PGE2 may be a trigger in the PVN for the activation of CRF and AVP neurons, and thereby ACTH secretion, which follows IL-1 beta injection.

Thirteen patients with pancreatic diabetes caused by calcifying pancreatitis were divided into 2 groups; 5 with diabetic autonomic neuropathy [AN(+) group] and 8 without [AN(-) group]. They were subjected to an insulin-induced hypoglycemic stress test to evaluate their blood pancreatic glucagon, adrenalin, and cortisol responses. When a blood glucose level below 45 mg/100 ml was defined to be hypoglycemia, all the patients in the AN(-) group exhibited peripheral adrenalin responses, with a significant increase (mean, 19.0 times the basal level) in the blood adrenalin level. Among the AN(+) group, on the other hand, central nervous symptoms became evident rather than the peripheral adrenalin response (the blood adrenalin level hardly exceeded the basal level). With the exception of a single patient, none exhibited responses in the blood pancreatic glucagon levels. Only one patient showed a minimal cortisol response but the remaining 12 reacted normally in the cortisol release. The findings are summarized as follows: in pancreatic diabetes, insulin-induced hypoglycemia causes little change in pancreatic glucagon secretion; when the condition is complicated with autonomic neuropathy, central nervous symptoms develop while the blood adrenalin level hardly increases. These findings indicated that patients with pancreatic diabetes complicated with diabetic autonomic neuropathy have a risk of lapsing into an acute hypoglycemic coma and difficulty in recovering from the hypoglycemic state.

In this study, we evaluated the control state of body weight, blood pressure, and blood glucose during the recent 10 years in 82 patients of non-insulin-dependent diabetes mellitus (NIDDM) who had long duration of diabetes for 20-25 years without ischemic heart disease (IHD) and diabetic nephropathy (Neph). The patients without either IHD or Neph showed significantly lower incidences of obese (11 vs. 40%, p < 0.05), hypertensive (0 vs. 20%, p < 0.05) and poor glycemic control state (7 vs. 27%, p < 0.05) for 10 years than the patients with IHD alone, and showed significantly lower incidences of hypertensive (0 vs. 20%, p < 0.05) and poor glycemic control state (7 vs. 33%, p < 0.01) than the patients with Neph alone. The control state of body weight was similar between the patients without either IHD or Neph and with Neph alone. In addition, the patients without either IHD or Neph showed significantly lower incidences of obese (11 vs. 56%, p < 0.01) and hypertensive control state (0 vs. 40%, p < 0.01) for 10 years than the patients with both IHD and Neph. The control state of blood glucose was similar between the two groups. These results suggest that for long survival of NIDDM patients without development or progression of IHD and Neph, non-obese and non-hypertensive state as well as good glycemic control should be maintained for long time.

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.

Eight non-insulin-dependent diabetes mellitus patients, in whom oral hypoglycaemic agents were not effective, were treated with an α-glucosidase inhibitor, AO-128 (0.9 mg/day) for 6 months. After 6 months of treatment there was a statistically significant decrease in the blood glucose level 1 and 2 h postprandially. The 2 h blood glucose level was also significantly reduced after 2 months' treatment. The insulin and HbAlC levels after 2 and 6 months' treatment were lower than those before administration. Faecal weight, the frequency of bowel movements, the ratio of hydroxy fatty acids to total fatty acids, and faecal short-chain carboxylic acid content were all increased significantly during treatment. The initially hard stools became normal or soft, although no actual diarrhoea developed. Both faecal bile-acid excretion and the ratio of primary bile acids to total bile acids were increased significantly after 2 months, but they showed some recovery towards the pretreatment levels after 6 months' treatment. There was no distinct change in neutral sterol and fatty acid excretion. Breath hydrogen excretion showed a slight increase after treatment. These results suggest that intestinal fermentation was promoted and the intestinal transit time was shortened by AO-128 administration.

TAMASAWA, N., YONEDA, M., MAKINO, I., TAKEBE, K., SONE, K, and KOGAWA, R. The Effect of Biliary Bile Acid Concentration and Composition on the Calcium Level in Human Gallbladder Bile. Tohoku J. Exp. Med., 1993, 171(4), 297-307 -We analyzed total and ionized calcium concentrations in gallbladder bile of 34 humans in four groups: 8 patients with no gallstone, 11 gallstone patients treated with no gallstone dissolution agents, 8 gallstone patients treated with chenodeoxycholic acid(CDCA) and 7 gallstone patients treated with ursod eoxycholic acid(UDCA). We found that total calcium level ranged from 1.40 to 8.01 mmol/liter, closely related to total bile acid concentration (r=0.759). However, ionized calcium level was maintained in a narrow range of 0.25 to 1.23mmol/liter and had no relation to total bile acid concentration. UDCA-rich bile showed relatively high level of ionized calcium. We performed ultrafiltration of bile with cut-off molecular weight 1, 000 to investigate the interaction between biliary calcium and bile acid aggregates. The proportion of ultrafiltrated bile acid level to that in original bile in the UDCA group was statistically higher than the other groups. Relatively large percentage of smaller bile acid aggregates in UDCA-rich bile may impair its calcium solubility.

It is almost generally accepted that an acute-phase ACTH response induced by interleukin (IL)-1 is mediated principally by CRH release from the hypothalamus. However, the precise cellular site of action of IL-1 in activating the CRH neuronal system remains to be determined. Two likely candidates comprise the paraventricular nucleus (PVN) where CRH neuronal cell bodies are located, and the median eminence (ME) where their nerve endings are terminated. Therefore, in this study we performed a comparative perfusion of the ME and the PVN with increasing concentrations of recombinant human IL-1β utilizing the push-pull perfusion technique in freely moving rats. We measured the plasma ACTH and ME and PVN levels of CRH, and also of AVP, because AVP, another secretagogue of ACTH, has its cell body in the PVN and axon terminals partly in the ME. In control groups, the ME or the PVN was perfused with artificial cerebrospinal fluid between 12:00 and 15:00 h, and perfusates and blood samples were collected every 20 min. In the other groups, either the ME or the PVN was perfused with three increasing concentrations (0.1, 1.0, and 10 nM) of recombinant human IL-1β dissolved in artificial cerebrospinal fluid only between 13:00 and 14:00 h with all the other procedures run in the same way as in the controls. In the control perfusions, the hypothalamic release of CRH and AVP and the plasma ACTH did not change significantly during the entire period of observation. In the ME perfusion with IL-1β, 1.0 and 10 nM, but not 0.1 nM, of the cytokine significantly and dose-dependently stimulated CRH and AVP secretions in the ME and the plasma ACTH. ACTH responses during the PVN perfusion with IL-1β were similar to those during the ME perfusion, except that at the PVN the lowest concentration (0.1 nM) of the cytokine was already effective in stimulating ACTH secretion. These in vivo data suggest that IL-1β may act on both the ME and the PVN to stimulate CRH and,’ thereby, ACTH secretions. The secretory response of hypothalamic AVP to IL-1β, which was similar to that of CRH, suggests that not only CRH but also AVP may mediate the IL-1β stimulation of ACTH secretion.

Dieticians computed the fat and cholesterol contents of 11 foods that were commercially produced as ready-to-eat food from food component lists and obtained the P/S ratio (polysaturated/saturated fatty acids) from the fatty acid component list. Meanwhile the same foods were diluted and homogenized. The internal standard was combined with hepatadecanoic acid and tricaprin. The samples that had been extracted by the Folch method were analyzed for their lipid content (GC analysis using a HS-SS-10 columns for fatty acids and an OV-1 column for lipid and cholesterol). A significant positive correlation was noted between the results of dieticians' analysis and those obtained from a gas chromatographic analysis of lipid and cholesterol contents and the P/S ratio, proving that lipid analysis of food by dieticians is highly reliable. Therefore for diseases (such as hyperlipemia, arteriosclerosis, obesity, diabetes mellitus, fatty liver, and pancreatitis) in which dietary factors have a significant effect on their clinical course, dietary instructions on dietary fats based on an analysis by dieticians are considered to be effective.

The effectiveness and safety of MCI-028, a synthetic human corticotropin-releasing hormone (hCRH), as a diagnostic drug were examined in 65 healthy male and 24 healthy female adult volunteers. Mean maximum concentrations of plasma ACTH and cortisol after intraveneous administration of 100 μg of MCI-028 were 3.0 and 2.0 times their basal concentrations, respectively, and there were no significant age or sex differences in the responses. Good reproducibility was observed in the responses in 59 male subjects who received a second administration after 1 to 2 weeks. Although slight adverse reactions such as mild and transient hot flushing were observed, these were not serious.

Faecal lipid excretion was determined in 16 females on an unrestricted diet and on a fat-restricted diet using a chromatographic method for the simultaneous analysis of faecal lipids. The fat-restricted diet reduced the total quantity of faeces and the amounts of fatty acids, neutral sterols and bile acids excreted were almost halved compared with when on an unrestricted diet. This indicates that dietary fat, fibre and cholesterol affect the amount of faecal bile acid, neutral sterol and fatty acid excretion. The amount of cholesterol/animal sterols excreted and the percentage of primary bile acids were, however, similar for both the fat-restricted and unrestricted diets.

We experienced a 41-year-old acromegalic male (Case 1) in whom the basal plasma GH was extremely high (320–450 ng/mL) but plasma IGF-I was only slightly elevated (2.0–2.8 U/mL). His nutritional condition and associated diabetes mellitus did not appear to be responsible for the relatively low IGF-I level, and a GH-autoantibody in the plasma was absent. We thus performed gel filtration analyses of his plasma and somatotroph adenoma to determine elution patterns of immunoreactive (IR) and receptor active (RA) GH. For comparison, the same studies were carried out on plasmas and somatotroph adenomas obtained from three other acromegalics (Cases 2-4) whose basal plasma GH and IGF-I levels were 22-45 ng/mL and 3.5–6.0 U/mL, respectively. IR GH in Case 1’s plasma distributed over an extremely wide range keeping similar titers rather than showing three discernible components (big-big, big, and little GH) as did plasmas and adenomas from Cases 2–4. And, most of the IR GH in Case 1’s plasma was eluted in such fractions that contained low levels of RA GH, indicating a minor proportion of biologically active GH. However, interestingly, the chromatographic profile and total GH content of Case 1’s adenoma were similar to those of Cases 2-4’s adenomas. These results may, at least in part, explain the discrepancy between the plasma GH and IGF-I levels of Case 1. The unexpectedly different GH elution patterns between the plasma and adenoma from this patient, may suggest a contribution of certain plasma factor(s) to the un-usual chromatographic profile of plasma GH.

An unusual case of coexisting acromegaly and Cushing's syndrome is reported in a 34-yr-old female. There was no biochemical or morphological evidence to suggest the presence of other endocrinopathies. She did not have any family history to suggest a hereditary tendency to endocrine disorders. Her acromegaly and Cushing's syndrome were proven to be due to a pituitary somatotroph adenoma and a cortisol-producing adenoma in the right adrenocortex, respectively. Surgical removal of both tumors led to a marked biochemical improvement of the two endocrinopathies. To account for the simultaneous occurrence of the two endocrine tumors, at least two endocrine syndromes may be considered. One of them is Carney's complex. However, Cushing's syndrome in this complex is unexceptionally due to primary pigmented nodular adrenocortical disease, differing from the adrenal pathology of our patient. In addition, a lack in this case of any other characteristic suggestive of this syndrome appears to speak against this possibility. A second possibility is multiple endocrine neoplasia type 1. The absence of a parathyroid or pancreatic islet cell tumor does not strongly support this possibility, but adrenocortical lesions are not rare in this syndrome although they are only rarely functional. However, existence of similar case reports, although very few, in the literature leaves the possibility that she represents another rare variant of sporadic multiple endocrine neoplasia type I syndrome.

The change of acid cholesteryl ester hydrolase activity in mononuclear leukocyte following treatment of diabetes mellitus was studied in 21 patients with non-insulin-dependent diabetes mellitus (NIDDM). Enzyme activity before treatment in the patients was significantly lower than that in 14 age-matched healthy subjects (1.20 +/- 0.15; mean +/- S.E. vs. 2.20 +/- 0.17 nmol/mg protein/h, P less than 0.01). Enzyme activity before treatment in the patients was significantly increased (P less than 0.05) after 4-8 weeks of treatment. However, enzyme activity of 1.43 +/- 0.14 nmol/mg protein/h observed after treatment in the patients was significantly lower (P less than 0.01) than that in the healthy subjects. There was a significant negative correlation between enzyme activity before treatment and the increase in enzyme activity following treatment (rs = -0.555, P less than 0.01, n = 21). These results indicate that low level of enzyme activity may be insufficiently improved by the treatment of diabetes, and the risk for the development of atherosclerosis as viewed from the enzyme activity may persist even after the treatment in NIDDM.

We compared the effects of neonatal androgenization (NA) and estrogenization (NE) on vasoactive intestinal peptide (VIP) levels in the anterior pituitary (AP) and the hypothalamus and on prolactin (PRL) secretion in adult female rats. Twenty-four hours after birth, a total of seven groups were treated as follows. Three NA groups received a single subcutaneous injection of 10, 100, or 1,000 micrograms of testosterone, respectively. Similarly, three NE groups received 1, 10, or 100 micrograms of 17 beta-estradiol, respectively. The remaining one group was injected with oil vehicle only, and served as controls. At 8 weeks of age, animals were sacrificed by rapid decapitation. NA (1,000 micrograms) and NE (100 micrograms) resulted in a similar degree of hyperprolactinemia and hyperestrogenemia, but this effect ratio between NA and NE (about 1:10) was not true with the lower doses, indicating a qualitative difference in the effects of the two treatments. This is in agreement with our previous study. VIP content determined in the suprachiasmatic nucleus, the paraventricular nucleus and the median eminence did not significantly correlate with plasma PRL. In contrast, there were significant correlations among AP VIP, plasma PRL and estradiol. These results suggest the possibility that the NA- and NE-induced hyperprolactinemia may be mediated, at least in part, by a paracrine and/or autocrine effect of the increased AP VIP on the lactotroph which may probably be mediated by hyperestrogenemia. However, the possibility was also suggested that the observed changes in AP VIP were related more to NA and NE's imprinting effects on the developing brain than to the PRL secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

We re-examined whether CRH stimulates GH secretion in acromegaly. Human CRH (100 μg) was given as an iv bolus to 15 patients with active acromegaly, and plasma GH levels were measured before and at intervals up to 120 min after the injection. For comparison, we assessed in all the patients the effects of TRH (500 μg), GnRH (100 μg), vasoactive intestinal peptide (100 μg) and peptide histidine methionine (100 μg), which are known paradoxically to stimulate GH secretion in acromegaly. A paradoxical GH response (>50% above the basal) to TRH, GnRH, vasoactive intestinal peptide and peptide histidine methionine was observed in 12 (80%), 4 (27%), 5 (33%) and 2 (13%) patients, respectively. All the patients were responsive to at least one of these 4 peptides. However, none of the patients showed a positive GH response to hCRH. These results do not support a GH-releasing activity of CRH in acromegaly. Even if CRH has such an effect, it does not appear as potent as TRH, GnRH, vasoactive intestinal peptide and peptide histidine methionine. However, the possibility cannot be excluded that our negative data might have been due to the use of hCRH vs ovine CRH in earlier studies.

Accumulating evidence suggests that vasoactive intestinal peptide (VIP) may be a physiological PRL-releasing factor. In the present study, we examined a possible involvement of VIP in the neonatal androgenization (NA)-induced hyperprolactinemia. Twenty-four hours after birth, newborn female rats were injected sc with 1,000 micrograms of testosterone (NA) or with oil vehicle only (control). Both groups were sacrificed at 8 weeks of age. Compared to controls, NA rats showed significantly higher plasma PRL levels (7.3 fold), anterior pituitary (AP) PRL content (2.1 fold) and plasma estradiol levels (2.1 fold). AP VIP content was extremely higher (61 fold) in NA rats than in controls. However, NA did not affect VIP content in the suprachiasmatic nucleus, paraventricular nucleus or median eminence. These results suggest that the NA-induced hyperprolactinemia may be mediated, at least in part, by paracrine and/or autocrine effects of the increased AP VIP on PRL secretion. However, since the potentiation by NA of the AP VIP content was extremely marked compared to those of the other parameters, the possibility was also raised that the increased AP VIP may be involved in other endocrine and/or nonendocrine events occurring in the AP.

Arginine vasopressin (AVP) is known to potentiate corticotropin (ACTH) secretion by human corticotropin-releasing hormone (hCRH), and a combined administration of hCRH and AVP appears useful as a pituitary ACTH reserve test. This study was designed to evaluate the appropriate dose of AVP and its route of administration, for better estimation of pituitary ACTH reserve in humans, when used in combination with a conventional hCRH stimulation test. First, intravenous (IV) doses of hCRH (100 micrograms) and AVP (0, 0.1, and 0.3 U) were administered simultaneously in six normal subjects. Second, IV hCRH was administered with intramuscular (IM) AVP (0, 1.0, 3.0, and 5.0 U) in 10 normal subjects. Blood samples for measurement of plasma ACTH were obtained at 0, 15, 30, 45, 60, 90, and 120 minutes after the hCRH with and without AVP administration. The order of AVP doses was randomly chosen in each subject. The peak plasma ACTH level was 65.0 +/- 16.0 pg/mL (30 minutes) with hCRH alone and 139.5 +/- 35.6 pg/mL (15 minutes) with hCRH plus 0.3 U IV AVP in six normal subjects. Similarly, the peak plasma ACTH level was 43.5 +/- 5.6 pg/mL (30 minutes) with hCRH alone and 116.0 +/- 19.6 (15 minutes) and 96.6 +/- 24.0 pg/mL (15 minutes) with hCRH plus 3.0 and 5.0 U IM AVP in 10 normal subjects, respectively. The hCRH-induced ACTH responses (delta ACTH) with both IV and IM AVP were significantly (P less than .05) greater than the respective control values with hCRH alone. The responses (delta ACTH) were comparable between the two phases of 3.0 and 5.0 U IM AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of phospholipid in the formation of large aggregates and the dissolution of insoluble calcium salts in bile was studied in mode bile solutions of various lipid compositions. Calcium carbonate was added as an insoluble calcium salt. As the ratio of phospholipid concentration to bile acid increased, the rate of bile acid in the formation of large aggregates increased; total calcium concentration also increased but Ca2+ concentration did not change. Furthermore, a close relationship between the sum of the bile acid and phospholipid concentrations in the large aggregate fraction and the total calcium concentration in model bile solutions was observed. It could be concluded that phospholipid plays a role in dissolution of insoluble calcium salts by promoting the formation of large aggregates in bile.

Effects of neonatal androgenization (NA) and estrogenization (NE) were compared especially in terms of the prolactin (PRL) secretion in female rats. Twenty-four h after birth, a total of seven groups of newborn female rats were treated as follows. Three NA groups received a single s.c. injection of 10, 100 or 1000 micrograms of testosterone, respectively. Similarly, three NE groups received 1, 10 or 100 micrograms of estradiol-17 beta, respectively. The remaining one group was injected with oil vehicle only, and served as controls. At 8 weeks of age, animals were killed by rapid decapitation. PRL, estradiol and progesterone were measured in the plasma. Anterior pituitary (AP) was weighed, and AP PRL content was measured. NA and NE, at the highest doses, resulted in a similar degree of hyperprolactinemia and hyperestrogenemia showing an effect ratio of about 1:10. This ratio was, however, not true with the lower doses. Furthermore, there was no dose-dependency in the effect of NE on the plasma PRL and estradiol levels. In turn, plasma progesterone levels were dose-dependently decreased by both NA and NE. AP PRL content, expressed per AP, was significantly higher than control values in only NA (1000 micrograms) and NE (100 micrograms) groups. AP weight was increased by NA (1000 micrograms) but not by any NE treatment. These results indicate that NA and NE do not always exert similar effects on the PRL secretion or on several other related parameters. Therefore, aromatization of testosterone to estradiol does not appear to be the sole mechanism mediating the neuroendocrine consequences of NA.

We examined whether peptide histidine methionine (PHM) induces a paradoxical rise in plasma GH in patients with acromegaly. PHM (100 micrograms) was given as an iv bolus to eight patients with active acromegaly, and plasma GH levels were measured before and at intervals up to 120 min after the injection. For comparison, the effects of TRH (500 micrograms) and vasoactive intestinal peptide (VIP, 100 micrograms), peptides known to paradoxically stimulate GH secretion in acromegalics, were assessed in all of the patients. A paradoxical rise (greater than 50% above the basal) in plasma GH was observed in five patients after both TRH and VIP administrations, although TRH responders were not always VIP responders, nor did VIP responders always respond to TRH. In two patients, the GH response to PHM fulfilled the criteria of a paradoxical increase. Both of these patients were also TRH and VIP responders. These results suggest that PHM may be another hypothalamic hormone capable of paradoxically stimulating GH secretion in at least some acromegalics, although PHM appears to be a less potent stimulator of GH release than TRH and VIP. The pathophysiological significance of this phenomenon is yet to be determined.

CS-045, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramkethylchroman-2- ylmethoxy)benzyl]-2,4-thiazolidinedione, lowers plasma glucose in several animal models of non-insulin dependent diabetes mellitus (NIDDM) presumably by increasing insulin sensitivity. Little adverse effect was found in a phase 1 study on healthy male subjects. In order to test its efficacy in lowering plasma glucose in NIDDM in man, a pilot multi-center clinical trial of CS-045 was carried out in 146 patients with NIDDM whose glycemic control was inadequate (FPG greater than 140 mg/dl) on diet and/or other oral hypoglycemic agents. CS-045 was given orally in a daily dose of 200 mg or 400 mg for 12 weeks in addition to the previous treatment. The mean fasting plasma glucose (FPG) and fructosamine began to decrease within 2 weeks and the mean HbA1c within 8 weeks. After 12 weeks, the FPG fell from 192 +/- 41 to 155 +/- 45 mg/dl (P less than 0.01), fructosamine from 3.7 +/- 0.6 to 3.3 +/- 0.6 (P less than 0.01), and HbA1c from 8.9 +/- 1.5 to 8.1 +/- 1.5% (P less than 0.01). The drug was effective in 39% of patients in that FPG fell by more than 20% of the initial value. This rate of efficacy was the same when CS-045 was given alone or together with other oral hypoglycemic agents. The drug was more effective in a dosage of 400 mg than with 200 mg (the rate of efficacy 46% vs 25%) and more effective in obese patients than in lean patients (46% vs 25%).(ABSTRACT TRUNCATED AT 250 WORDS)

A double blind study was conducted to objectively evaluate the usefulness of Cefuzonam (CZON) in the treatment of bacterial pneumonia and lung abscess. Cefotiam (CTM) was used as a control drug. Each drug was administered by intravenous drip infusion at 1 g at a time, twice daily, for 14 days as a rule. The results are as follows: 1. Enrolled in this study were 145 cases in total, comprising 72 of CZON group and 73 of CTM group. Of the total cases, 109 (53 of CZON group and 56 CTM group) were evaluated for clinical efficacy by the evaluation committee. Exclusion rate and background of patients were not significantly different between the two groups. 2. Clinical effectiveness assessed by the committee showed the efficacy rates of 84.9% (45 cases out of 53) for the CZON group and 83.3% (47 cases out of 56) for the CTM group, with no significant difference between the two groups. 3. The bacteriological eradication rates were 89.5% (17 strains out of 19) for the CZON group and 78.3% (18 strains out of 23) for the CTM group, with no significant difference between the two groups. 4. The incidence of side effects was 5 cases (7.5%) for the CZON group and 3 cases (4.2%) for the CTM group. The incidence rate of laboratory test abnormality was 28.4% (19 cases out of 67) for the CZON group and 31.3% (12 cases out of 67) for the CTM group. There was no significant difference between the two groups. 5. Usefulness rates calculated by the committee were 79.2% (42 cases out of 53) for the CZON group and 76.8% (43 cases out of 56) for the CTM group. There was no significant difference between the two groups. These results show that CZON is a useful drug in the treatment of bacterial pneumonia and lung abscess.

To evaluate the relationship between gallbladder function and calcification of gallstones, we studied gallbladder contractility by oral cholecystography, the computed tomography (CT) number of stones for 30 gallstone patients, calcium content of 13 stones operatively extirpated, and the degree of inflammatory change in 13 surgical gallbladder specimens. There was significant correlation between the calcium content and CT numbers of stones, and 1% of the calcium content of gallstone was approximately equal to 40 Hounsfield Units (HU) of the CT number. The calcium content of stones in patients with normal gallbladder contractility was extrapolated to be below 1.5%, while that with poor contractility ranged from 0% to 21%. Additionally there is a possibility that calcium content increases, related to the inflammatory change of gallbladder. Hence our results suggested that measurement of the CT number of stones is useful to evaluate the calcium content of gallstones, and that the gallbladder contractility could be one of the factors to influence calcification of stones.

Renal effects of 4-week fixed maintenance doses of bunazosin three times daily (2.0 mg t.i.d., n = 8) and propranolol (40 mg t.i.d., n = 8) were evaluated in patients with mild-to-moderate essential hypertension [World Health Organization (WHO) stages I and II]. Both bunazosin and propranolol decreased blood pressure (BP) significantly (p less than 0.05), but the magnitude of reduction in diastolic BP (DBP) was greater with bunazosin (p less than 0.05) than with propranolol. Bunazosin produced a nonsignificant increase in renal blood flow (RBF) by 14%, a significant increase in glomerular filtration rate (GFR) 11% (p less than 0.05), and a decrease in total renal vascular resistance (TRR) by 15% (p less than 0.05), whereas propranolol caused no significant changes in these parameters. Urinary sodium excretion rate and the fractional excretion of sodium were unchanged by either of the drugs. The results of this short-term study suggest that bunazosin may be a drug that will increase RBF and GFR and decrease TRR with a concomitant hypotensive action in patients with mild-to-moderate essential hypertension. Whether these renal functional effects of the drug would benefit such patients must be determined in long-term studies.

ONUMA, T., TSUTSUI, M., OCHIAI, S., BOKU, A., YANADA, A., HIRAI, Y., NAKAHATA, H. and TAKEBE, K. Acid Cholesteryl Ester Hydrolase Activity of Mononuclear Leukocyte in Type 2 (Non-Insulin-Dependent) Diabetic Patients. Tohoku J. Exp. Med., 1990, 160 (4), 375-381-Acid cholesteryl ester hydrolase activity of mononuclear leukocytes was measured in 52 Type 2 (non-insulin-dependent) diabetic patients. Enzyme activity was significantly lower in the diabetic patients than in 14 age-matched control subjects (0.89±0.08 (mean±S.E.) vs. 2.20±0.17nmol/mg protein/hr, p

To examine the effects of growth hormone-releasing factor (GRF) on islet hormone release, rat pancreas was perfused. rhGRF at the concentration of 10(-7) M or more enhanced insulin secretion stimulated by 16.7 mM glucose, hpGRF slightly enhanced insulin secretion as well. The insulin secretion induced by 10(-6) M rhGRF was completely inhibited by 10(-6) M propranolol. rhGRF at the concentration of 10(-8) M or more stimulated glucagon secretion even in the presence of 16.7 mM glucose. The glucagon secretion stimulated by 10(-6) M rhGRF was inhibited in the early period but increased thereafter by 10(-6) M propranolol. 10(-6) M rhGRF slightly stimulated glucagon secretion in the presence of 16.7 mM glucose when STZ diabetic rat pancreas was perfused. rhGRF at the concentration of 10(-6) M enhanced somatostatin secretion stimulated with 16.7 mM glucose. We concluded that rhGRF stimulated insulin, glucagon and somatostatin secretion and the insulin secretion was inhibited by beta-blocker. hpGRF stimulated insulin and glucagon secretion as well.

OBJECTIVE To evaluate change both in lipoprotein(a) [Lp(a)] and lipid levels in other lipoproteins in non-insulin-dependent diabetes mellitus (NIDDM) after short-term improvement of glycemie control. RESEARCH DESIGN AND METHODS We compared Lp(a) levels in 210 NIDDM patients with those in 46 control subjects and evaluated the relationship between glycemie control and Lp(a) levels in diabetic patients. In addition, changes in Lp(a) levels and lipid levels were assessed after the improvement of glycemie control in 54 poorly controlled NIDDM patients. RESULTS In NIDDM, Lp(a) levels in all patients, 62 patients with HbA1c CONCLUSIONS These results suggest that elevated Lp(a) levels do not reflect poor glycemie control and that Lp(a) levels are independent of lipid levels in other lipoproteins after improved glycemie control in NIDDM.

OBJECTIVE To evaluate the effect of gastric emptying on postprandial insulinrequirement in insulin-dependent diabetes mellitus (IDDM) patients with and without gastroparesis. RESEARCH DESIGN AND METHODS Postprandial insulin requirement and gastric emptying were simultaneously evaluated in five IDDM patients with gastroparesis and in six control IDDM patients without gastroparesis. Postprandial insulin requirement after test-meal intake was assessed by measuring the insulin infusion rate during a 4-h feedback control with an artificial endocrine pancreas device (Biostator, Life Science Instruments, Miles, Elkhart, IN). Gastric solid and liquid emptyings were evaluated during the Biostator study by measuring the disappearance rate of 99mTc in the stomach and in the time course of plasma acetaminophen concentration, respectively. RESULTS Total insulin requirement during the first 120 min after the test-meal intake was significantly lower in the gastroparetic patients than in the control patients. The gastroparetic patients showed no apparent postprandial peak for insulin infusion rate during the 4-h study, although the peak rate was observed within 120 min after the test-meal intake in the control patients. The disappearance of 99mTc in the stomach was significantly slower, and plasma acetaminophen concentrations were significantlylower in the gastroparetic patients compared with those in the control patients, respectively. CONCLUSIONS The results suggest that IDDM patients with gastroparesis, accompanied by impaired solid and liquid emptying, have an altered postprandial insulin requirement.

Utilizing the push-pull perfusion technique, we examined the secretory profiles of neuropeptide Y (NPY) and luteinizing hormone (LH)-releasing hormone (LHRH) in the median eminence (ME) of ovariectomized adult rats which were primed with estrogen and progesterone to provoke LH and prolactin (PRL) surges. The ME was perfused with artificial cerebrospinal fluid between 13.00 and 18.00 h, and perfusates and blood samples were collected every 20 min. NPY and LHRH in the ME started to significantly increase 40 min earlier than the initial significant rise in the plasma LH, and the highest ME levels of the neuropeptides clearly preceded the occurrence of the LH surge. Regarding the PRL surge, however, such temporal relationship was not apparent. These in vivo data appear to support the putative facilitatory role of NPY in the generation of the steroid-induced LH surge. This is the first study to characterize the temporal profile of in vivo release of NPY in rat ME in terms of its relationship to LH and PRL surges.

We describe a case with unilateral chorea associated with thyrotoxicosis. A 23-year-old female with no family history of neurological diseases acutely developed choreic movements of the left extremities during gross thyrotoxicosis. CT scan and MRI study demonstrated no abnormality. Single-photon emission CT with technetium Tc 99m-labeled hexamethylpropyleneamine oxime revealed normal cerebral perfusion. Although the choreic movements were partially improved by dopamine antagonist, they persisted for two months until successful treatment of the thyrotoxicosis finally abolished these movements. Increased sensitivity of dopamine receptors may be responsible for persistent choreic movements in thyrotoxicosis.

The effects of 6 weeks of treatment with dilevalol 100 mg once daily, or carteolol 10 mg once daily, on renal blood flow (RBF), glomerular filtration rate (GFR) and total renal vascular resistance (TRR) were studied in 10 patients with mild-to-moderate essential hypertension in a randomised cross-over experiment. Both drugs lowered the systolic and diastolic blood pressures to a similar extent without altering the heart rate. Carteolol non-significantly decreased RBF by 9.2% and GFR by 12.3% without altering. TRR, whereas dilevalol produced a significant reduction in TRR by 13.2% (p less than 0.05), a non-significant decrease in RBF by 4.6% and no change in GFR. Neither drug changed plasma osmotic pressure, serum total protein concentration, electrolytes or plasma aldosterone concentration. Plasma renin activity tended to be lower in the dilevalol phase as compared to the carteolol phase. The results suggest that dilevalol may cause a greater decrease in TRR and less reduction in GFR when compared to carteolol in patients with mild-to-moderate essential hypertension. The difference in the renal effects might be due to the difference in the potency of vasodilatory properties of both drugs at the doses applied.