Experimental transplantation of endocrine tissues has led to significant advances in our understanding of endocrinology and metabolism. Endocrine cell transplantation therapy is expected to be applied to the treatment of metabolic endocriopathies. Restoration of functional pancreatic beta-cell mass or of functional adipose mass are reasonable treatment approaches for patients with diabetes or lipodystrophy, respectively. Human induced pluripotent stem (iPS) cell research is having a great impact on life sciences. Doctors Takahashi and Yamanaka discovered that the forced expression of a set of genes can convert mouse and human somatic cells into a pluripotent state [1, 2]. These iPS cells can differentiate into a variety of cell types. Therefore, iPS cells from patients may be a potential cell source for autologous cell replacement therapy. This review briefly summarizes the current knowledge about transplantation therapy for diabetes mellitus, the development of the endocrine pancreas and adipocytes, and endocrine-metabolic disease-specific iPS cells.

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A 62-year-old woman presented with a mass on the left side of the neck. Biochemical testing revealed primary hyperparathyroidism. Further, a prolactinoma was detected, and the patient’s son and daughter also had primary hyperparathyroidism, indicating that the patient had multiple endocrine neoplasia type 1 (MEN1). Neck ultrasonography revealed several cystic nodules (≤30 mm) that appeared to be adenomatous. After parathyroidectomy with autotransplantation, the largest cystic mass, in the left lower thyroid lobe, was pathologically diagnosed as a functioning parathyroid cyst, and all laboratory data returned to normal. On genetic analysis of blood, we found a novel single base insertion (duplication) in exon 10 codon 552 of the MEN1 gene (c1659dupT) that creates an early stop codon. This is the first case report of a parathyroid cyst resulting from parathyroid hyperplasia in a MEN1 patient.

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Type 2 diabetes (T2D) is characterized by a steady worsening of β-cell dysfunction as the disease progresses. The objective of this study was to estimate the decline of insulin secretion in Japanese type 2 diabetic patients (T2D-patients) by glucagon injection over an observation period of more than 10 years. Thirty-three T2D-patients were followed for 10.4±1.4 years. Fasting C-peptide immunoreactivity (FCPR), the 6 min value of CPR after glucagon injection (6MCPR), and the increment of CPR (ΔCPR) were measured at baseline and follow-up. FCPR, 6MCPR, ΔCPR were significantly lower at follow-up than at baseline (p<0.05, p<0.005, and p<0.0005, respectively). The annual change of ΔCPR was significantly (p<0.05) greater than the annual change of FCPR (-0.062±0.076 ng/mL/year and -0.025±0.067 ng/mL/year, respectively). In contrast, CPR-index (an index of β-cell function) and SUIT-index (secretory units of islets in transplantation) calculated based on fasting blood samples were unaltered. The annual changes of FCPR, 6MCPR, and ΔCPR were negatively correlated with the FCPR, 6MCPR, and ΔCPR values at baseline, respectively. Duration of diabetes, BMI, diabetic retinopathy, and secondary sulfonylurea failure at baseline were not correlated with the annual changes of FCPR, 6MCPR, and ΔCPR. In conclusion, our longitudinal observations suggest that β-cell function progressively declines in Japanese T2D-patients. The annual declines of ΔCPR were more prominent than the annual declines of FCPR. ΔCPR after glucagon injection may be more useful for estimating individual longitudinal insulin secretion than fasting blood samples.

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Short term intensive insulin therapy has been reported to induce long term euglycemia remission in patients with newly diagnosed type 2 diabetes mellitus, but the factors that are responsible for long-term remission or hyperglycemia relapse are unknown. Original data of 188 patients with newly diagnosed type 2 diabetes treated with short term intensive insulin therapy was reanalyzed. Patients who maintained glycemic control for 12 months with only life style intervention were defined as remission while those who failed to maintain glycemic control for 12 months as hyperglycemia relapse. Relationships of metabolic control, β cell function and insulin sensitivity with remission time and hyperglycemia relapse were explored. Totally 93 patients achieved 12-month euglycemic remission. Substantial improvement in blood glucose, parameters of β cell function and insulin sensitivity were obtained in both remission and relapse patients. The duration of remission was correlated with fasting plasma glucose measured after cessation of continuous subcutaneous insulin infusion (CSII) therapy (fasting plasma glucose (FPG) after CSII, r= -0.349, p<0.0001). Multivariate logistic regression show that FPG after CSII was independent predictor of hyperglycemic relapse (Odds ratio=1.585, p=0.001). All patients were stratified into three groups according FPG after CSII. As multivariate Cox proportional hazards regression demonstrated, compared with the patients with FPG<6.1mmol/L, risk for hyperglycemia relapse was increased 60% in those with 6.1 mmol/L≤FPG≤7.0 mmol/L (Hazard ratio=1.60, p=0.049), and 1.69 folds in those with FPG>7.0 mmol/L (Hazard ratio=2.69, p<0.0001). Our study demonstrated that fasting plasma glucose after intensive insulin therapy is a convenient and significant predictor for hyperglycemic relapse.

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The effect of add-on therapy with sitagliptin on glycemic control was prospectively investigated in patients with type 2 diabetes mellitus (T2DM) receiving insulin alone or insulin combined with oral antidiabetic drugs. Seventy-one patients were evaluated (38 men and 33 women aged 63.9±10.2 years). They were divided into three groups, which were 45 patients receiving premixed insulin twice daily, 15 patients receiving multiple daily insulin injections, and 11 patients receiving basal insulin with oral antidiabetic drugs (basal insulin therapy). Concomitant oral drugs included sulfonylureas, α-glucosidase inhibitors and metformin. The hemoglobin A1c (HbA1c) of all patients improved significantly from 8.1±1.2% to 7.6±1.1% after 12 weeks of add-on therapy with sitagliptin (p<0.01), and the insulin dosage was reduced from 27.3±15.8 U/day to 24.5±16.5 U/day (p<0.001). Body weight did not change after the start of concomitant therapy and severe hypoglycemia was not observed. The baseline HbA1c and glycated albumin levels were identified as factors that predicted the response to add-on therapy with sitagliptin. These findings suggest that add-on therapy with sitagliptin can be expected to achieve improvement of poor glycemic control irrespective of a patient’s demographic profile. Stratified analysis based on the insulin regimen revealed a stronger antidiabetic effect and a high efficacy of sitagliptin when it was added to basal insulin therapy. The results of this investigation confirmed that add-on therapy with sitagliptin to various insulin regimens could improve glycemic control without severe hypoglycemia and/or weight gain.

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Recent studies suggest an association of vitamin D with obesity, diabetes and cardiovascular diseases. We analyzed the association of serum vitamin D level assessed by 25-hydroxyvitamin D₃ {25(OH)D₃ } with nonalcoholic fatty liver disease (NAFLD) in apparently healthy men. We performed a cross-sectional study of 6,567 Korean men who participated in a health screening program, evaluating the association of serum 25(OH)D₃ levels with the risk of NAFLD assessed by abdominal ultrasonogram. Of the participants, 43.6% had NAFLD and 21.1% had metabolic syndrome. Age, serum calcium, and aspartate aminotransferase levels showed weak but significant positive correlations with 25(OH)D₃ level; total cholesterol, triglycerides, low-density lipoprotein cholesterol and fasting insulin level showed weak but significant negative correlations with 25(OH)D₃ level. The mean 25(OH)D₃ level was significantly lower in participants with NAFLD than in those without (38.7 ± 9.0 vs. 39.7 ± 9.7 nmol/L, p < 0.001). When participants were divided into tertiles based on mean 25(OH)D₃ level, the proportion with NAFLD significantly increased as mean 25(OH)D₃ level decreased (40.0, 45.0 and 45.9%, p for linear trend < 0.001). Multiple logistic regression analyses with NAFLD as the dependent variable showed that the tertiles with lower 25(OH)D₃ levels had a significantly increased risk for NAFLD compared with the highest tertile, even after adjusting for body mass index and metabolic syndrome (OR 1.247 and 1.408 vs. the highest tertile, p < 0.001). Thus, participants with higher serum 25(OH)D₃ showed a significantly reduced risk for NAFLD compared with the low 25(OH)D₃ groups, independent of obesity and metabolic syndrome.

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The aim of the study was to assess female sexual dysfunction (FSD), quality of life and depression status in female patients with acromegaly. Fifty-seven sexually active female patients with acromegaly disease (21 controlled, 36 uncontrolled) monitored by Cerrahpasa Medical School, Endocrinology and Metabolism out-patient clinic and age and body mass index-matched 46 healthy female subjects were included in the study. Sexual functions and status of depression in both patient and control groups were evaluated by using the Female Sexual Function Index Form (FSFI) and the Beck Depression Inventory (BDI), respectively. Quality of life was evaluated by using the Acromegaly Quality of Life (AcroQoL) Scale. Hormone levels were studied in the groups. The FSFI total score and desire, arousal, orgasm, and satisfaction domains in patients with acromegaly were significantly lower than in the healthy controls (p≤ 0.0001). There was no difference between biochemically controlled and uncontrolled patients with acromegaly with respect to FSFI scores (p= 0.7). AcroQoL total score in female patients with controlled acromegaly and uncontrolled acromegaly were 46.33±16.5% and 50.13±18.21%, respectively (p= 0.53). The difference in BDI scores between controlled and uncontrolled acromegaly patients was not significant but they were significantly higher in the control group (p≤ 0.0001). In the correlation analysis, a negative correlation was found between FSFI total and BDI score (r= -0.69, p< 0.001), age (r= -0.45, p< 0.001), and IGF-I (r= -0.28, p= 0.006). This study showed that sexual dysfunction and depression rates in female patients with acromegaly are higher than in healthy females.

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The objective of this study was to evaluate the efficacy and safety of stepwise introduction of insulin lispro mix 50 (LM50) from once to 3 times daily in Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy. This was a multicenter, open-label, non-randomized trial consisting of three 16-week periods (48 weeks total); all patients were given once-daily injections of LM50 in Period 1. The regimen was intensified to twice daily in Period 2, and 3 times daily in Period 3 if HbA_1c was ≥6.9% before the start of the period. A total of 135 patients were enrolled, and 116 patients completed the study. Main baseline characteristics of enrolled patients were a mean age of 60.3 years, mean diabetes duration of 11.4 years, mean BMI of 25.2 kg/m², and mean HbA_1c of 8.71%. The percentages of patients who achieved HbA_1c levels <6.9% and <7.4% at endpoint were 18.5% (25/135 patients) and 52.6% (71/135 patients), respectively. Mean HbA_1c decreased significantly from 8.70% to 7.44% (p<0.001). The incidence of hypoglycemic episodes over the treatment periods was 65.9% (89/135 patients); severe hypoglycemia occurred in 2.2% (3/135 patients). There were no other clinically significant safety issues related to the study drug. Stepwise introduction of LM50 from once to 3 times daily can be a safe, effective, and simple therapy for Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy.

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Studies on the relationship between thyroid stimulating hormone (TSH) within the reference range and coronary artery disease (CAD) have produced conflicting results. Furthermore, the effect of age on this relationship has never been explored. The aim of this study was to investigate the association between TSH levels and CAD among euthyroid subjects and whether age influenced this relationship. A total of 318 subjects who underwent coronary angiography were included. Serum TSH, T3, T4, lipid, blood glucose and creatinine levels were measured and compared between the groups with and without CAD. Age-stratified analysis and multivariate logistic regression analysis were performed. Levels of TSH, T3 and T4 did not differ significantly between CAD (n=196) and non-CAD group (n=122) (TSH: 1.77±0.99 vs 1.89±0.98 mIU/L, T3: 1.45±0.36 vs 1.51±0.35 nmol/L, T4: 100.06±20.49 vs 103.95±24.06 nmol/L, respectively) when comparisons were performed among all subjects. A significant between-group difference in levels of TSH was observed among subjects less than or equal to 65 years old (CAD group: n=121, non-CAD group: n=106), with higher TSH levels in CAD group (2.03±0.94 vs 1.75±0.97 mIU/L, adjusted p=0.024). Multivariate logistic regression analysis revealed that elevated level of TSH was an independent predictor for CAD (odds ratio: 1.512, p=0.011). No significant between-group difference in TSH levels was observed among subjects older than 65 years (CAD group: n=75, non-CAD group: n=16). The results showed that higher levels of TSH within the reference range were independently associated with the presence of CAD only among subjects less than or equal to 65 years old, suggesting age might influence the relationship.

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Adult hippocampal neurogenesis is important in mediating hippocampal-dependent learning and memory. Exogenous ghrelin is known to stimulate progenitor cell proliferation in the dentate gyrus of adult hippocampus. The aim of this study was to investigate the role of endogenous ghrelin in regulating the in vivo proliferation and differentiation of the newly generating cells in the adult hippocampus using ghrelin knockout (GKO) mice. Targeted deletion of ghrelin gene resulted in reduced numbers of progenitor cells in the subgranular zone (SGZ) of the hippocampus, while ghrelin treatment restored progenitor cell numbers to those of wild-type controls. We also found that not only the number of bromodeoxyuridine (BrdU)-positive cells but also the fraction of immature neurons and newly generated neurons were decreased in the GKO mice, which were increased by ghrelin replacement. Additionally, in the GKO mice, we observed impairment of memory performance in Y-maze task and novel object recognition test. However, these functional deficiencies were attenuated by ghrelin administration. These results suggest that ghrelin directly induces proliferation and differentiation of adult neural progenitor cells in the SGZ. Our data suggest ghrelin may be a plausible therapeutic potential to enhance learning and memory processes.

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Women with primary ovarian insufficiency (POI)/premature ovarian failure exhibit hypergonadotropic hypogonadism due to follicle dysfunction and depletion before the age of 40 years. Because ovulation is extremely rare and thought to be unpredictable in women with POI and because no ovulation induction regimens have been shown to be efficacious, oocyte donation is the only evidence-based treatment for women with POI with desired fertility. Oocyte donation is, however, extremely limited in several countries including Japan. Here, we report four women with POI who achieved pregnancies resulting from timed intercourse or intrauterine insemination in combination with cyclic estrogen/progesterone therapy and close monitoring of follicle development. These four patients were diagnosed with POI at the mean age of 27.5 ± 8.5 (mean ± SD; range, 19-35), subjected to follicle monitoring at the mean age of 29.8 ± 5.7 (23-35), and conceived at the mean age of 34.5 ± 3.9 (29-38). The interval between the initiation of follicle monitoring and pregnancy was 4.8 ± 2.8 (2-8) years. In one of the patients, her most recent ovulation occurred after a three-year interval. All four patients had uncomplicated pregnancies with term deliveries. In the event that oocyte donation and adoption are not available and/or various treatments with intensive ovulation induction have been unsuccessful, close and continuous monitoring of follicle growth to identify very rare ovulatory events might be considered for patients with POI and desired fertility.

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Reference ranges for serum thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in children were set using the assay kits currently used in clinical settings. A total of 342 children (111 males and 231 females) who were negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonographic examination of the thyroid gland were divided into 6 age groups: 4-6 years (45 children), 7-8 years (40), 9-10 years (53), 11-12 years (65), 13-14 years (83), and 15 years (56) for the study. FT3, FT4 and TSH levels were determined by electrochemiluminescence immunoassay (ECLIA) (ECLusys FT3, FT4 and TSH).The reference range for FT3 (pg/mL) was 2.91-4.70 for the age group of 4-6 years, 3.10-5.10 for the age group of 7-8 years, 3.10-4.87 for the age group of 9-10 years, 2.78-4.90 for the age group of 11-12 years, 2.77-4.59 for the age group of 13-14 years, and 2.50-4.64 for the age group of 15 years . The reference range for FT4 (ng/dL) was 1.12-1.67, 1.07-1.61, 0.96-1.60, 1.02-1.52, 0.96-1.52, 0.95-1.53. The reference range for TSH (μU/mL) was 0.62-4.90, 0.53-5.16, 0.67-4.52, 0.62-3.36, 0.54-2.78, 0.32-3.00. Serum FT3, FT4 and TSH levels in children differ from those in adults. It is, therefore, of importance to perform evaluation of thyroid function in children using reference values appropriate for the chronological ages, because misdiagnosis of hypothyroidism or inappropriate secretion of TSH (SITSH) and oversight of mild subclinical hypothyroidism could occur if the diagnosis is made using reference values for adults.

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Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, a partial defect in iodide organification, and dyshormonogenetic goiter. Several cases of Pendred syndrome with follicular thyroid carcinomas were reported previously. Here we report identical twin patients with Pendred syndrome, who had thyroid tumors with distinct histopathological findings. 34-year-old identical twins with congenital deafness and goiter were referred to our hospital with complaint of neck discomfort. The genetic testing showed that these twin patients were compound heterozygotes carrying the same two mutations in the Pendred’s syndrome (PDS / SLC26A4) gene (c2168A > G and ins2110GCTGG), which confirmed the diagnoses of Pendred syndrome. They underwent thyroidectomy. Histological examination of the thyroid tumors resected from these twin patients revealed follicular variant of papillary thyroid carcinoma, and diffuse and nodular goiter without any evidence of malignancy, respectively. To our knowledge, the former is the first case of follicular variant of papillary thyroid carcinoma in Pendred Syndrome.

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Postprandial glucagon secretion was shown to be dysregulated in patients with type 2 diabetes. However, the differences in secretory patterns between obese and non-obese patients and their physiological effects on plasma glucose levels are not fully understood. This study population consisted of 21 (10 obese and 11 non-obese) consecutive patients with type 2 diabetes admitted for glycemic control. A 3-hour mixed-meal tolerance test was performed after glycemic control improved. Six non-diabetic subjects were also enrolled in the test. Postprandial glucagon levels increased after 30 min in diabetic patients but not in non-diabetic subjects. The glucagon levels in obese diabetic patients were significantly higher than those in non-obese diabetic patients, while the percent values of postprandial glucagon levels were not different between these groups. In diabetic patients, there were significant positive correlations between the percent value at 30 min and the early postprandial glucose levels at 0, 15 and 30 min and the areas under the curve (AUC_0-30 and AUC_30-90). Interestingly, the ratio of this percent glucagon value to the C-peptide level at 30 min was significantly associated with the late half of the postprandial glucose levels at 90, 120, 150 and 180 min and the AUC_90-180. This is the first report that demonstrates the glucagon secretory patterns and the close correlations in detailed time course between the early postprandial glucagon response and the early and the late half of the postprandial glucose levels in obese and non-obese patients with type 2 diabetes.

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Breast cancer in young women younger than 35 years old is rare, aggressive and associated with a poor prognosis. Endocrine therapy is a preferred treatment modality in hormone receptor-positive early stage and advanced breast cancer, combined therapy of goserelin and letrozole presents an option for premenopausal women. We reported the efficacy and safety of therapy of goserelin plus letrozole on very young women with advanced breast cancer as first-line endocrine therapy. Thirty-five patients with first diagnosed as advanced breast cancer, age younger than 35 years, were enrolled in the study. All patients received goserelin 3.6mg by subcutaneous injection every 4 weeks along with letrozole 2.5mg daily by mouth as first-line endocrine therapy. The study endpoints were objective response rate (ORR), clinical benefit (CB), progression-free survival (PFS), overall survival (OS) and toxicity. The median duration of response to the therapy was 21 (range, 10-56) months, and median duration of follow-up was 44 (range, 5-79) months. The ORR was 25.7%, with one complete response (CR, 2.9%) and eight partial response (PR, 22.9%). Twenty-two patients had stable disease at 24 weeks, for a clinical benefit rate of 65.7%. The median PFS was 9.6 (range 5-58) months and median OS was 33 (range 6-72) months. During the therapy and follow-up, no serious toxicities were reported. Combined therapy of goserelin and letrozole appears to be an efficacious and well-tolerated therapy for very young women with advanced breast cancer. Further investigations involving more patients, combination of other therapies and longer follow-up are requisite.

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In contrast to minimally invasive follicular thyroid carcinoma (FTC), widely invasive FTC is aggressive and is associated with a dire prognosis. However, prognostic factors of widely invasive FTC have not been intensively investigated. In this study, we investigated this issue in a series of 79 widely invasive FTC patients. In the subset of 70 patients who did not show distant metastasis at diagnosis (M0), only a tumor size larger than 4 cm had a prognostic impact on disease-free survival (DFS) both on uni- and multivariate analyses. Regarding the cause-specific survival (CSS) of 79 patients, only distant metastasis at diagnosis (M1) had a significant prognostic value on uni- and multivariate analyses. None of the 70 M0 patients with a tumor measuring 4 cm or less died of FTC. Other clinicopathological features such as age, gender, and oxyphilic carcinoma were of no prognostic value. These findings suggest that 1) M1 is the strongest prognostic factor for CSS of widely invasive FTC patients, and 2) a tumor size larger than 4 cm significantly affects the DFS and CSS of M0 patients. Aggressive therapies with careful follow-up are recommended, especially for these patients.

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