ATP-sensitive potassium (K_ATP) channels play a key role in glucose-dependent insulin secretion in pancreatic β-cells. Recently, activating mutations in β-cell K_ATP channels were found to be an important cause of neonatal diabetes. In some patients, these mutations may also affect K_ATP channel function in muscles, nerves and brain which can result in a severe disease termed DEND syndrome (Developmental delay, Epilepsy and Neonatal Diabetes). This review focuses on mutations in the pore-forming K_ATP channel subunit (Kir6.2) that cause neonatal diabetes and discusses recent advances in our understanding of clinical features of neonatal diabetes, its underlying molecular mechanisms and their impact on treatment.

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Differentiated thyroid carcinoma originates from thyroid follicular cells and is the most prominent malignancy of the endocrine organs. There are two histological types of differentiated carcinoma, namely, papillary and follicular carcinoma. According to reports from Western countries, papillary carcinoma comprises 85.3% of thyroid malignancies in whites, and 72.3% in blacks [1, 2]. In Japan, a previous study showed that the prevalence of papillary carcinoma was 78.4% based on material registered between 1977 and 1986 [3], but according to recent findings reported in 2004 by Japanese Society of Thyroid Surgeons (JSTS), papillary carcinoma accounted for as much as 93% of all thyroid carcinomas. Papillary carcinoma frequently metastasizes to the regional lymph node and shows multicentricity in the thyroid gland. It usually shows a typical ultrasonographic appearance and can be rather easily diagnosed by fine needle aspiration biopsy (FNAB) [4-6]. Follicular carcinoma accounts for 10.9-20.5% of the patients in the United States [1, 2]. In Japan, the prevalence of follicular carcinoma was reported to be 17.2% [3], but it decreased to 5% in a report by JSTS in 2004. This carcinoma is only occasionally diagnosed preoperatively, because it is hard to discriminate follicular carcinoma from benign adenoma on imaging studies and cytologic findings. In contrast to papillary carcinoma, follicular carcinoma more often metastasizes to distant organs than regional lymph nodes. In Japan, the prevalence of papillary carcinoma increased and that of follicular carcinoma decreased between reports from 1977 to 1986 and that in 2004, which may be because follicular variant of papillary carcinoma was classified into follicular carcinoma in the previous results. Generally, these carcinomas show an indolent character, but when the lesion dedifferentiates and becomes undifferentiated carcinoma, it displays very rapid growth with an adverse prognosis and is regarded even as the most aggressive malignancy among human solid carcinomas [7, 8]. Furthermore, cases showing certain characteristics are likely to be constantly progressive and even become life-threatening. Such cases should be regarded as "high-risk" requiring careful and extensive surgical treatment and postoperative follow-up. Indeed, it is most important for physicians to correctly distinguish high-risk cases from those with an indolent character, although how to evaluate the biological characteristics of thyroid carcinoma and how to identify high-risk cases remains highly controversial. In this review, the methods of distinguishing high-risk cases and the appropriate therapeutic strategies for papillary and follicular carcinomas predominantly based on our experience are emphasized and our proposals for therapies including surgical treatment are demonstrated.

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To evaluate the efficacy of a multiple-daily injection regimen and a twice-daily injection regimen using biphasic insulin, we performed an observational study of 56 insulin-naïve patients with type 2 diabetes mellitus who began receiving insulin therapy while they were hospitalized. The subjects were divided into two groups: a multiple-daily injection group (n = 33), and a twice-daily injection group (n = 23). At baseline, the demographic and clinical characteristics were comparable between the two groups. The HbA1c levels were 10.0 ± 1.6% and 9.5 ± 2.2% (p = 0.36), respectively. At 12 weeks, the HbA1c levels decreased equally in the two groups (7.2 ± 1.8% in the multiple-daily injection group and 7.3 ± 1.6%, p = 0.80 in the twice-daily injection group). The baseline HbA1c, the duration of diabetes, and the endogenous insulin secretory capacity did not affect the change in HbA1c in either group. These results suggest that twice-daily insulin regimen using biphasic insulin is as effective and beneficial as multiple-daily injection regimen for the treatment in type 2 diabetic patients with very poor glycemic control and that in order to achieve the targeted glycemic goal, insulin therapy should be initiated at an early stage.

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Objective: To investigate apoptosis in the thyroid of Graves disease (GD) induced by thyroid arterial embolization. Materials and methods: Forty one patients with clinically and laboratorily ascertained GD were treated with thyroid arterial embolization and followed up for 3-54 months following embolization. Prior to embolization and at 1, 3, 6, 12 and 36 months following embolization, thyroid autoimmunue antibodies were tested respectively, including thyroid stimulating antibody (TSAb), thyroglobulin antibody (TGAb) and thyroid microsomal antibody (TMAb). Thyroid biopsy was performed under the guidance of computed tomography for immunohistochemistry examination using semi-quantity analysis. Results: The positive staining of Fas and FasL was mostly in the cytoplasma and cell membrane, the positive expression of Bax was mainly in the cytoplasma, and no positive expression of P53 was detected in the thyroid cells before embolization. After arterial embolziation, the positive cell number and staining degree of these genes were both greater than before embolization. Conclusion: The treatment method of thyroid arterial embolization can effectively enhance the positive expression of pro-apoptotic genes of Fas, FasL, Bax, Bcl-2 and P53 in GD thyroid, thus promoting apoptosis of GD thyroid and helping restore the thyroid size and function to normal conditions.

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A 40-year-old female, diagnosed as essential hypertension, demonstrated a 2 cm mass in left adrenal gland by computed tomography without abnormal endocrinological findings. ¹³¹ I-adosterol and ¹²³ I-metaiodobenzylguanidine (MIBG) scintigraphy at 39 years of age showed no abnormal accumulation. Follow up ¹³¹ I-adosterol scintigraphy performed one year later showed apparently abnormal uptake and slightly elevated uptake in left adrenal gland. Her physical examination was unremarkable except for mild hypertension. Routine blood chemistry was normal except for hypokalemia. Endocrinological date revealed suppressed plasma renin activity, and elevated plasma aldosterone concentration, and noradrenalin levels. Serial T2-weighted magnetic resonance imaging clearly demonstrated two distinct tumors. Furthermore, selective adrenal venous sampling with intravenous ACTH infusion indicated aldosterone-producing adrenocortical adenoma (APA) in left adrenal gland. During operation of adrenal tumor, blood pressure elevated markedly and complication of pheochromocytoma (PC) was suspected. Immunohistochemical findings after left adrenolectomy revealed that the adrenal mass was compatible with APA and PC. Risk of operation against undiagnosed PC is very high and, therefore, it must be diagnosed before surgery. Herein, we present an extremely rare case of the simultaneous occurrence of both APA and PC in an ipsilateral adrenal gland.

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Objectives. To evaluate the effect of atorvastatin on bone mass and markers of bone remodeling in patients with acute coronary syndrome according to the Lys656Asn leptin receptor gene polymorphism. Methods. Sixty-two patients with acute coronary syndrome were included. Patients were allocated to low and high doses of atorvastatin according to baseline levels of cholesterol and triglycerides and the index of vascular risk and were studied at hospital admission and at 12 months. Cholesterol, triglycerides, total calcium, phosphorus, magnesium, osteocalcin and urinary deoxypyridinoline were determined in all patients at baseline and at 12 months of follow up. Densitometric studies were conducted in the lumbar spine and hip. Patients with a T-score<-2.5 were considered osteoporotic. The Lys656Asn leptin receptor gene polymorphism was determined by PCR. Results. Forty-two patients were Lys/Lys homozygotic and 20 Lys/Asn heterozygotic. The prevalence of osteoporosis was 31% for the Lys/Lys genotype and 27% for the Lys/Asn genotype with no significant differences between groups. There was a significant increase in bone mineral density in the lumbar spine (1.117 ± 0.24 versus 1.135 ± 0.24, P = 0.008) in patients with the Lys/Lys genotype. Conclusion. Atorvastatin increases lumbar spine bone mineral density only in patients with the Lys/Lys genotype of the Lys656Asn polymorphism.

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Given the potential for β-cells to increase their mass, glucose intolerance might be ameliorated by a compensatory increase in β-cell mass. However, it remains uncertain whether such amelioration is feasible in vivo. In this study, we investigated glucose tolerance, islet morphology, and islet gene expression of Fatty Liver Shionogi (FLS) mice, a model for non-alcoholic fatty liver disease (NAFLD). Relative to control mice, FLS mice showed an age-dependent increase in glucose intolerance up to the age of 24 weeks, leading to the development of diabetes. After this time, glucose tolerance ameliorated spontaneously and diabetes resolved by 48 week of age, associated with marked hyperinsulinemia. Islets of the FLS mice demonstrated a marked increase in β-cell mass with an increase in β-cell numbers. Islet gene expression analysis in FLS mice demonstrated no changes in gene expression of glucokinase or insulin receptor substrate 2. These data demonstrated that the 24-week-old FLS mouse is a model for type 2 diabetes with NAFLD and that the 48-week-old FLS mouse exhibits spontaneous amelioration of type 2 diabetes associated with augmented β-cell number/mass.

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While the physiological role for calcium in the insulin action on glucose transport has been disputed, it was reassessed in a recent study by using a calcum chelator, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl) ester (BAPTA-AM). Although BAPTA has been widely used to study the role for calcium in a variety of cell functions, it has also been suggested to have properties unrelated to the calcium chelating activity. Here, we investigated the effects of BAPTA and dimethyl BAPTA on the cytoskeletons in 3T3-L1 adipocytes. Both calcium chelators were successfully loaded in 3T3-L1 adipocytes and inhibited endothelin-1-induced cytosolic calcium elevation. Confocal fluorescence microscopy revealed that BAPTA and dimethyl BAPTA caused profound depolymerization of the microtubules without affecting the cortical actin filaments in 3T3-L1 adipocytes. Biochemical quantification also showed that BAPTA and dimethyl BAPTA significantly decreased the amount of polymerized tubulin but had little effect on filamentous actin. Consistent with these results, GLUT4-positive perinuclear compartments were dispersed throughout the cytoplasm in BAPTA- or dimethyl BAPTA-loaded adipocytes. Intriguingly, these calcium chelators did not disrupt the microtubules in undifferentiated preadipocytes. The microtubule-depolymerizing property of BAPTA and dimethyl BAPTA is unrelated to calcium chelation, since the microtubules were resistant to depletion of cytosolic calcium by using a calcium ionophore A23187. Insulin-stimulated glucose transport was not affected by cytosolic calcium depletion with A23187, but significantly inhibited with BAPTA and dimethyl BAPTA to the extent similar to that with nocodazole. BAPTA and its derivatives should be used with caution in studies of cytoskeleton-related cell functions.

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Anaplastic thyroid carcinoma (ATC) is the most aggressive of thyroid cancers whose treatment is not yet established and mortality is extremely high. Recent in vitro studies have shown that valproic acid (VA), a newly identified histone deacetilase (HDAC) inhibitor, induces apoptosis, modulates differentiation gene expression of thyroid tumors and enhances the sensitivity of anaplastic cancer cell lines to doxorubicin. We report a case of successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy consisting of cisplatin and doxorubicin, external and intra-operative radiation and surgery. Tumor volume decreased by 50.7% under CT measurement and 44.6% under sonogram measurement over the course of the treatment. No significant rebound of tumor size was observed between each cycle of chemotherapy. Serial cytology performed via fine needle aspiration (FNA) presented a rapidly changing profile of cell types, starting with anaplastic and proceeding through increasingly well differentiated presentations. Only microscopic remnants of ATC cells were found in the histological examination of the resected thyroid. Ga scintigraphy and whole body PET scan six months after surgery revealed no evidence of recurrence or metastasis. As of Nov. 22, 2008, the patient is alive and disease free two years after diagnosis.

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Extrathyroid extension is a prominent prognostic factor of papillary thyroid carcinoma (PTC). In the UICC TNM classification, minimal extension to the sternothyroid muscle and perithyroid soft tissue is classified as T3 and further massive extension is classified as T4, the highest T grade. However, there have been few studies on the clinical significance of extension to the parathyroid gland in a large case series. In this study, we investigated the prognosis of PTC with extension to the parathyroid gland in a series of 3208 patients who underwent initial surgery between 1997 and 2004. Of these patients, 51 (1.6%) showed extension to the parathyroid gland on pathological examination. Twenty-one of these patients had massive extrathyroid extension to other adjacent organs corresponding to pT4. The remaining 30 were enrolled in this study. The disease-free survival (DFS) of these 30 patients was significantly better (p<0.0001) than that of pT4 patients and did not differ from that of patients showing minimal extrathyroid extension without extension to the parathyroid gland (p = 0.6264). Furthermore, none of these 30 patients died of carcinoma. Taken together, it is appropriate that extension to the parathyroid gland of PTC is graded as minimal extrathyroid extension (pT3), but not massive extension (pT4). Since minimal extension did not affect patient prognosis in our series, it is suggested that extension to the parathyroid gland has little clinical significance in PTC.

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In 2007, we screened urinary iodine (UI) concentrations in urban (Gomel city) and in rural areas (Hoiniki city) of the Gomel Region, Republic of Belarus, which was heavily contaminated by the accident at the Chernobyl Nuclear Power Plant, in order to evaluate the current state of iodine supplementation in these areas. Median levels of UI were 220.5 μg/L (151.5-358.5) μg/L in Gomel city, and 228.0 μg/L (130.0-337.5) μg/L in Hoiniki city. Urinary concentrations in Gomel city were significantly improved, as compared to our previous results in 2000 (p<0.001). There were no differences of UI concentrations between Gomel city and Hoiniki city (p = 0.39), and none of the samples showed moderate (<50 μg/L) or severe (<20 μg/L) iodine deficiency in either city. These results suggest that the state of iodine supplementation has improved in rural areas, as well as in urban areas in the Republic of Belarus, probably due to appropriate fortification of iodized salt in this region.

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A case of a brown tumor due to iatrogenic malabsorption following biliopancreatic diversion (BPD) is presented. A 52 year old women with a history of BPD 2 years before was referred to orthopedic surgery because of a painful lytic lesion of the left ankle. A bone biopsy revealed a giant cell tumor compatible with the diagnosis of a brown tumor. Subsequent metabolic evaluation showed severe 25-hydroxy vitamin D deficiency and secondary hyperparathyroidism (PTH 60 ng/L or twice the upper normal limit). Bone mineral density was decreased at the femoral neck (0.50 g/cm ² ; T score of -3.92 or 66% of the expected value) and lumbar spine (T score of -1.75 or 93% of the expected value). A brown tumor can be the presenting symptom of iatrogenic malabsorption due to BPD. This case illustrates the severity of potential bone complications after BPD and the necessity of lifelong surveillance and vitamin supplements after BPD.

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The prevalence and titer of glutamic acid decarboxylase antibody (GADAb) in type 1 diabetes mellitus (T1DM) has been reported to be higher in patients with autoimmune thyroid diseases (AITD) than those without them. However, we have no data about the influence of GADAb on AITD. We therefore studied the clinical characteristics of Graves' disease (GD) with GADAb in order to clarify the influence of GADAb on GD. Twelve GD patients with GADAb were enrolled and were compared to 40 GD patients without DM. The male to female ratio and age of onset of GD showed no statistical difference. The titer of TSH receptor antibody (TRAb) at the onset of GD was similar in both groups. Initial treatment with methimazole (MMI) was started in all patients with GADAb but radioactive iodine (RI) therapy was carried out in five patients because of adverse effects of MMI or poor control of hyperthyroidism. The initial titer of TRAb was significantly lower in patients treated with MMI alone compared to that in RI treated patients but none of the patients treated with MMI alone went into remission after more than 3-years of follow up. We also compared these GADAb-positive patients with 14 patients with diabetes mellitus who had matched clinical features. The number of diabetic patients who remained in possible remission was significantly higher than that of GADAb-positive patients (5 in 14 vs 0 in 12). Moreover, the rate of remission in the diabetic patients was no different from that of 21 control patients without diabetes followed for more than 7 years (5 in 14 vs 7 in 21). These data suggested that GADAb-positive patients are unlikely to go into remission with antithyroid agents. Therefore, definitive therapies might be preferable for the initial treatment of GADAb-positive patients.

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Genetic analysis of the KLF11 gene revealed two rare variants, A347S and T220M, segregating in families with early-onset type 2 diabetes, and one frequent polymorphic Q62R variant significantly associated with type 2 diabetes in Northern Europeans. Furthermore, it has been reported that over-expression of KLF11 has a deleterious effect on insulin promoter activity. Thus, an altered expression level of KLF11 may contribute to the occurrence of type 2 diabetes. To investigate the contribution of KLF11 to type 2 diabetes in Japanese, we surveyed the 5' flanking region of KLF11 by reporter assay and identified the minimal promoter region of the gene. The promoter region from -250 to +162 bp including five Sp1 binding sites showed basal promoter activity both in MIN6-m9 and HepG2 cells. We also examined the entire region of KLF11 to detect genetic variants. A total of 19 polymorphisms, six of which are novel, were identified, but none of them showed association with the occurrence of type 2 diabetes. Two of the identified polymorphisms, R29Q and S124F, are novel coding variants. Functional analyses of these variants were performed, and similarly reduced effects on transcriptional activities of insulin, catalase1, and the Smad7 gene were found. We conclude that variants of KLF11 are not a major factor in the occurrence of type 2 diabetes in Japanese. The promoter region of KLF11 identified in the present study should be useful in further elucidation of the transcriptional regulation mechanism of the gene and genetic analyses of type 2 diabetes.

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The present study was undertaken to determine retinol-binding protein 4 (RBP4) levels in subjects with diabetic nephropathy. A total of 149 type 2 diabetic subjects and 19 control subjects were enrolled. Serum levels of RBP4 were measured by a method of ELISA. Serum RBP4 levels were significantly greater in the subjects with type 2 diabetes mellitus than the controls (70.5 ± 35.3 vs. 40.1 ± 13.0 μg/ml, mean ± SD, p<0.01). Serum RBP4 levels were gradually increased according to the progression of diabetic nephropathy (p value in trend test: <0.001). Its elevation was significantly greater in the diabetic subjects with stages 1, 3B and 4 than the control subjects (Stage 1: 64.6 ± 29.7, Stage 3B: 123.3 ± 71.8, Stage 4: 91.4 ± 33.8 vs. Control: 40.1 ± 13.0 μg/ml, p<0.01). Similar results were obtained in the subjects based on the amount of albuminuria (Normo-: 64.6 ± 29.7, Micro-: 63.7 ± 29.4, and Marcoalbuminuria: 90.3 ± 44.6 μg/ml, p <0.001). Serum RBP4 levels had a positive correlation with serum creatinine levels(r = 0.377, p<0.001), and a negative correlation with 1/creatinine (r = -0.420, p<0.001). Also, there was a negative correlation between serum RBP4 and the estimated glomerular filtration rate(r = -0.436, p<0.001). Multiple regression analysis showed that estimated glomerular filtration rate was an independent determinant for increased serum RBP4 levels. There was no difference in serum RBP4 levels between the advanced nephropathy with and without macrovascular diseases. These results indicate an increase in serum RBP4 levels in the type 2 diabetic subjects, particularly complicated with advanced renal impairment.

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Somatostatin analogues such as octreotide are used to treat active acromegalic patients by reducing serum growth hormone (GH) levels. However, the acute effect of octreotide on GH secretion differs among patients. To elucidate factors influencing the acute effect of octreotide, we collected data from 56 patients with somatotroph adenoma from two institutions. We analyzed the correlation of the following factors with the acute effect of octreotide: immunohistochemical staining of somatostatin receptor subtype 2A (SSTR 2A), presence of gsp mutation, proliferative potentials analyzed by Ki-67 staining index (SI). We found that the acute effect of octreotide significantly correlated with two factors: Ki-67 SI and the plasma membrane-dominant staining pattern of SSTR 2A. Monovariate analysis revealed a statistically significant inverse relation of Ki-67 SI with the reduction of GH by octreotide. We assessed the contribution of each factor on the acute effect of octreotide by multivariate analysis. Significant multiple regression was confirmed with p value of 0.003. Post-test revealed that the plasma membrane-dominant staining pattern of SSTR 2A was significantly related to the reduction of GH by octreotide. These results show that the acute effect of octreotide is positively related to SSTR 2A staining on the plasma membrane.

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