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In this study, we compared the efficacy of a dipeptidyl peptidase-4 inhibitor (DPP4i) to improve glucose control in patients with type 2 diabetes mellitus (T2DM) with or without Hashimoto's thyroiditis (HT). First, we compared the change in glycated hemoglobin (HbA1c) between the hypothyroid condition (before levothyroxine sodium hydrate [LT4] treatment) and euthyroid condition (after LT4 treatment when patients had achieved euthyroidism for at least six months) in patients with T2DM and HT. Next, we compared the change in HbA1c levels before and six months of DPP4i treatment in patients with T2DM with and without HT. In hypothyroid condition the change in HbA1c after six months of DPP4i treatment was 0.13% ± 0.86%. The change in HbA1c levels from when patients first achieved euthyroidism to after six months in the euthyroid condition was 0.26% ± 0.90%. DPP4i efficacy in patients with T2DM and HT was reduced compared to patients with T2DM but without HT (-0.40 ± 0.90 vs. -0.99 ± 0.5, p = 0.0032). These data suggest that hypothyroidism does not impact on DPP4i efficacy. However, the effect of DPP4i in patients with T2DM and HT was reduced compared to that in T2DM patients without HT. An estimation of thyroid function before prescribing DPP4i may be useful tool for predicting the efficacy of DPP4i, allowing the ruling out complications from HT. more...

Anemia due to angiotensin receptor blocker (ARB) therapy has been previously reported in patients with diabetes mellitus with glomerular filtration rates of <60 mL min -1t> /1.73 m 2 . However, whether Japanese patients with type 2 diabetes mellitus (T2DM) receiving ARB therapy for chronic cardiac failure and chronic kidney disease develop reduced hemoglobin (Hb) levels has not been elucidated. Thus, this cross-sectional study was conducted, and Hb levels were compared between patients with T2DM with and without ARB administration. No significant difference in the prescribed proportion of antidiabetic medicines such as biguanide, sodium glucose co-transporter 2 inhibitors, and α-glucosidase inhibitors was found between the group treated with ARBs and the group without ARBs. Thus, we considered that the effects of antidiabetic medicines on the results were minimum. In this study, the Hb levels of patients who received ARBs (13.8 ± 1.7 g/dL) were significantly lower than those of patients without ARBs (14.9 ± 1.35 g/dL) (p = 0.034). The difference between this study and a previous study relies on eGFR levels. Thus, the eGFR levels of the patients in this study and the previous study were above 60 and below 60 mL min -1 /1.73 m 2 , respectively. Despite those differences, both studies showed that the use of ARBs was associated with a decrease in Hb levels in patients with T2DM. Thus, the evaluation of glycated Hb levels should be focused on whether ARBs are prescribed for patients with T2DM. more...

The Abbott FreeStyle Libre flash glucose monitoring system (FGM) is a recently introduced, but widespread continuous glucose monitoring system. While its mean absolute relative difference (MARD) value indicating its accuracy is acceptable with reference to the self-monitoring of blood glucose (SMBG) levels, few reports have examined the MARD in sensor glucose values of FGM (FGM-SG) with reference to plasma glucose (PG) levels and the factors determining it. We performed oral glucose tolerance tests (OGTTs) in 25 Japanese subjects without diabetes. Parkes error grid analyses showed that FGM-SG with either SMBG or PG levels as a reference met International Organization for Standardization criteria. The MARD in FGM-SG with reference to SMBG levels was 10.9 ± 4.1% during OGTTs. Surprisingly, the MARD in FGM-SG with reference to PG levels was 20.3 ± 10.3% during OGTTs, revealing a discrepancy in the accuracy of FGM-SG compared with that of PG levels; moreover, the MARD showed negative correlations with fasting blood sugar level, homeostasis model assessment insulin resistance index, and body mass index (BMI). Multiple regression analyses revealed that BMI contributed the most to the MARD when FGM-SG and PG level were compared, as lean individuals have a greater MARD regardless of glucose levels. Inaccurate FGM data could potentially increase the risk of inappropriate treatment; consideration of such factors is critical to ensure reliable FGM values. more...

Mutations in TBL1X, a component of the nuclear receptor co-repressor (N-CoR) and silencing mediator of retinoic acid and thyroid hormone receptor co-repressor complexes, have recently been implicated in isolated central hypothyroidism (CeH). However, the mechanisms by which TBL1X mutations affect negative feedback regulation in the hypothalamus-pituitary-thyroid axis remain unclear. N-CoR was previously reported to paradoxically enhance the ligand-independent stimulation of TRH and TSHβ gene promoters by thyroid hormone receptors (TR) in cell culture systems. We herein investigated whether TBL1X affects the unliganded TR-mediated stimulation of the promoter activities of genes negatively regulated by T3 in cooperation with N-CoR. In a hypothalamic neuronal cell line, the unliganded TR-mediated stimulation of the TRH gene promoter was significantly enhanced by co-transfected TBL1X, and the co-transfection of TBL1X with N-CoR further enhanced promoter activity. In contrast, the knockdown of endogenous Tbl1x using short interfering RNA significantly attenuated the N-CoR-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of N365Y or Y458C, TBL1X mutants identified in CeH patients, showed impaired co-activation with N-CoR for the ligand-independent stimulation of the TRH promoter by TR. In the absence of T3, similar or impaired enhancement of the TSHβ gene promoter by the wild type or TBL1X mutants, respectively, was observed in the presence of co-transfected TR and N-CoR in CV-1 cells. These results suggest that TBL1X is needed for the full activation of TRH and TSHβ gene promoters by unliganded TR. Mutations in TBL1X may cause CeH due to the impaired up-regulation of TRH and/or TSHβ gene transcription despite low T3 levels. more...

Adrenal aldosterone-producing adenomas (APA) are rarely associated with the clear co-secretion of cortisol. Somatic mutations of the potassium channel KCNJ5 gene, with the hotspots G151R and L168R, have been recently identified in patients with APA. However, whether APAs that secrete cortisol have these mutations remains unclear. We examined three patients with APAs showing clear autonomous secretion of cortisol who possessed a 1 mg dexamethasone suppression test (DST) with a failure of the serum cortisol level to drop below 3.0 μg/dL, a morning plasma ACTH level of less than 10 pg/mL, and suppressed accumulation in the intact adrenal on (131)I- adosterol scintigraphy, or postoperative adrenal insufficiency. Laparoscopic adrenectomy revealed all tumors to be golden yellow, and histological examination confirmed them to be adrenocortical adenomas. All these patients required replacement therapy with hydrocortisone after surgery. Sequencing demonstrated that 2 of three cases showed a mutation of the KCNJ5 gene, one with c.451G>A, p.G151R and one with c.503T>G, p.L168R. Furthermore, the mRNA levels of steroidogenic enzymes including CYP11B1, CYP11B2, HSD3B2, CYP17A1, CYP11A1 and KCNJ5 in the 3 cases did not differ from those in 8 pure APAs not showing any of the above conditions for autonomous cortisol secretion. In addition, all 8 pure APAs harbored mutations of the KCNJ5 gene. These findings suggested that at least some aldosterone- and cortisol-co-secreting adrenal tumors have mutations of the KCNJ5 gene, suggesting the origin to be APA, and pure APAs may show a high incidence of KCNJ5 mutations. more...

Tumors in multiple endocrine neoplasia type 1 (MEN1) are generally benign. Since information on the pathogenesis of MEN1 in malignant cases is limited, we conducted genetic analysis and compared the expression of menin, p27(Kip1)(p27)/CDKN1B and p18(Ink4C)(p18)/CDKN2C with levels in benign cases. We describe the case of a 56 year-old male with an atypical prolactinoma and malignant pancreatic neuroenocrine tumor. At age 50, he had undergone transsphenoidal surgery to remove a prolactinoma. However, the tumor relapsed twice. Histological analysis of the recurrent prolactinoma revealed the presence of prolactin, a high MIB-1 index (32.1 %), p53-positive cells (0.2%), and an unusual association with FSH-positive cells. A few years later, he was also found to have a non-functioning pancreatic tumor with probable metastasis to the extradullar region. The metastatic region tested positive for chromogranin and CD56, and negative for prolactin, with 1.2 % of cells p53-positive. Although genetic analyses of the MEN1, p27, and p18 genes demonstrated no mutation, numbers of menin, p27 and p18 immuno-positive cells were significantly down-regulated in the recurrent prolactinoma, but that of p18 was intact in the metastatic region. Furthermore, MEN1 and p27 mRNA levels of the recurrent prolactinoma were down-regulated, particularly the MEN1 mRNA level, compared to levels in 10 cases of benign prolactinoma, while the p18 mRNA level was similar to that of normal pituitary. The tumor in this case may be a subtype of MEN1 showing more aggressive and malignant features probably induced by low levels of menin and p27. more...