Obesity may be viewed as a chronic low-grade inflammatory disease as well as a metabolic disease. Indeed, unbalanced production of pro- and anti-inflammatory adipocytokines critically contributes to the obesity-induced insulin resistance. In addition to lipid-laden mature adipocytes, adipose tissue is composed of various stromal cells such as preadipocytes, endothelial cells, fibroblasts, and immune cells that may be involved in adipose tissue functions. Accumulating evidence has suggested that adipocytes and stromal cells in adipose tissue change dramatically in number and cell type during the course of obesity, which is referred to as “adipose tissue remodeling.” Among stromal cells, infiltration of macrophages in obese adipose tissue precedes the development of insulin resistance in animal models, suggesting that they are crucial for adipose tissue inflammation. We have provided evidence suggesting that a paracrine loop involving saturated fatty acids and tumor necrosis factor-α derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. On the other hand, storing excessive energy as triglyceride is also a fundamental function of adipose tissue. Recent evidence suggests that reduced lipid storage in obese adipose tissue contributes to ectopic lipid accumulation in non-adipose tissues such as the liver, skeletal muscle, and pancreas, where lipotoxicity impairs their metabolic functions. Notably, chronic inflammation is capable of inducing insulin resistance, lipolysis, and interstitial fibrosis in adipose tissue, all of which may reduce the lipid-storing function. Understanding the molecular mechanism underlying adipose tissue remodeling may lead to the identification of novel therapeutic strategies to prevent or treat obesity-induced adipose tissue inflammation.
More than 50% of patients with multiple endocrine neoplasia type 1 (MEN1) develop gastroenteropancreatic neuroendocrine tumors (GEPNETs), and insulinoma is the second most common functioning GEPNET. Compared to other functioning and nonfunctioning GEPNETs in MEN1, insulinoma is considered to develop at a younger age. To clarify the clinical features of insulinoma developed in Japanese patients with MEN1, a recently constructed database of Japanese MEN1 patients was analyzed. Among 560 registered cases, insulinoma was seen in 69 patients and information on age at diagnosis was available for 54 patients. Tumors predominantly occurred in the body and tail of the pancreas. The mean age at diagnosis of insulinoma (34.8 ± 16.7 yrs) was significantly younger than that of gastrinoma (50.6 ± 14.3 yrs) and nonfunctioning tumor (44.7 ± 13.3 yrs) in patients with MEN1. Patients diagnosed as having insulinoma during middle-age (30 - 49 yrs) tended to have a long period from appearance of hypoglycemic symptoms to diagnosis of the tumor. Of note, 13 patients (24%) were diagnosed as having insulinoma before 20 yrs of age. Such young onset was not seen in other GEPNETs. Since the development of GEPNETs during adolescence is quite rare, insulinoma diagnosed before 20 yrs strongly suggests the presence of MEN1 and warrants further investigation, including MEN1 genetic testing. Also, clinicians should be aware that insulinoma can often be missed in middle-aged patients.
We examined the effects of sex steroids on prolactin promoter activity in rat somatolactotrophic GH3 cells. Both estradiol (E2) and progesterone (P4) were found to inhibit basal prolactin promoter activity, but to potentiate Thyrotropin-releasing hormone (TRH)-induced prolactin promoter activity. P4 had a greater inhibitory effect on basal prolactin promoter activity than E2, and P4 also potentiated TRH-induced prolactin promoter more potently than E2. Combined treatment with E2 and P4 further increased TRH-induced prolactin promoter activity. E2 and P4 also both reduced basal serum response element (SRE) promoter activity, and increased TRH-induced SRE promoter activity. Combination treatment with E2 and P4 reduced basal activity of SRE promoter and increased TRH-induced SRE activity more potently than E2 or P4 alone. In contrast, basal cAMP response element (CRE) promoter activity was not influenced by either E2 or P4, although TRH-induced CRE promoter was potentiated by each of these steroids, and was further increased by E2 and P4 combination treatment. Both E2 and P4 increased TRH-induced extracellular signal-regulated kinase (ERK) phosphorylation; however, intracellular cAMP levels was not influenced by E2 or P4. TRH-induced CRE promoter was inhibited by mitogen-activated protein kinase/ERK kinase (MEK) inhibitor and was increased by overexpression of MEK kinase (MEKK). This study showed that ERK and SRE transcriptional pathways, but not the cAMP/CRE pathway, may be involved in the suppression of basal prolactin promoter activity, whereas both the ERK/SRE and MAP kinase-mediated CRE pathways appear to be involved in the increased transcriptional efficiency of the prolactin promoter induced by TRH stimulation.
Successful long-term management of patients with Cushing’s disease (CD) remains a challenge. To date, studies on the long-term outcome of patients with CD have been conducted mainly in Caucasians. Our objective was to assess the recurrence rate in patients who underwent transsphenoidal surgery (TSS) in the management of CD and to identify predictive markers for the long-term outcomes of CD in Korea. The long-term outcome in 54 patients who underwent TSS for the treatment of CD from 1984 to 2010 was retrospectively reviewed. Recurrence was defined as an elevated serum cortisol or an elevated 24 hour urine free cortisol or a suppressed serum cortisol by dexamethasone higher than 138 nmol/L. Mean age at diagnosis was 35.8 ± 12.8 years and median follow-up duration was 50.7 months. Initial successful TSS was obtained in 38 patients (70.4%). Among these 38 patients, 18 (47.4%) patients had a recurrence of CD. Preoperative serum cortisol level was significantly associated with recurrence. Pathologic confirmation of an adenoma was marginally associated with lower risk of recurrence. Positive results of imaging study and presence of microadenoma were not associated with risk of recurrence. Recurrence rate of CD after initial successful TSS was 32.4% at 5 years and 54.6% at 10 years, respectively. Following initial successful TSS, close long-term endocrine surveillance is mandatory as the recurrence rate increases with time. Preoperative serum cortisol level and pathologic confirmation of an adenoma may have a predictive value for recurrence of CD after TSS.
Prader-Willi syndrome (PWS) is a genetic disease characterized by severe morbid obesity in association with hyperphagia and type 2 diabetes mellitus. Liraglutide is a glucagon-like peptide (GLP)-1 analog that controls appetite, decreases body weight and improves glycemic control. However, it is unclear if PWS patients with diabetes experience similar benefits of liraglutide therapy. In a 25 year-old female hyperglycemic PWS patient, liraglutide monotherapy improved her Hemoglobin A1c remarkably (12.6% to 6.1%) while steadily decreasing her body mass index (BMI: 39.1 kg/m2 to 35.7 kg/m2). We offered this patient continued liraglutide therapy for one year to determine the effect on various metabolic parameters. Her hyperphagia was controlled soon after liraglutide treatment commenced and remained so throughout the treatment. The metabolic parameters changed as follows: visceral fat area fell from 150.1 to 113.2 (cm2); plasma insulin rose from 108.1 to 277.0 (pmol/L); plasma active GLP-1 dropped from 2.1 to 1.2 (fmol/L); plasma active ghrelin diminished from 137.0 to 27.7 (pmol/L). While plasma active ghrelin before treatment was abnormally high, even though her GLP-1 was normal, both decreased following liraglutide therapy. These results suggest that in addition to its insulinotropic effects, other potential mechanisms activated by liraglutide therapy may reduce the plasma ghrelin levels elevated in PWS, leading to an improvement in overeating, BMI and visceral fat, as well as glycemic control.
In this study, we investigated the difference in lymph node-recurrence free survival (LN-RFS), distant recurrence-free survival (DRFS), and cause-specific survival (CSS) between patients with papillary thyroid carcinoma (PTC) in the entire group (Group I) and those with lymph node- and distant-recurrence-free survival (DFS) for 5 years after initial surgery (Group II). The LN-RFS of patients with all risk classifications in Group II was significantly better than that of those in Group I. The LN-RFS of intermediate-risk patients in Group II did not differ from that of low-risk patients in Group I, but LN-RFS of high-risk patients in Group II was significantly poorer than intermediate- and low-risk patients in Group I. DRFS and CSS of Group II patients did not significantly differ from those of Group I patients in the same risk classification. DRFS and CSS of high-risk patients in Group II were significantly poorer than those of intermediate- and low-risk patients in Group I, and those of intermediate-risk patients in Group II were also significantly poorer than those of low-risk patients in Group I. Taken together, the lymph node recurrence rate, but not distant recurrence and carcinoma death rates, of patients in all classifications significantly improved after DFS for 5 years. However, careful follow-up for lymph node recurrence of high-risk patients and for distant recurrence of intermediate- and high-risk patients is necessary thereafter.
Hyponatraemia (serum sodium concentration<135mmmol/L) is the most common electrolyte disorder in hospitalised patients. We analysed the safety and efficacy of tolvaptan in the treatment of hyponatraemia in hospitalised inpatients and report the first consecutive retrospective clinical case series report based on a single centre experience from the United Kingdom. We sought out the case records of all patients treated with tolvaptan for hyponatraemia over a period of 19 months; 15 episodes of treatment with tolvaptan in 14 patients were analysed. There were 8 women and 6 men (age 72±16, (mean ± standard deviation), range 36 to 90 years, mean BMI 24.9±8.67, 13.9 to 46.4 kg/m2). Thirteen patients were diagnosed with euvolaemic hyponatraemia. One patient had hypovolaemic hyponatraemia. The median duration of tolvaptan therapy was 3 days (1 to 21 days). A serum sodium level of 130mmol/L was targeted during therapy and fluid restriction was discontinued. There was a significant change in sodium level from baseline (mean sodium 120.1±4.6, 108-126mmol/L) to cessation of tolvaptan therapy (mean sodium 131.9±3.6, 125-139mmol/L, P<0.0001). The maximum rate of change of sodium was observed in the first 24 hours of therapy (mean 6.7±2.8, 1 to 11mmol/L) with no patient exceeding 12mmol/L in 24 hours and 18mmol/L in 48 hours at any point whilst on tolvaptan. No patient developed the osmotic demyelination syndrome. Tolvaptan appears to be safe and effective in the management of hospitalised inpatients with definitive euvolaemic hyponatraemia when close monitoring is observed.
Thyrotropin levels are outside normal reference range in subclinical thyroid disease. Metabolic syndrome (MetS) involves clustered cardiovascular risk factors, including abnormal lipids, insulin resistance, and hypertension. This study aimed to investigate associations between subclinical thyroid disease, thyrotropin levels, and metabolic syndrome in healthy subjects and identify associated biochemical markers. This cross-sectional study evaluated 9,055 healthy subjects examined at the Health Management Center, National Taiwan University Hospital from January 1, 2009 to December 31, 2009. Data collected included age, sex, height, weight, body mass index, waist circumference, pulse rate, and systolic/diastolic blood pressure. History of pregnancy, smoking/drinking status, family/personal thyroid disease, diabetes, dyslipidemia, and hypertension was obtained. Laboratory data included thyroid function tests, fasting glucose level, lipid profile, and C-reactive protein level. Participants were classified into subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid groups according to thyrotropin levels. In euglycemic subjects, thyroid-stimulating hormone (TSH) levels correlated positively with waist circumference, triglycerides (TG), non-high density lipoprotein (HDL) cholesterol, diastolic blood pressure. In subclinical hyperthyroid subjects, TSH levels correlated positively with low density lipoprotein cholesterol (LDL-C), non-HDL cholesterol. No significant correlations were found between TSH levels and variables in the subclinical hypothyroid group. In the entire study population, TSH levels correlated positively with TG, non-HDL cholesterol, and systolic blood pressure (SBP)/diastolic blood pressure (DBP), but no correlation was shown with HDL-C. No significant associations were seen between MetS prevalence and thyrotropin levels. No clinically relevant biochemical markers, differences in thyrotropin levels, or statistical correlations are shown between subclinical thyroid disease and metabolic syndrome in healthy individuals.
This study evaluated the effects of irbesartan and propranolol on thyroid hormone (TH)-induced cardiac functional and structural remodeling. A rat model of thyrotoxicosis was established by daily intraperitoneal injections of L-thyroxine (T4, 100 μg/kg) for 4 weeks. Forty Sprague-Dawley rats were randomly divided into four groups (n = 10 each): control group, T4 group (T4 alone), T4 plus irbesartan group (T4-Irb, 30 mg/kg), and T4 plus propranolol group (T4-Pro, 0.5mg/mL of drinking water). Cardiac chamber size and functional parameters were measured by echocardiography and cardiomyocyte diameter. Heart rate (HR) and cardiac fibrosis were determined. T4 alone showed significantly increased HR and cardiomyocyte width (25.0 ± 1.77 vs. 18.8 ± 0.84 μm, P < 0.001) with fibrosis, reduced left ventricle (LV) longitudinal strain (Slong; -16.0 ± 6.27 vs. -22.7 ± 5.19 %, P < 0.001) compared with control. When compared with T4 alone, T4-Irb showed significantly improved LV Slong (-21.4 ± 1.84 vs. -16.0 ± 6.27 %, P =0.017) and reduced cardiomyocyte width (21.0 ± 1.0 vs. 25.0 ± 1.77 μm, P =0.002) with comparable HR (458.4 ± 24.3 vs. 486.6 ± 30.1 bpm, P = 0.086). However, T4-Pro showed significantly reduced HR with improved LV Slong without alteration of cardiomyocyte width and fibrosis compared with T4 alone. In conclusion, renin-angiotensin system (RAS) blocking by irbesartan could significantly attenuate TH-induced cardiac structural and functional remodeling. However, HR reduction by propranolol could not alternate structural remodeling, which may implicate the RAS as having an important role in thyrotoxic cardiomyopathy beyond tachycardia.
Health related quality of life (HRQoL) is impaired in adult patients with 21-hydroxylase deficiency (21-OHD). Up to now, only cross-sectional and no longitudinal studies are available. It is not known if HRQoL can be improved in adult 21-OHD patients. We performed a longitudinal, prospective, single centre, follow-up study over seven years including 15 adult female 21-OHD patients. Two standardized questionnaires (Short Form 12 (SF-12); Hospital Anxiety and Depression Scale (HADS)) were completed in 2003, 2006 and 2010. Adjustment for age and sex was performed by transformation of score values into age- and sex-adjusted Z-scores using data sets from respective normative groups. Data regarding glucocorticoid therapy, clinical and hormonal parameters were assessed. We found that two of eight scales of SF-12 showed a significant improvement and four of eight scales a positive trend to better scores. No significant changes were seen in scores for HADS or for steroid hormone levels. Daily hydrocortisone equivalent dose per body surface significantly decreased over the study period. No changes in BMI were observed over the study period. We conclude that improvement of HRQoL in adult female 21-OHD patients is possible. Several factors might be involved in this improvement including reduced daily hydrocortisone equivalent dose per body surface.
Stratification of risk factors for cervical lymph node metastasis (LNM) in thyroid papillary carcinoma is important for providing standards for post-operative adjuvant radio-iodine therapy and for patient prognosis. We investigated pathological factors based on the lymphatic vessel system and radiological features associated with tumor with cervical neck LNM. Among patients who had undergone thyroidectomy confirmed to be papillary thyroid carcinoma, we selected 126 age-sex matched paired patients without cervical LNM (group 1) and with LNM (group 2) to evaluate risk factors. Pathological factors evaluated were size, multiplicity, and extra thyroid extension state, based on the pathological reports using stored data. The lymphatic vessel density (LVD) of each tumor was evaluated by staining for VEGFR-3 and D2-40 and correlated with cervical LNM state. Malignant ultrasound features were evaluated to compare the differences between these two groups. Larger tumor size, multiplicity, extrathyroid extension were more common in group 2 (p<0.05). The median percentage of VEGFR-3 for group 1 was 20 (range 0-30) and D2-40 was 13 (range 7-23) while for group 2, VEGFR-3 was 80 (70-90) and D2-40 was 78 (54-114). LVD measured by intratumoral D2-40 staining was 20.6% and 79.4% for group 1 and group 2, respectively. Intra-tumoral lymphatics measured by D2-40 stain had a strong correlation with cervical LNM (Odds 1.230, CI 1.01.-1.499 p value 0.040). Ultrasound (US) features had no significant differences between the two groups although calcifications tended to be higher in group 2 (84% vs. 76% p=0.264). Lymphatic vessel density and nodule echogenicity were not associated with LNM. Intratumoral lymphangiogenesis was most strongly associated with LNM and thus, could be a useful predictive marker for cervical LNM.
We previously found that plasma dipeptidyl peptidase 4 (DPP4) activity was associated with the development of obesity, type 2 diabetes, and type 1 diabetes using animal models. In this study, we investigated whether DPP4 activity is correlated with the clinical parameters of obesity and/or diabetes in healthy young subjects. Body mass index (BMI), plasma DPP4 activity, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, fasting blood glucose, adiponectin concentration, and body fat were measured in 165 subjects (110 males and 55 females, age 23.2 ± 2.4 years). In correlation analyses, DPP4 activity displayed strong positive correlations with BMI (p = 5.5 × 10-5) and total cholesterol (p = 0.0014), and a negative correlation with the plasma adiponectin concentration (p = 0.013), but not fasting blood glucose. Our findings suggest that plasma DPP4 activity is correlated with the clinical parameters of obesity rather than diabetes in young people.