IDDM is caused by autoimmune destruction of insulin-producing β cells of the pancreas in genetically susceptible individuals. Although the incidence and prevalence of IDDM in Japan are much lower than those in Caucasian countries, the recurrence risk in siblings of IDDM probands is much higher than the population prevalence, indicating that IDDM is clustered in families even in Japan, where the incidence of the disease is the lowest in the world. The higher concordance rate in monozygotic twins than in dizygotic twins indicates that genetic factors contribute to the familial clustering of IDDM in Japan. Analysis of the HLA region revealed that susceptibility genes (IDDM1) consist of multiple components, those in class II DR and DQ regions and another in the class I region. Analysis in NOD mice, an animal model of IDDM, supports this observation: susceptibility genes (Idd1) are mapped to class II A and E regions, but the incidence of the disease is strongly affected by a gene or genes outside of this segment (Idd16). Studies in both humans and an animal model will clarify the genetic components of IDDM, facilitating prediction of the disease and the development of effective strategies for its prevention.
Sera from 30 Japanese insulin-dependent diabetes mellitus (IDDM) patients of short duration were examined to determine whether they had antibodies to proteolytic fragments of islet antigen, the molecular weights of which were 37, 000 and/or 40, 000 Mr (37KAb). The median age and disease duration of the patients were 13 (range; 6-22) years old and 12 (range; 0-24) months, respectively. Twelve out of the 30 IDDM patients (40%) had 37KAb, while none of the 16 control subjects was positive for 37KAb. The frequency of the 37KAb was not correlated with disease duration tested. We further investigated the antibodies to ICA512, by radioligand binding assay, which has been proposed to be a target antigen for the 37KAb. Twenty-two (73.3%) patients had antibodies to ICA512 (ICA512AA), but none of the control subjects did. The levels of ICA512AA, which were described as indexes using standard sera, were significantly higher in the patients than in the control subjects (1.436±2.674 and 0.001±0.002, respectively, P<0.05). The frequency of antibodies to glutamic acid decarboxylase 65 (GAD65Ab) was also higher in the patients than in the control subjects (70% and 0%, respectively), but 7 out of 9 GAD65Ab-negative patients had ICA512AA and/or 37KAb. Since 93% of the IDDM patients had at least one of these antibodies, combined analysis with 37KAb, ICA512AA, and GAD65Ab facilitates diagnosis of Japanese IDDM.
To analyze direct effects of estrogen on gene expressions of Inhibin subunits in vitro, the mRNA levels of inhibin a- and βA-subunits were measured in rat granulosa cells cultured with FSH or estradiol. Through the culture process of the granulosa cells with serum-free medium, both the α- and βA subunit mRNAs decreased, and were partially increased again by adding FSH to the culture medium. To examine whether these FSH effects are mediated via estrogen production, estradiol or tamoxifen was added to the cultured granulosa cells. After 36-h culture with estradiol, the inhibin α-subunit decreased but the Inhibin βA-subunit increased, in a dose-responsive manner. Tamoxifen showed completely opposite effects to estradiol, and a combination of estradiol and tamoxifen resulted in similar levels of inhibin-α and -βA mRNAs to the control. These results indicate that estrogen would by a certain pathway affect gene expressions of the inhibin subunits in the rat granulosa cells, and may regulate the production of inhibin and activin through the paracrine system.
Stressful stimuli induce the transcriptional activation of the corticotropin-releasing factor (CRF) gene as well as that of various immediate-early genes (IEGs). Among them, members of the fos/ jun families play an important role in the regulation of gene expression. The possible relation between stress-induced IEG expression and CRF gene transcription was investigated by analysis of stressinduced changes in the abundance of c-fos, c jun, jun-B, jun-D, and NGFI-B mRNA as well as CRF heteronuclear RNA (hnRNA), which reflects gene transcription, in the rat paraventricular nucleus (PVN) by in situ hybridization. Restraint stress induced rapid (within 5min) and transient increases in the level of c-fos mRNA and CRF hnRNA in the PVN, with peak expression apparent 30min after the onset of stress. The induction of jun-B and NGFI-B gene expression was also rapid and transient, but was delayed relative to that of c-fos mRNA and the CRF hnRNA. In contrast, both jun-D and c-jun were constitutively expressed in the PVN, and the amount of the corresponding transcripts increased only slightly in response to stress. These results reveal differential patterns of expression of IEGs in the PVN in response to stress. The observation that the level of mRNAs corresponding to these IEGs did not increase before that of CRF hnRNA may suggest that the products of these genes do not seem to directly mediate the stress-induced increase in CRF gene transcription in the PVN.
The C-peptide suppression test employing the euglycemic hyperinsulinemic clamp technique has been proposed as a useful diagnostic measure for insulinoma. To examine the specificity of the C- peptide suppression, we applied this test to subjects with symptoms suggesting reactive hypoglycemia. Five subjects studied had never experienced fasting hypoglycemia, and were negative in ultrasound, CT and MRI of the pancreas. Plasma C-peptide was not suppressed by physiological (50-100μU/ml) and supraphysiological (200-500μU/ml) hyperinsulinemia (% of baseline: 97.3±8.6% and 90.6±10.4%, ± SEM, respectively, both NS). Three subjects were re-examined one year later, when their hypoglycemic episodes were noticeably attenuated. No significant suppression was found. Significant suppression was observed when plasma glucose was clamped at 50-60mg/dl in four of five subjects (61.7±11.5%, P<0.05), but one subject responded to neither higher plasma insulin nor low-normal glucose. In contrast, normal glucose tolerance (n=13), IGT (n=12) and obese NIDDM (n=31) subjects showed highly significant suppression during euglycemic and physiological hyperinsulinemia (37.1 ±3.8%, 46.3±5.6%, 39.9±2.6%, respectively, all P<0.001). In conclusion, the results of the present study indicate that a failure of hyperinsulinemic suppression of C-peptide in euglycemia is not specific for insulinoma, and that suppression of C-peptide by insulin at lower plasma glucose levels (50-60mg/dl) would be a better diagnostic test.
Carbohydrate and lipid metabolism was cross-sectionally assessed in 16 patients with endogenous hypercortisolism (endogenous Cushing syndrome). Five patients (31%) had fasting glucose levels over 6.6mmol/l and a HbA1C over 7.5%. Six patients (38%) had diabetes mellitus based on an abnormal 75g oral glucose tolerance test (OGTT) and two additional patients (13%) had impaired glucose tolerance based on an OGTT. Compared to obese individuals, patients with Cushing syndrome had an elevated glucose but no elevated insulin response to the OGTT. Regression analysis showed positive correlations between 24-h urinary free cortisol (UFC) and fasting blood glucose (P<0.0005), UFC and OGTT glucose area under the curve (AUC) (P<0.01), and UFC and HbAlc (P<0.005). UFC levels were negatively correlated (P<0.05) with OGTT insulin AUC and insulin/glucose ratios. Eleven (69%) patients required anti-hypertensive therapy for blood pressure control. Total cholesterol and triglycerides were elevated in patients with Cushing syndrome compared to obese controls, while LDL and HDL cholesterol, and Lp(a) were similar in the two groups. We conclude that impaired glucose tolerance and/or diabetes in patients with endogenous Cushing syndrome is due to the hyperglycemic effects of cortisol with relative insulinopenia. Thus, Cushing syndrome shares features with both the Metabolic Syndrome X and NIDDM, including impaired glucose uptake, hyperlipidemia and hypertension. However, in Cushing syndrome, a relative insulinopenia occurs, while in Metabolic Syndrome X and NIDDM, insulin excess is observed. In Cushing syndrome, as the hypercortisolemia exacerbates, insulinopenia becomes more paramount, suggesting that cortisol exerts a direct or indirect “toxic” effect on the β-cell.
The aim of this study was to evaluate the relationship between subclinical hypothyroidism and/or autoimmune thyroid disease and coronary heart disease (CHD). Ninety seven patients diagnosed as having CHD by a coronary angiography (CHD group) and 103 healthy subjects matched for age, sex and body mass index (control group) were included in the study. Thyroid function, thyroid autoantibodies and serum lipid concentrations were measured in the CHD and control groups. The CHD group exhibited significantly decreased serum free T3 (FT3) and free T4 (FT4) levels, and significantly increased serum TSH levels as compared with the control group, indicating a significant decrease in thyroid function in the CHD patients. Serum high density lipoprotein cholesterol (HDL-C) levels were significantly decreased in the CHD group. The incidence of subclinical hypothyroidism and thyroid autoantibodies was similar in both two groups. These observations were also true of women even after those who had diabetes mellitus (DM), hypertension (HT) and a smoking habit were excluded. This was not the case, however, in men without DM, HT, or a smoking habit. Patients with CHD had significantly lower serum levels of HDL-C than the control subjects, regardless of gender (P<0.01). In the group with CHD, there was no difference between the serum lipid levels in patients with subclinical hypothyroidism and those with normal thyroid function. Female patients with CHD had significantly lower serum levels of thyroid hormone and HDL-C, but their subclinical hypothyroidism or thyroid autoimmunity did not seem to be related to the development of CHD.
Unexplained high serum corticosteroid-binding globulin (CBG) concentrations (mean±SD, 74.1±12.1μg/dl; normal women, 32.5±5.6μg/dl) were found in an unmarried woman who was not pregnant or taking exogenous estrogens. She was also found to suffer from subclinical chronic thyroiditis, pituitary adenoma and empty sella. The increased serum CBG concentrations in this patient were not due to any of the factors known to increase CBG. Consistently high basal serum GH levels and unusual GH responses to GH-releasing factor (GRF) and L -dopa were also noted.
The present investigations were performed in order to clarify the effects of mazindol on body weight and insulin sensitivity in patients with morbid obesity who had already been treated with a verylow- calorie diet containing 480kcal food (VLCD) with various amino acids. We attempted to study whether a further decrease in body weight would be achieved by the administration of mazindol, because it is difficult to obtain sufficient and continuous reduction of body weight after VLCD therapy. Thirteen female severely obese subjects were 51.0±13.9 years old (25-73 years old), with a mean height of 154.7±5.6cm (146.0-160.5cm), mean weight of 84.5±9.4kg (69-98kg) and a mean body mass index (BMI) of 35.3±3.6kg/m2 (29.2-41.0kg/m2). Their mean body weight decreased to 76.7±2.2kg (net decrease: 6.3±0.9kg) after VLCD therapy for 2-4 weeks. Then they were treated by the administration of mazindol with diet restriction (1000-1200kal/day). Mazindol administration resulted in a further weight reduction of 2.9±0.5kg after 4 weeks, 4.9±0.5kg after 8 weeks and 6.9±0.9kg after 12 weeks. Their blood pressure was not changed after mazindol treatment. The responses of blood glucose and insulin levels in a 75g oral glucose tolerance test (OGTT) were not significantly different before and after mazindol administration. The blood glucose area calculated from the data obtained during OGTT for 120min did not significantly differ before and after mazindol administration, while the insulin area significantly decreased after mazindol treatment (from 98.0±12.1 before administration to 70.1±7.8). The mean M value reflecting insulin sensitivity in the whole body determined by euglycemic glucose clamping was increased significantly after mazindol treatment (from 4.92±0.30mg/kg/min to 6.36± 0.43mg/kg/min). The results demonstrated that mazindol administration with diet restriction further reduced body weight in the morbidly obese subjects after treatment with VLCD, with an increase in the M value and a decrease in insulin release. The results suggest that mazindol is useful for reducing body weight as well as improving insulin sensitivity.
The effects of thyroidectomy on patterns of TRH and somatotropin release-inhibiting factor (SRIF) release from the hypothalamus were investigated by using a microdialysis technique. Thyroidectomized and sham-operated rats underwent placement of a guide cannula into the anterior pituitary gland to obtain dialysates, or implantation of an intravenous cannula into the right atrium for blood sampling. Seven days postoperatively dialysates were collected at a flow rate of 2μl/min every 1 h. TRH concentrations in dialysates from thyroidectomized rats (0.43±0.22pg/h) were significantly higher than those from control rats (0.17±0.02pg/h). In contrast, SRIF concentrations in dialysates from thyroidectomized rats (2.45±0.05pg/h) were significantly lower than those from control rats (3.80 ±0.22pg/h). In addition, plasma TSH concentrations in thyroidectomized rats (24.8±0.5ng/ml) were increased compared with those in control rats (2.5±0.1ng/ml), and plasma GH concentrations were decreased from 68.6±6.4ng/ml in control rats to 21.2±0.6ng/ml in thyroidectomized rats. These findings indicate that TRH and SRIF releases from the hypothalamus are detectable by microdialysis method, and directly show the increase in TRH secretion and the decrease in SRIF secretion from hypothalamus in the hypothyroid state.
To evaluate the efficacy of high-dose intravenous steroid pulse followed by oral steroids in the treatment of thyroid-associated ophthalmopathy, we performed clinical assessment and measurement of retroorbital muscle enlargement in 27 patients before and after the therapy, and followed them up longitudinally. The mean duration of follow up is (mean±SD) 29.8±23.8 months (range 4-92). Diplopia disappeared in 10 patients and ameliorated in 11 patients. The degree of proptosis decreased in 15 patients and the fall in visual acuity improved in a third of the patients. The total ophthalmopathy index (OI) decreased from 7.0±1.9 to 3.0±1.5. The extraocular muscle enlargement (EME), expressed as the maximal ratio of extraocular muscle thickness to the diameter of the optic nerve, decreased from 2.33 ±0.56 to 1.27±0.26. No major side effects were found in any patient. The improvement in the eye disease was found immediately after the pulse therapy, prior to the start of the following therapy by oral steroids and/or orbital irradiation. Both of OI and EME decreased with time after the therapy and did not get worse after withdrawing oral steroids. The efficacy of the therapy evaluated by degrees of improvement in OI and in EME was significantly greater in females than in males. Although there was a significant positive correlation between initial OI and EME values and initial TBII and TSAb activities, a significant correlation was seen only between the degrees of improvement in EME and changes in TBII activity due to the therapy. The duration of eye disease, thyroid status, treatment with anti-thyroid drug, smoking and experience of previous treatment did not affect the efficacy of the present therapy. We conclude that high-dose intravenous steroid pulse therapy is effective and safe for thyroid-associated ophthalmopathy.
We measured serum levels of the carboxy-terminal propeptide of type 1 procollagen (P1CP) as a marker of bone formation and the carboxy-terminal telopeptide of type 1 collagen (1CTP) as a marker of bone resorption by RIA in sera from 40 Graves' disease patients and 14 Hashimoto's disease patients before and during treatment. The serum P1CP levels of the untreated Graves' disease were significantly higher than in the controls (176.8±93.5 vs. 107±35ng/ml, P<0.01), and these levels decreased significantly during treatment with antithyroid drugs. There was a significant statistical correlation between serum P1CP levels and serum total alkaline-phosphatase activity (r=0.61, P<0.01) in the patients with Graves' disease and Hashimoto's disease as a whole. 1CTP levels were also significantly increased in untreated Graves' patients (6.5±2.8 compared with 2.7±1.1ng/ml in normal subjects, P<0.01). The P1CP/1CTP ratio, which reflects the relative ratio of bone formation to bone resorption, was lower than normal in untreated Graves' disease, but increased following the normalization of thyroid function. The results of this study suggest that the measurement of serum P1CP and 1CTP levels may be useful in evaluating bone metabolism in thyroid disease.
Adhesion molecules relate to cell invasion of autoimmune thyroid disease. We studied plasma soluble P-Selectin (platelet activation-dependent granule-external membrane protein), E-Selectin (endothelial leukocyte adhesion molecule) and L-Selectin (leukocyte endothelial cell adhesion molecule- 1) levels in patients with Graves' disease before and during methimazole treatment. Plasma P-, E- and L-Selectin levels in patients with untreated Graves' disease were significantly higher than those in normal subjects. Plasma P-Selectin levels decreased when their thyroid functions were normal for more than 6 months after the start of methimazole treatment. No significant change in plasma E- and L- Selectin levels in patients with Graves' disease was found between hyperthyroid state and euthyroid state after the start of methimazole treatment, but plasma L-Selectin levels in patients with untreated Graves' disease were significantly lower than those in the patients in the first euthyroid state. There was no significant correlation between plasma P-Selectin levels and serum FT4 levels, nor between plasma P- Selectin levels and serum FT3 levels. These results suggested that thyroid hormones might reflect expression of P-, L- and E-Selectin from endothelial cells, or lymphocytes, or platelets in patients with Graves' disease.
We encountered a 91-year-old patient with acromegalic features. The serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) were increased to 23.3ng/ml and to 268ng/ml, respectively. Both thyrotropin-releasing hormone and luteinizing hormone-releasing hormone tests demonstrated a 2-3 fold increase in the serum GH level. Magnetic resonance imaging disclosed a pituitary mass in the enlarged sella. The patient was diagnosed as having acromegaly due to overproduction of GH from a pituitary tumor. She manifested cardiac hypertrophy with severe aortic stenosis and mild hypertension, but without diabetes mellitus. After the administration of octreotide subcutaneously at a dose of 25 to 50μg daily for 20 days, the serum GH level increased transiently but decreased rapidly to approximately half the initial level, and suppression of the GH level persisted thereafter for over 2.5 months. This patient seems to be the oldest patient with acromegaly among those reported in Japan.
A 46-year-old man was found to have numerous cerebellar hemangioblastomas on magnetic resonance imaging (MRI). He denied any symptoms and had no history of hypertension, but his family history was remarkable for a father who died of renal cell carcinoma. Computed tomography (CT) of the abdomen revealed bilateral adrenal pheochromocytomas with significant enhancement in the regions where 131I-metaiodobenzylguanidine (MIBG) had noticeably accumulated. Endocrinological examinations demonstrated high plasma and urine catecholamine concentrations which were very responsive to metoclopramide and glucagon loading tests, without a significant change in blood pressure. After resection of bilateral pheochromocytomas, he underwent an operation for the cerebellar tumors. Since pheochromocytomas associated with Lindau or von Hippel-Lindau (VHL) disease have a tendency to multiple occurrence in normotensive patients, we suggest that patients with a family history involving VHL lesions should undergo cranial MRI, abdominal CT, MIBG scintigraphy and endocrinological examinations.
Aminoguanidine (AG) is a potential therapeutic agent for preventing the generation of advanced glycation end products in diabetes mellitus. In this study, the effects of AG on glucagon and insulin secretion in in vitro rat pancreatic islets were investigated. The islets were aseptically isolated and cultured in tissue culture medium 199 for 48h with or without 9.1mM AG (1mg/ml). After the culture, 50 islets were perifused in Krebs-Ringer bicarbonate buffer containing 20mM arginine or 1U/ ml pancreozymin in the presence of 3.3mM glucose. Islets previously exposed to AG showed similar glucagon response to control islets at a 20mM arginine concentration, and insulin response, too. Glucagon release caused by 1U/ml pancreozymin from the islets previously exposed to AG was also not different from that of the control islets, but the release of insulin was much lower than that of control. These results suggest that AG would not be toxic to a-cells but toxic to β-cells at high concentrations, although there is slightly different sensitivity to β-cell secretagogues.
Subclinical hypothyroidism is a frequent disorder in populations and has been shown to be a risk factor for coronary heart disease (CHD). Less is known about the contribution of lipoprotein (a) [Lp(a)] to the development of CHD in this disorder. Therefore this study was designed to evaluate Lp(a) and other lipoprotein concentrations before and after L-T4 therapy in 20 patients with subclinical hypothyroidism and 20 normal healthy subjects matched for sex, age and BMI. In the basal state of subclinical hypothyroidism, a significant increase in total cholesterol, LDL-cholesterol and apolipoprotein (apo) B concentrations was observed in patients compared with those in the control group. The mean Lp(a) concentration before treatment was 163±15mg/L. This is slightly but not significantly higher than those in the control group (131±15mg/L). Treatment of subclinical hypothyroidism with a low dose of L-T4 (25μg daily) for 3 months after restoration of euthyroidism led to decreases in levels of Lp(a) from 163mg/L to 126mg/L (23% reduction, P<0.001), total cholesterol from 5.5mmol/L to 5.1mmol/L (7% reduction, P<0.001), LDL-cholesterol from 4.14mmol/L to 3.63 mmol/L (12%, P<0.001), and apo B from 98mg/dL to 86 mg/dL (12% reduction, P<0.05), but triglyceride, HDL-cholesterol and apo A-I concentrations were unchanged. These data suggest that L-T4 replacement therapy in patients with subclinical hypothyroidism has beneficial effects on the lipid profile since L-T4 replacement therapy lowered the concentrations of Lp(a) and other atherogenic lipid particles.
Estrogen provides beneficial effects on hyperlipidemia in climacteric and elderly women. In this study of 68 women (37 to 67 years old), hepatic triglyceride lipase (HTGL), lipoprotein lipase (LpL) serum lipids and apolipoproteins were analyzed to investigate the effects of estrogen replacement therapy (ERT). After menopause, LpL, total choresterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B increased. But ERT suppressed total cholesterol, LDL-cholesterol, apolipoprotein B, and especially apolipoprotein E in menopausal women. The mechanism was thought that ERT significantly suppressed HTGL, but LpL was not affected. Estrogen also increases hepatic LDL receptors and accelerates transfer of serum LDL-C (and TC). It was said that HTGL accelerates conversion of intermediate-density lipoprotein (IDL) to LDL. The suppression of HTGL by the ERT may decrease conversion of IDL to LDL and lower LDL-C (and TC). These estrogen's beneficial effects on lipids, may prevent the atherosclerosis. In addition, apolipoprotein E increases senile plaques in senile dementia-Alzheimer's type. The decrease in apolipoprotein E with ERT may be related to cognitive functions of elderly women.
We report herein a case of hyperthyroid Graves' disease developed from asymptomatic autoimmune thyroiditis (AAT). A 25-year-old single female with AAT was followed up for over 3 years. Thereafter her condition progressed to hyperthyroidism with both positive TSH receptor antibodies (TRAb) and an increase in antithyroidal antibodies. It is possible that there was continuous destruction of thyroid epithelial cells without a hyperthyroid state, followed by production of TRAb, although Graves' disease very rarely develops from destructive thyroiditis including AAT.