The islet contains a dense vascular structure of several features. The expression of vascular endothelial growth factor (VEGF)-A in beta cells is indispensable for the formation of this structure. Thus, the beta cell-specific VEGF-A-deficient mouse (RIP-Cre:Vegffl/fl) is useful for studying the role of the islet vasculature on the function of islets and regulation of beta cell mass. Studies using RIP-Cre:Vegffl/fl mice revealed that defects in the normal vascular structure are associated with abnormal insulin secretion and concluded that the islet vascular system is essential for normal insulin secretion into the blood stream. On the other hand, whereas the endothelial cells might be involved in regulation of islet mass and the mouse model of diabetes shows that the number of endothelial cells correlate with the islet mass, RIP-Cre:Vegffl/fl mice show almost normal response of islet expansion in the presence of insulin resistance. However, whereas bone marrow transplantation induces islet expansion in control mice, it does not induce the proper expansion of beta cell mass in RIP-Cre:Vegffl/fl mice. These data indicate that the roles of VEGF-A and islet vasculature in the regulation of beta cell mass depends on the stimulus for the islets.
Tumor necrosis factor-α (TNF-α) in placenta is believed to be involved in pathogenesis of intrauterine growth restriction. In contrast, insulin-like growth factors (IGFs) are believed to be important for stimulation of fetal and placental growth. IGF-I stimulates metabolic and growth-promoting actions directly through its receptors: IGF-I receptor (IGF-IR), insulin receptor (IR) and IGF-I/insulin hybrid receptor (HR). However, it has not been elucidated which receptor mediates the growth promoting effects in fetal and placental growth. The current studies were undertaken to test whether TNF-α affects IGF-I action on placenta using human trophoblast cell cultures, and to test which receptor mediates growth promoting effects of IGF-I in placenta. Primary culture of trophoblast cells, which express IGF-IR, IR, and HR, were exposed to TNF-α, and the effects of IGF-I in stimulating trophoblast cell proliferation and migration were determined. Exposure to TNF-α attenuated the effects of IGF-I on cell proliferation and migration. To determine which receptors are involved in this inhibitory effect, the ability of IGF-I to stimulate phosphorylation of its receptors was analyzed in the presence of TNF-α. TNF-α exposure neither attenuated the phosphorylation of IGF-IR homodimer by IGF-I nor changed receptor abundance. In contrast, TNF-α reduced the ability of IGF-I to stimulate phosphorylation of HR with reducing amounts of HR. Exposure to TNF-α also attenuated phosphorylation of insulin receptor substrate-1 (IRS-1) and the association of IRS-1 with phosphatydilinositol-3 kinase (PI-3 kinase). Taken together, these findings indicate that TNF-α induces a loss of sensitivity to stimulation by IGF-I, through reducing amounts of HR and the stimulation of HR tyrosine kinase activity by IGF-I.
Although hyperandrogenism is an important condition and is considered the possible pathogenesis behind polycystic ovary syndrome (PCOS), data supporting this is still scarce. We sought to determine whether or not prenatal androgen exposure leads to PCOS and the possible cellular mechanisms involved. To induce prenatal androgen exposure, pregnant rats were treated with daily subcutaneous injections of free testosterone (T) or dihydrotestosterone (DHT) from embryonic days 16 to 19, and their female offspring were studied as adults. The mRNA expression of the progesterone receptor (PR) in the preoptic area (POA) hypothalamus was higher in the experimental groups than in the control group after ovariectomy and stimulation with estradiol benzoate. The levels of T, P, leutinizing hormone (LH), and estradiol were higher in the experimental groups than in the control groups. The frequency and magnitude of LH secretion was increased in experimental rats as compared with the control group. The anogenital distance of the experimental groups was prolonged and the nipple number was lower than that of the control group. Almost all experimental rats had prolonged or irregular estrous cycles. The experimental groups had fewer corpus luteum and preovulatory follicles and more preantral follicles and antral follicles than the controls. Our findings are consistent with the hypothesis that excess androgen during the prenatal period may cause PCOS. Additionally, we show that hyperandrogenic interference in the release of preovulatory LH surges is mediated by the suppressive effects of androgens on PR expression in POA-hypothalamic tissue.
Fulminant type 1 diabetes, established in 2000, is defined as a novel subtype of diabetes mellitus that results from remarkably acute and almost complete destruction of pancreatic beta cells at the disease onset. In this study, we aimed to clarify the pathogenesis of fulminant type 1 diabetes with special reference to insulitis and viral infection. We examined pancreatic autopsy samples from three patients who had died soon after the onset of disease and analyzed these by immunohistochemistry and in situ-hybridization. The results were that both beta and alpha cell areas were significantly decreased in comparison with those of normal controls. Mean beta cell area of the patients just after the onset was only 0.00256 % while that of normal control was 1.745 %. Macrophages and T cells-but no natural killer cells-had infiltrated the islets and the exocrine pancreas. Although both of them had massively infiltrated, macrophages dominated islet infiltration and were detected in 92.6 % of the patients' islets. Toll-like receptor (TLR) 3, a sensor of viral components, was detected in 84.7± 7.0 % of T cells and 62.7± 32.3 % of macrophages (mean± SD) in all three patients. TLR7 and TLR9 were also detected in the pancreas of all three patients. Enterovirus RNA was detected in beta-cell positive islets in one of the three patients by in situ-hybridization. In conclusion, our results suggest that macrophage-dominated insulitis rather than T cell autoimmunity contributes to beta cell destruction in fulminant type 1 diabetes.
Serum levels of insulin-like growth factor-1(IGF-1) and insulin-like growth factor binding protein-3(IGFBP-3) reflect endogenous growth hormone secretion, and serum IGF-1 and IGFBP-3 values should be ethnic-specific, thus we established the reference ranges for serum IGF-1 and IGFBP-3 in Chinese children aged 6-18 yr according to age, sex, puberty stage and BMI. The study was included 837 children (age 6-18 yr, 416 boys and 421 girls) from different schools in Daqing, Beijing and Shanghai. Serum IGF-1 and IGFBP-3 were determined by a chemiluminescent assay system (IMMULITE 1000). The results show that IGF1 reached peak levels at around 13 yr in boys and 11 yr in girls while IGFBP-3 peaked at 14 yr in boys, and 11 yr in girls. Both IGF-1 and IGFBP-3 were at platform or decreased slightly after these ages. At each corresponding age, IGF-1 levels tended to be higher in boys compared to girls, while girls had higher IGFBP-3 levels than boys. A model for calculation of standard deviation scores of IGF-1 and IGFBP3 according to age, sex and pubertal stage was established. These normative data should facilitate child care, growth monitoring, clinical diagnosis and to follow up on GH treatment.
Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 μg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.
Insulin therapy represents the most effective and reliable means of achieving satisfactory glycemic control. However, few studies have evaluated the predictors of future insulin use. The purpose of this study was to investigate the predictors of future insulin use in type 2 diabetic patients. In this study, we conducted a chart review of 158 Japanese type 2 diabetic patients admitted to our hospital for stringent glycemic control. Of the 158 subjects, 92 satisfied the inclusion criteria for this study. We assessed the associations between baseline BMI, fasting plasma glucose levels (FPG) and serum and urinary C-peptide levels (sCPR and uCPR), and insulin usage at 6 months after discharge. We also computed the areas under the curve (AUCs) in receiver operator characteristic (ROC) curves for each predictor to predict the future insulin use. After adjustment for gender, age, and BMI, the multivariable odds ratios (ORs) for future insulin use in the highest tertile as compared with lowest tertile were 0.12 for BMI (95% confidence interval (CI), 0.03-0.52), 17.0 for FPG (95% CI, 3.27-88.7), 0.12 for sCPR (95% CI, 0.02-0.71), and 0.03 for uCPR (95% CI, 0.00-0.24). Prediction analyses showed that the AUCs for BMI, FPG, sCPR, and uCPR were 0.73, 0.76, 0.74, and 0.78, respectively, which suggests that the predictive abilities of these predictors do not differ substantially. In conclusion, this study suggests that BMI, FPG, sCPR, and uCPR are strong predictors of the future insulin use in type 2 diabetic patients.
Cushing’s syndrome (CS) as represented by chronic glucocorticoid excess is associated with increased rate of cardiovascular morbidity and mortality. Because endothelial dysfunction is an early event of atherosclerosis, we investigated whether endothelial dysfunction is associated with CS and reversible. Twenty-one CS patients due to different causes were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), among whom 12 patients were re-evaluated after surgical and medical treatment; 12 age- and gender-matched subjects served as control. Percent (%) FMD in CS patients (5.8±1.9 %) was significantly (p =0.0014) lower than that in control subjects (8.1±1.7 %). In CS patients, %FMD showed significant (p <0.01) negative correlations with morning serum cortisol levels (r =-0.58) and 24-h urinary free cortisol excretion (r =-0.58). After surgical and medical treatment in CS patients, morning cortisol levels significantly (p =0.0025) decreased from 23.4 [15.6-37.3] to 10.2 [7.7-12.9] μg/dL, whereas %FMD significantly (p =0.0024) increased from 5.2±1.9 to 7.8±2.3 %; changes of %FMD after treatment significantly (p =0.0004) and inversely correlated with those of morning cortisol levels (r =-0.85), but not with those of body mass index, blood pressure, glycemic or lipid profiles. Taken together, the present study clearly revealed that endothelial dysfunction in CS patients is related to hypercortisolemia and reversible after treatment, suggesting the possible role of cortisol excess in the development of endothelial dysfunction, thereby possibly leading to increased cardiovascular complications.
To evaluate the prevalence of dyslipidemia in the population of Hashimoto thyroiditis, we reviewed medical records on the consecutive 1181 cases with adult Hashimoto thyroiditis and 830 cases were adopted for the study. First, the serum TSH level increased and serum free T4 level decreased, slightly but significantly, with increasing age. There were significant positive correlations between serum TSH levels and lipid parameters such as total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), non-HDL-C and LDL-C/HDL-C ratio (L/H). In contrast, there were significant negative correlations between serum free T4 levels and all of these lipid parameters. According to the thyroid function, the cases were classified into 4 groups such as thyrotoxicosis (TT), euthyroidism (EU), subclinical hypothyroidism (SH) and overt hypothyroidism (OH). TC, HDL-C, non-HDL-C and LDL-C of TT were significantly lower than those in EU. In contrast, TC, TG, non-HDL-C, LDL-C, L/H and age of OH were significantly higher than those in EU. Interestingly, LDL-C and L/H of SH were significantly higher compared with EU. Thirty-two of SH patients were treated with small doses of levothyroxine and the effects on the lipid profile were examined. The TC, non-HDL-C, LDL-C and L/H were significantly decreased after treatment. In conclusion, the prevalence of dyslipidemia increases along with hypofunction of the thyroid and T4 replacement therapy may improve lipid profile in the cases of SH with Hashimoto thyroiditis.
Studies from overseas have indicated that postprandial glucose excursions are predominant in subjects with moderate hyperglycemia, while fasting hyperglycemia become the predominant abnormality with worsening of hyperglycemia; however, few studies have yet investigated the correlation between HbA1c and fasting and/or postprandial hyperglycemia in Japanese subjects. We investigated the correlation between fasting and postprandial hyperglycemia and the overall diabetic status, as assessed by measurement of HbA1c, in Japanese patients with type 2 diabetes. Blood glucose (BG) concentrations were determined in the fasting state (8:00 A.M.), during the postprandial phases (at 10:30 A.M., 2:30 P.M. and 8:30 P.M.) and during the postabsorptive periods (at 11:30 A.M. and 17:30 P.M.) in 66 patients with type 2 diabetes who were not being treated with prandial/premixed insulins or α-glucosidase inhibitors. The areas under the curve above the fasting BG concentrations (AUC1) and over 110 mg/dl (AUC2) were calculated for further evaluation of the correlations of the postprandial (AUC1) and fasting (AUC2 - AUC1) BG increments to the overall diurnal hyperglycemic status. Subjects were separated into two groups using the HbA1c cutoff value of 8%. The fasting BG was not correlated with the HbA1c in the group with a HbA1c values of less than 8% (r = 0.125, p = 0.473). On the other hand, fasting hyperglycemia was strongly correlated with the HbA1c level in the group with HbA1c values of over 8.0% (r = 0.406, p = 0.023). Furthermore, postprandial hyperglycemia was strongly correlated with the HbA1c in the group with HbA1c levels less than 8.0% (r = 0.524, p = 0.001). Thus, there existed a progressive shift in the contribution of fasting and postprandial hyperglycemia to the overall hyperglycemic status with progression from moderate to severe diabetes mellitus in Japanese type 2 diabetic patients.
Cushing’s syndrome, including its mild form/state of adrenal-dependent subset (subclinical Cushing’s syndrome; subCS), is known to enhance glucose intolerance, hypertension and obesity. Recently, subclinical Cushing’s disease (subCD) has been identified, but its prevalence and the extent of consequent metabolic derangement are unclear. We screened 90 type 2 diabetic patients hospitalized in our department for subCD, according to the diagnostic guideline proposed by the working group of Japanese Ministry of Health, Welfare and Labor in 2006. Plasma ACTH and cortisol levels in the morning and at midnight were determined, and overnight 0.5 mg dexamethasone suppression test (DST) was performed. Those who showed poor cortisol suppression in DST underwent the desmopressin (DDAVP) test. Fifty-seven patients (63.3%) demonstrated abnormally high midnight cortisol levels (≥2.5 μg/dL), while only nine of them failed to suppress plasma cortisol levels to <3 μg/dL after DST. Although none of the eight patients who underwent the DDAVP test demonstrated the anticipated paradoxical rise in plasma ACTH, these eight patients (8.9%) endocrinologically met the screening criteria of subCD. Since a considerable percentage of pituitary adenomas causing overt Cushing’s disease are not identifiable in magnetic resonance imaging, many of those causing subCD may also be unidentifiable. Further follow-up studies including confirmatory testing and pituitary imaging are necessary.