The intraperitoneal administration of the methanol extract of Polygonati Rhizoma (OM) into normal rats caused a significant decrease in the blood glucose level at 4h after its administration of 800 mg/kg (P<0.01), but not the serum insulin level. Using the perfused rat liver in vitro, a significant decrease of the hepatic glucose output was observed by the infusion of OM (P<0.05 at 250μg/ml OM). In addition, the hepatic content of facilitative glucose transporter isoform 2 (GLUT2) mRNA and its protein content in the total membrane fraction from rat liver significantly decreased in the intraperitoneally Om-treated rats when compared to that in the controls (mRNA P<0.01, protein P<0.001). On the other hand, OM (500μg/ml) exhibited no apparent stimulatory effect on the insulin secretion from the isolated rat pancreatic islets. These results suggest that the hypoglycemic effect of OM is derived, at least in part, from the decrease in hepatic glucose output, due presumably to the reduction of GLUT2 mRNA expression and its protein content in total membrane of the liver, and that because of its unique therapeutic mechanism, OM could be a new category of therapeutic agent for non-insulin-dependent diabetes mellitus.
We assessed the usefulness and reliability of computed tomography (CT scan) in evaluating adrenal hyperplasia in 38 patients, including 14 with Cushing's disease, 17 with idiopathic hyperaldosteronism (IHA), and 7 with the adrenogenital syndrome (AGS). Eighty-two normal subjects were also examined. We analyzed the shape of the adrenal gland and quantitated its thickness, widthand length. Visual inspection revealed V-shaped right adrenal glands in 100% of patients with Cushing's disease, 94% of patients with IHA, 100% of patients with AGS and in 41% of the normal subjects. Triangular left adrenal glands were observed in 100% of patients with Cushing's disease, 82% of patients with IHA, 67% of patients with AGS and in 12% of the normal subjects. Quantitative analysis showed that the right adrenal gland was significantly thicker and longer in patients with Cushing's disease, IHA and in those with AGS than in normal subjects. The right adrenal gland was significantly wider in the patients with Cushing's disease and AGS than in control subjects. The left adrenal gland was significantly wider and longer in patients with Cushing's disease and AGS than in the normal controls. Analysis of individual data indicated that the upper limit of normal for thickness of the right adrenal was 7 mm. Therefore, adrenal hyperplasia was strongly suggested when the right adrenal gland was more than 7mm thick. Our findings suggest that the CT scan is useful and reliable in diagnosing adrenal hyperplasia.
A 39-year-old woman with Sipple's syndrome and a malignant pheochromocytoma (PHE) is presented. She is a member of a big family with this syndrome and had undergone bilateral, subtotal adrenalectomy because of bilateral PHE six years prior to the present admission. In 1989, a small nodule was identified in her right thyroid lobe by ultrasonography and was suspected to be a medullary thyroid carcinoma (MTC). Further examinations revealed the coexistence of multiple lung and liver masses. These tumors were considered to be metastases of PHE because of the increased urinary excretion of catecholamines as well as extremely high catecholamines both in the hepatic venous blood and in the cystic fluid of the liver tumor even though there was no apparent recurrences of PHE in the adrenalregion. After surgical removal of the MTC in August, 1989, she was given 3.7 GBq of 131I-metaiodobenzyl guanidine (131I-MIBG) infusions twice-in October, 1989 and in August, 1990. 131I-MIBG showed a strong accumulation in the lung and liver masses on both occasions. Periodic increases in blood pressure and tachycardia with an excessive catecholamine secretion were observed over two weeks after the first treatment. However, this treatment was not effective in reducing urinary catecholamines nor the size of the metastatic tumors. She, therefore, underwent chemotherapy with cyclophosphamide, vincristine and dacarbazine in 1991, which slightly but significantly reduced urinary excretion of catecholamines and the size of the lung tumors. She had clinically stable period for one year after the treatment but rapid growth of these metastatic tumors occurred afterwards and she died in August, 1992. Unlike previous reports, 131I-MIBG therapy for malignant PHE was not as effective as expected but the patient showed a partial response to the combined chemotherapy.
Progestin supplementation has been advocated in estrogen treatment for postmenopausal women to avoid proliferation of the endometrium. In this study we investigated the morphologic and biochemical effects of progestins on the endometrium of estrogen primed, ovariectomized rats. As the progestin derivatives, Allylestenol (AE), Norethisterone (NE), Danazol (DZ), Dydrogesterone (DG), Medroxyprogesterone acetate (MPA) and Cyproterone acetate (CPA), and as a anti-estrogen compound, Tamoxifen (TMX), were applied. To evaluate the effects of these different compounds on the endometrium, histologic studies and measurement of estrogen receptor concentrations were performed. When 19-nortestosterone groups, AE, DZ and NE, were orally administered to the conjugated equine estrogen (CE) treated, ovariectomized rats, the histologic pattern of the endometrium revealed rather a marked inhibition of hyperplasia induced by CE than a progestational response. Two of 3 of 17α-hydroxyprogesterone groups, DG and MPA, provided slightly endometrial protection against the hyperplastic response, but another one, CPA, did not have any inhibitory effect on the estrogenic stimulation of the endometrium. TMX was not capable of suppressing the endometrial hyperplasia caused by CE administration. The average plasma concentrations of estradiol (E2) were 82.0±27.0pg/ml (Mean±SD) after CE administration and there were no significant differences among these groups. Estrogen receptor concentrations of endometrium of progestins or antiestrogen added groups were not changed, when comparedwith the CE alone group. There was also no relationship between the estrogen receptor concentrations and the histologic findings in the endometrium. This discrepancy may be chiefly due to the low dose of the progestins as compared with the CE dose. In view of the morphologic findings for the endometrium, this study suggests that opposed estrogen treatment with 19-nortestosterone derivatives provides the most satisfactory endometrial protection against hyperplasia.
The female patient in this report was suffering from a pancreatic islet cell tumor which exhibited ectopic ACTH syndrome associated with Zollinger-Ellison syndrome. When this combined syndrome was diagnosed, there were already multiple metastasis to the liver. Zollinger-Ellison syndrome was treated with a histamine-H2-receptor blocker, and ectopic ACTH syndrome was controlled with trilostane, metyrapone and o, p'-DDD. She survived more than 6years after the diagnosis, mostly as an outpatient. During treatment she became cachexic. After she died, an autopsy was done. Immunohistochemical staining established that tumor cells contained ACTH- and gastrin-like immunoreactivity. Our treatment suggested the efficacy of chemical adrenalectomy in managing ectopic ACTH syndrome associated with Zollinger-Ellison syndrome.
We present a patient with Cushing's syndrome due to adrenocortical adenoma who developed acute adrenal insufficiency one month after unilateral adrenalectomy. She had received lithium carbonate for five years for manic-depressive psychosis. Drug administration was interrupted for 2 weeks postoperatively and was resumed thereafter. At the adrenal crisis, her serum free T4 and T3 levels were both high and serum TSH was subnormal. The thyrotoxicosis subsided spontaneously within 2weeks. Serum thyroglobulin was markedly increased during the thyrotoxic state. Tests for antimicrosomal antibodies and antithyroglobulin antibodies remained negative. Examination of an open-biopsy specimen of the thyroid gland showed no evidence of thyroiditis. We considered the transient thyrotoxicosis to be due to lithium-induced thyrotoxicosis. Caution should therefore be exercised in administering lithium carbonate, especially when the patient's adrenal reserve is low, since even a mild degree of thyrotoxicosis can precipitate an acute adrenal crisis.
Since insulin negatively controls its own secretion, we examined if insulin also inhibits the secretion of its precursor, proinsulin, in subjects with varying degrees of glucose tolerance. Under comparable hyperinsulinemia (50-70μU/ml) achieved by the euglycemic insulin clamp technique, plasma C-peptide concentrations were equally suppressed to approximately 40-50% in nonobese subjects with normal glucose tolerance (NGT) (n=13, 35.5±3.7%, M±SEM), borderline glucose intolerance (BGI) (n=12, 46.7±5.6%), and non-insulin-dependent diabetes mellitus (NIDDM) (n=12, 48.9±5.4%). In contrast, plasma proinsulin concentrations were slightly but significantly suppressed in NGT (4.1±0.2 to 3.7 ±0.2 pmol/L, P<0.05), but not in patients with BGI (4.6±0.3 to 4.8±0.5 pmol/L, NS) and NIDDM (5.5 ±0.5 to 4.9±0.4 pmol/L, NS). The basal concentrations of proinsulin increased as glucose tolerance declined (P<0.05 between NGT and NIDDM). These results suggest that the basal secretion of proinsulin by beta-cells seems relatively insensitive to insulin compared with C-peptide, and that the insulin-proinsulin feedback loop is disturbed in glucoseintolerant subjects. Therefore, a defective feedback inhibition of proinsulin secretion by insulin may be partly involved in the disproportionate increase of plasma proinsulin concentrations in patients with NIDDM.
Bradykinin is recognized to be involved in the process of bone resorption in chronic inflammatory diseases. We previously reported that prostaglandin E2 (PGE2), known as a potent bone resorbing agent, induces phosphoinositide hydrolysis, cAMP production and Ca2+ influx in osteoblast-like MC3T3-E1 cells, and these dose-dependencies are different to one another. To clarify the signaling mechanism of bradykinin, we compared the intracellular signaling system of bradykinin with that of PGE2 in these cells. Bradykinin stimulated Ca2+ influx dose-dependently in the range between 0.1nM and 0.1μM even in the presence of nifedipine, a Ca2+ antagonist that inhibits the voltage-dependent L-type Ca2+ channel. The maximum effect of bradykinin (0.1μM) on Ca2+ influx was almost as great as that of PGE2 (0.5μM). Bradykinin had little effect on cAMP accumulation, while PGE2 significantly stimulated it. Bradykinin stimulated the formation of inositol phosphates much less strongly than PGE2. Bradykinin stimulated inositol 1, 4, 5-trisphosphate [Ins(1, 4, 5)P3] formation dose-dependently between 0.1nM and 0.1μM, and the dose-dependent curves of bradykinin-induced Ca2+ influx and Ins(1, 4, 5)P3 were similar. However, the maximum effect of PGE2 (10μM) on Ins (1, 4, 5) P3 formation was about 2-fold higher than that of bradykinin (0.1μM). These results suggest that bradykinin induces Ca2+ influx independent of the voltage-dependent L-type Ca2+ channel and phosphoinositide hydrolysis in a similar dose-dependent manner in osteoblast-like cells.
The effect of plasma glucose and nonesterified fatty acid (NEFA) on basal and insulin-stimulated glucose utilization in skeletal muscle was assessed by perfused hindlimb preparations. Two-month-old male Wistar rats were divided into four groups: starved, glucose-loaded, hypoglycemic and control. Diabetic rats were made by means of streptozotocin, and divided into three groups: non-treated, insulin-treated normoglycemic and insulin-treated hyperglycemic. The effect of NEFA on glucose clearance was also investigated by adding palmitate to the perfusate. Basal glucose utilization decreased with a rise in plasma glucose concentrations, and increased with a fall in them in each group. The available data strongly support the view that plasma glucose levels play an important role in the control of basal glucose utilization by the hindlimb muscle. In contrast, continuous hyperglycemia in the diabetic state decreased insulin-stimulated glucose utilization by the skeletal muscle, whereas an acute rise in plasma glucose concentrations in the glucose-load state did not. Palmitate stimulated basal glucose utilization, while it decreased insulin-stimulated glucose uptake. It was also clarified that it increased the affinity for glucose in the skeletal muscle in the basal state. This finding seems to indicate that NEFA has some influence on an increase in basal glucose utilization in starvation.
Effects of prolactin and bromocryptine on neutral and phospholipids of liver, adipose tissue and serum were studied in mature male bonnet monkeys. Hyperprolactinemia (ovine prolactin, 250μg/kg body weight/day, i.p. for 30days) elevated hepatic total lipids and phospholipids and decreased total and free cholesterol. While triacyl glycerol accumulated, mono-and diacyl glycerols diminished in liver and adipose tissues of prolactin treated monkeys. Concentrations of all phospholipid fractions, except sphingomyelin and cardiolipin in adipose tissue accrued in both tissues. Serum triacylglycerol, phosphatidyl ethanolamine, phosphatidyl choline and phosphatidyl inositol showed a significant increase in hyperprolactinaemic monkeys. Bromocryptine (1mg/kg body weight/day for 30days) treatment reduced serum phospholipids without altering hepatic or adipose tissue lipids. The present study indicates that hyperprolactinaemia leads to hyperlipidemia due to accretion of hepatic and adipose tissue triacyl glycerol and certain phospholipid fractions. Bromocryptine has a specific inhibitory effect on serum phospholipids.
A patient with 17α-hydroxylase deficiency (17OHD) who continued to menstruate is reported. A 24-year-old woman who presented with hypertension, hypokalemia and irregular menses had increased plasma ACTH and mineralocorticoids without any increase in glucocorticoids or sex steroids, and a bilateral adrenal enlargement on abdominal X-ray CT. ACTH stimulation test revealed hyperresponse of the metabolites of the mineralocorticoid pathway and blunted or absent response of those of the glucocorticoid and androgen pathway. Almost all of the abnormalities disappeared after dexamethasone administration. While 17OHD is usually known to accompany hypergonadotropic hypogonadism, the patient continued to menstruate, though irregularly. Although human chorionic gonadotropin administration failed to induce response, basal plasma levels of ovarian steroid (estradiol) and gonadotropins as well as response to LHRH stimulation test were all normal. Thus, the clinical and biochemical features of this case is compatible with the partial deficiency of both adrenals and ovaries, being less severe in the latter. A further analysis especially at molecular level is needed to elucidate the basis for the heterogeneity of this disorder.