Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28-amino acid acylated peptide mainly produced in the stomach. The pharmacological administration of ghrelin is known to exert diverse effects, such as stimulating GH secretion, promoting food intake, and increasing adiposity. In recent years, genetically engineered mouse models have provided important insights into the physiology of various hormones. In this review, we discuss current knowledge regarding the physiological significance of ghrelin on the basis of studies using genetically engineered mouse models with modifications in the ghrelin system.
Estrogen replacement therapy (ERT) is necessary for uterine development and bone mass acquisition in women with Turner syndrome (TS) suffering from ovarian insufficiency. However, adequate ERT regimens have not yet been established. The aim of this study was to evaluate the efficacy of ERT for both uterine development and bone mass acquisition. One hundred TS patients from Yokohama City University Hospital (88 with primary amenorrhea (PA) and 12 patients with spontaneous menstrual cycles (MC)) were enrolled after obtaining consent. Clinical profiles, uterine length (UL) measured by ultrasonic examination, and bone mineral density (BMD) of the lumbar vertebrae (L2-4) assessed by DEXA were evaluated. At the time of the first visit, the ULs of patients in the PA group were significantly shorter than those in the MC group. After receiving ERT, there were no significant differences in UL between patients with PA and MC. Forty-seven patients for whom the ERT initiation age was known were investigated to clarify the influence on BMD. The results showed that the BMD in the late initiation (18 years or older) group at the latest visit (0.770 ± 0.107 g/cm2: n = 16) was significantly lower than that in the early initiation (under 18 years) group (0.858 ± 0.119 g/cm2: n = 21) or the MC group (0.941 ± 0.118 g/cm2: n = 10). No significant differences were seen between the early initiation and MC group. ERT was effective in increasing UL and BMD. However, early initiation of ERT is necessary to increase BMD.
Preclinical studies on liraglutide have suggested related improvements in β-cell function. Therefore, we investigated these effects in patients with type 2 diabetes (T2D) using the glucagon stimulation test (GST). We conducted a retrospective cohort study of 73 insulin-treated patients with T2D who had their treatment switched to liraglutide monotherapy. Their β-cell function was measured using a 1-mg intravenous GST at baseline and 24 weeks after treatment. The effect of liraglutide treatment on β-cell function was assessed by the change in the area under the curve (AUC) of serum C-peptide immunoreactivity during the GST (AUC-CPR). The AUC-CPR increased after 24 weeks of liraglutide treatment (9.80 ± 0.55 ng/mL⋅min to 11.50 ± 0.52 ng/mL⋅min, p = 0.001). In the univariate and adjusted multivariate regression analyses, a negative relationship between the change in the AUC-CPR and T2D duration was noted (β = -0.22, 95% confidence interval [CI] = -0.35 to -0.09, R2 = 0.14, p = 0.001 and β = -0.20, 95% CI = -0.34 to -0.05, R2 = 0.23, p = 0.008, respectively). In the analysis using T2D duration tertiles, early liraglutide treatment (T2D duration ≤10 years) significantly improved the AUC-CPR (<4 years: +2.56 ± 0.73 ng/mL⋅min, p = 0.002; 4-10 years: +2.60 ± 0.56 ng/mL⋅min, p < 0.001), whereas late liraglutide treatment did not (>10 years: -0.33 ± 1.15 ng/mL⋅min, p = 0.78). We conclude that early liraglutide treatment potentially improves β-cell function and subsequently glycemic control in patients with T2D, preventing further diabetic complications.
Periodontitis and insulin resistance (IR) show bidirectional relationship. No studies have assessed the associations of periodontitis with IR, impaired β-cell function, and impaired fasting glucose (IFG) in the general population. We investigated these associations in a representative sample of the Korean population. The subjects were 8,248 males and 10,874 females, who were ≥ 20 years of age and participants in the third, fourth, and fifth Korea National Health and Nutritional Examination Surveys (2008-2010). Periodontitis was defined as community periodontal index (CPI) ≥ code 3 according to World Health Organization criteria. Homeostasis model assessments of IR and β-cell function (HOMA-IR and HOMA-β) were calculated. Participants with periodontitis showed a higher prevalence of diabetes than those without periodontitis. Among subjects without diabetes, after adjustment for confounding factors including age, gender, body mass index, systolic blood pressure, serum total cholesterol, smoking status, alcohol consumption, region, and regular exercise, a comparison of participants with periodontitis vs those without showed a significantly higher prevalence of IFG (28.5% vs. 17.7%, p<0.001) and lower HOMA-β (115.2 vs. 130.8, p<0.001). Periodontitis was identified as a risk factor for IFG (OR, 1.301; 95% CI, 1.193∼1.418; p<0.001). Conversely, participants with and without periodontitis had similar HOMA-IR. In conclusion, periodontitis showed an association with decreased β-cell function and increased prevalence of IFG before onset of diabetes as well as increased prevalence of diabetes in the Korean population. Future longitudinal studies are warranted to elucidate the shared pathophysiology between periodontal disease and diabetes mellitus.
Most types of thyroid carcinomas express PAX8 transcription factor; however, whether thyroid squamous cell carcinoma (SCC) also expresses PAX8, currently remains unknown. We herein examined the immunoreactivity of PAX8 in SCC of thyroidal and extrathyroidal origin, and discussed the diagnostic significance of PAX8. We immunohistochemically examined specimens from 11 SCC, 22 papillary thyroid carcinoma (PTC), 8 anaplastic thyroid carcinoma (ATC), and 2 mucoepidermoid carcinoma (MEC) cases as well as 5 uterine cervical SCC, 5 esophageal SCC, and 5 pulmonary SCC cases. The rates of PAX8-positive SCC, PTC, ATC, and MEC were 90.9%, 90.9%, 75.0%, and 100%, respectively. Two PAX8-negative PTC cases were cribriform variants. No uterine cervical, esophageal, or pulmonary SCC specimen reacted with PAX8 antibody. Thyroid transcription factor-1 (TTF-1) was positive in 9.1% and 95.5% of SCC and PTC cases, respectively, but negative in all ATC and MEC cases. These results demonstrate that PAX8 staining is useful for distinguishing between primary thyroid SCC and invasion or metastasis from extrathyroidal SCC. We recommend using an immunohistochemical panel of antibodies to PAX8 and TTF-1 to confirm a diagnosis of primary thyroid carcinoma.
This work aimed to clarify the expression and roles of anti-Müllerian hormone (AMH) and its type 2 receptor (AMHR2) in seminiferous tubules of maturing rat testes. By quantitative RT-PCR, we determined the relative expressions of Amh, Amhr2, Scp1, Rsbn1, Ngfr, and Rhox5 in rat testes aged 5-49 days (d), and in germ cells and Sertoli cells isolated from 21d testes. Smad 1,5 and 8 expressions were also determined in 21d testes and isolated germ cells. Moreover, we performed in situ hybridization (ISH) of Amh and Amhr2 in 21d testes, and immunohistochemical staining (IHCS) in 10, 15 and 21d testes using antibodies of AMH and AMHR2. In 21d testes, expression of the spermatocyte specific gene, Scp1, increased but that of the round spermatid specific gene, Rsbn1, was faint. By ISH and IHCS, expressions of AMH and AMHR2 were strongly observed in spermatocytes of 21d testes, but not in spermatogonia. In 21d testes, expressions of immature Sertoli cell specific gene, Ngfr, and mature Sertoli cell specific gene, Rhox5, were observed. IHCS confirmed the presence of AMH and AMHR2 in Sertoli cells. Smad 1, 5 and 8 were highly expressed in 21d testes and isolated germ cells. These results indicate that not only immature Sertoli cells but also spermatocytes express AMH and AMHR2 in maturing testes. In this study, we first clarified that spermatocytes coexpressed AMH and AMHR2 in rats. We speculated that AMH produced by spermatocytes and Sertoli cells binds AMHR2 of spermatocytes and acts through SMADs.
We have previously shown that follicular thyroglobulin (Tg) has an unexpected function as an autocrine negative-feedback regulator of thyroid hormone (TH) biosynthesis. Tg significantly suppressed the expression of genes necessary for iodide transport and TH synthesis by counteracting stimulation by TSH. However, whether follicular Tg also regulates intracellular TH transport and its secretion from thyrocytes is not known. In the present study, we examined the potential effect of follicular Tg on TH transport and secretion by quantifying the expression of two TH transporters: monocarboxylate transporter 8 (MCT8) and μ-crystallin (CRYM). Our results showed that follicular Tg at physiologic concentrations enhanced both the mRNA and protein expression levels of MCT8 and CRYM in a time- and dose-dependent manner in rat thyroid FRTL-5 cells. Although both the sodium/iodide symporter (NIS), an essential transporter of iodide from blood into the thyroid, and MCT8, a transporter of synthesized TH from the gland, were co-localized on the basolateral membrane of rat thyrocytes in vivo, Tg decreased NIS expression and increased the expression of MCT8 by counteracting TSH action. Thus, the effect of Tg on TH secretion opposed its previously described negative-feedback suppression of TH synthesis. Our results indicate that Tg mediates a complex intrinsic regulation of gene expression that is necessary to balance two opposing vectorial transport systems: the inflow of newly synthesized TH and the outflow of TH by external secretion.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by insulin resistance and hyperandrogenism. The interaction of these factors might result in increased risks of miscarriage and pregnancy complications such as gestational diabetes mellitus (GDM). To examine the pregnancy risks in women with PCOS, we compared obstetrical outcomes between patients with and without PCOS. We also studied the differences in maternal characteristics, glucose intolerance and pregnancy complications between PCOS patients with and without GDM, with and without obesity, and between successful pregnancies and miscarriages. We observed a high incidence of GDM and prevalence of GDM diagnosis in the first trimester in PCOS. Patients with GDM had higher body mass index (BMI) and lower homeostasis model assessment of β-cell function (HOMA-β) at preconception than those without GDM. Obese pregnant women with PCOS demonstrated a high incidence of GDM with severe insulin resistance, including high fasting insulin, HOMA of insulin resistance (HOMA-IR), and HOMA-β at preconception compared with normal-weight patients. BMI was significantly correlated with HOMA-IR or HOMA-β, and both indices were lower in PCOS patients with than without GDM for the same BMI. There were no significant differences in maternal characteristics (excluding maternal age) between PCOS patients with successful pregnancy and PCOS patients with miscarriages. Our data suggest that pregnant women with PCOS have an increased risk of GDM, especially if they have obesity and/or poorer insulin secretion. Measure of β-cell function, such as HOMA-β, at preconception might be a useful predictor of the risk of GDM in pregnant PCOS patients.
Nonalcoholic fatty liver disease (NAFLD) is a serious health-related condition all over the world; the number of patients is increasing in Asian countries including Japan. Better understanding of its pathophysiology is required to develop effective therapeutics, as patients may go on to develop non-alcoholic steatohepatitis and hepatocellular carcinomas. While NAFLD is believed to be associated with metabolic risk factors such as obesity, diabetes, and dyslipidemia, its etiology remains largely unknown and the development or co-existence of NAFLD in patients with insulinoma has not been investigated. A 33-year-old male with an insulinoma, who had been hypoglycemic during the previous four years, developed abnormally elevated levels of liver enzymes and histological fatty liver characteristic of NAFLD by the time of admission to our hospital for resection of an insulinoma. His medical records for the previous eight years revealed that his bodyweight had increased gradually from 60 kg to 71 kg for seven years and then acutely increased to 79 kg in the latest one-year period. This sudden increase was thought to be due to the patient’s self-described overeating of fruits to forestall hypoglycemia. Fresh fruits are rich in fructose, and the patient’s triglycerides, alanine and aspartate transaminases showed an acute increase in the previous one-year period. After resection of the insulinoma, the levels of these parameters all were mostly restored, which suggests that hyperinsulinemia and subsequent hyperphagia played a role in the development of NAFLD in this case. This is the first report of patient with NAFLD and an insulinoma.
Growth hormone and insulin-like growth factor-I play important roles in regulating bone metabolism and bone mineral density in adulthood. However, the effect of excess growth hormone on bone metabolism and bone mineral density is not fully understood. Here, we investigated the long-term changes in bone metabolism and bone mineral density after a rapid decline in growth hormone levels due to transsphenoidal surgery in acromegalic patients. Eighteen acromegalic patients (10 males and 8 females) who underwent transsphenoidal surgery were enrolled in this prospective study. Bone formation marker (serum bone alkaline phosphatase), bone resorption marker (urinary type I collagen cross-linked N-telopeptide), and bone mineral density were measured before surgery and at 3 months, 1 year, and 3 years after transsphenoidal surgery. While both serum bone alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide levels decreased significantly after surgery, serum bone alkaline phosphatase/urinary type I collagen cross-linked N-telopeptide ratio was significantly increased at 3 months and 3 years after surgery. Bone mineral density did not change markedly after surgery. In conclusion, the rapid decline in growth hormone levels following transsphenoidal surgery had no marked effect on bone mineral density for up to 3 years, despite significant changes in levels of bone turnover makers post-surgery.