Faculty Profiles - SUGIYAMA Mariko

Papers - SUGIYAMA Mariko

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GABAB Receptor Signaling in the Mesolimbic System Suppresses Binge-like Consumption of a High-Fat Diet. International journal Open Access

Taku Tsunekawa, Ryoichi Banno, Hiroshi Yaginuma, Keigo Taki, Akira Mizoguchi, Mariko Sugiyama, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Bernhard Bettler, Hiroshi Arima

iScience Vol. 20 page： 337 - + 2019.10

Language：English Publishing type：Research paper (scientific journal)

Binge eating could contribute to the development of obesity, and previous studies suggest that gamma-aminobutyric acid (GABA) type B receptor (GABABR) signaling is involved in the regulation of binge eating. Here, we show that time-restricted access to a high-fat diet (HFD) induces binge-like eating behavior in wild-type mice. HFD consumption during restricted time was significantly increased in corticostriatal neuron-specific GABABR-deficient mice compared with wild-type mice. Furthermore, the GABABR agonist baclofen suppressed HFD intake during restricted time in wild-type mice but not in corticostriatal or dopaminergic neuron-specific GABABR-deficient mice. In contrast, there were no significant differences in food consumption among genotypes under ad libitum access to HFD. Thus, our data show that the mesolimbic system regulates food consumption under time-restricted but not ad libitum access to HFD and have identified a mechanism by which GABABR signaling suppresses binge-like eating of HFD.

DOI： 10.1016/j.isci.2019.09.032

PTP1B deficiency improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under high-fat diet conditions. International journal

Mariko Sugiyama, Ryoichi Banno, Akira Mizoguchi, Takashi Tominaga, Taku Tsunekawa, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Yoshiaki Morishita, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Hiroshi Arima

Biochemical and biophysical research communications Vol. 488 ( 1 ) page： 116 - 121 2017.6

Language：English Publishing type：Research paper (scientific journal)

Hypothalamic insulin receptor signaling regulates energy balance and glucose homeostasis via agouti-related protein (AgRP). While protein tyrosine phosphatase 1B (PTP1B) is classically known to be a negative regulator of peripheral insulin signaling by dephosphorylating both insulin receptor β (IRβ) and insulin receptor substrate, the role of PTP1B in hypothalamic insulin signaling remains to be fully elucidated. In the present study, we investigated the role of PTP1B in hypothalamic insulin signaling using PTP1B deficient (KO) mice in vivo and ex vivo. For the in vivo study, hypothalamic insulin resistance induced by a high-fat diet (HFD) improved in KO mice compared to wild-type (WT) mice. Hypothalamic AgRP mRNA expression levels were also significantly decreased in KO mice independent of body weight changes. In an ex vivo study using hypothalamic organotypic cultures, insulin treatment significantly increased the phosphorylation of both IRβ and Akt in the hypothalamus of KO mice compared to WT mice, and also significantly decreased AgRP mRNA expression levels in KO mice. While incubation with inhibitors of phosphatidylinositol-3 kinase (PI3K) had no effect on basal levels of Akt phosphorylation, these suppressed insulin induction of Akt phosphorylation to almost basal levels in WT and KO mice. The inhibition of the PI3K-Akt pathway blocked the downregulation of AgRP mRNA expression in KO mice treated with insulin. These data suggest that PTP1B acts on the hypothalamic insulin signaling via the PI3K-Akt pathway. Together, our results suggest a deficiency of PTP1B improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under HFD conditions.

DOI： 10.1016/j.bbrc.2017.05.019

Deficiency of PTP1B Attenuates Hypothalamic Inflammation via Activation of the JAK2-STAT3 Pathway in Microglia. International journal Open Access

Taku Tsunekawa, Ryoichi Banno, Akira Mizoguchi, Mariko Sugiyama, Takashi Tominaga, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Yoshihisa Sugimura, Hiroshi Arima

EBioMedicine Vol. 16 page： 172 - 183 2017.2

Language：English Publishing type：Research paper (scientific journal)

Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions.

DOI： 10.1016/j.ebiom.2017.01.007

Hypothalamic Contribution to Pituitary Functions Is Recapitulated In Vitro Using 3D-Cultured Human iPS Cells. International journal Open Access

Takatoshi Kasai, Hidetaka Suga, Mayu Sakakibara, Chikafumi Ozone, Ryusaku Matsumoto, Mayuko Kano, Kazuki Mitsumoto, Koichiro Ogawa, Yu Kodani, Hiroshi Nagasaki, Naoko Inoshita, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Motomitsu Goto, Ryoichi Banno, Jun Takahashi, Hiroshi Arima

Cell reports Vol. 30 ( 1 ) page： 18 - + 2020.1

Language：English Publishing type：Research paper (scientific journal)

The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.

DOI： 10.1016/j.celrep.2019.12.009

Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled trial. International journal Open Access

Takeshi Onoue, Motomitsu Goto, Eri Wada, Mariko Furukawa, Takayuki Okuji, Norio Okada, Tomoko Kobayashi, Shintaro Iwama, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Yoshiaki Morishita, Yusuke Seino, Hidetaka Suga, Ryoichi Banno, Yoji Hamada, Masahiko Ando, Etsuko Yamamori, Hiroshi Arima

PloS one Vol. 15 ( 1 ) page： e0228004 2020.1

Language：English Publishing type：Research paper (scientific journal)

Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.

DOI： 10.1371/journal.pone.0228004

Diagnosis of central diabetes insipidus using a vasopressin radioimmunoassay during hypertonic saline infusion. Open Access

Hiroshi Takagi, Daisuke Hagiwara, Tomoko Handa, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Kunihiko Takahashi, Shigeyuki Matsui, Hiroshi Arima

Endocrine journal Vol. 67 ( 3 ) page： 267 - 274 2020

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japan Endocrine Society

Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia caused by impairment of arginine vasopressin (AVP) secretion. In this study, we evaluated plasma AVP concentrations during a hypertonic saline infusion test using a new AVP radioimmunoassay (RIA) which is now available in Japan. Thirteen control subjects, mostly with hypothalamo-pituitary disease but without CDI, and 13 patients with CDI were enrolled in the study. Whether or not subjects had CDI was determined based on the totality of clinical data, which included urine volumes and osmolality. Regression analysis of plasma AVP and serum Na concentrations revealed that the gradient was significantly lower in the CDI group than in the control group. The area under the receiver-operating-characteristic (ROC) curve was 0.99, and the <0.1 gradient cut-off values for the simple regression line to distinguish CDI from control had a 100% sensitivity and a 77% specificity. The ROC analysis with estimated plasma AVP concentrations at a serum Na concentration of 149 mEq/L showed that the area under the ROC curve was 1.0 and the <1.0 pg/mL cut-off values of plasma AVP had a 99% sensitivity and a 95% specificity. We conclude that measurement of AVP by RIA during a hypertonic saline infusion test can differentiate patients with CDI from those without CDI with a high degree of accuracy. Further investigation is required to confirm whether the cut-off values shown in this study are also applicable to a diagnosis of partial CDI or a differential diagnosis between CDI and primary polydipsia.

DOI： 10.1507/endocrj.EJ19-0224

Improved methods for the differentiation of hypothalamic vasopressin neurons using mouse induced pluripotent stem cells. International journal Open Access

Kazuki Mitsumoto, Hidetaka Suga, Mayu Sakakibara, Mika Soen, Tomiko Yamada, Hajime Ozaki, Takashi Nagai, Mayuko Kano, Takatoshi Kasai, Chikafumi Ozone, Koichiro Ogawa, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Ryoichi Banno, Hiroshi Arima

Stem cell research Vol. 40 page： 101572 - 101572 2019.10

Language：English Publishing type：Research paper (scientific journal)

High differentiation efficiency is one of the most important factors in developing an in vitro model from pluripotent stem cells. In this report, we improved the handling technique applied to mouse-induced pluripotent stem (iPS) cells, resulting in better differentiation into hypothalamic vasopressin (AVP) neurons. We modified the culture procedure to make the maintenance of iPS cells in an undifferentiated state much easier. Three-dimensional floating culture was demonstrated to be effective for mouse iPS cells. We also improved the differentiation method with regards to embryology, resulting in a greater number of bigger colonies of AVP neurons differentiating from mouse iPS cells. Fgf8, which was not used in the original differentiation method, increased iPS differentiation into AVP neurons. These refinements will be useful as a valuable tool for the modeling of degenerative disease in AVP neurons in vitro using disease-specific iPS cells in future studies.

DOI： 10.1016/j.scr.2019.101572

Tanycyte-Like Cells Derived From Mouse Embryonic Stem Culture Show Hypothalamic Neural Stem/Progenitor Cell Functions. International journal Open Access

Mayuko Kano, Hidetaka Suga, Takeshi Ishihara, Mayu Sakakibara, Mika Soen, Tomiko Yamada, Hajime Ozaki, Kazuki Mitsumoto, Takatoshi Kasai, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Ryoichi Banno, Hiroshi Arima

Endocrinology Vol. 160 ( 7 ) page： 1701 - 1718 2019.7

Language：English Publishing type：Research paper (scientific journal)

Tanycytes have recently been accepted as neural stem/progenitor cells in the postnatal hypothalamus. Persistent retina and anterior neural fold homeobox (Rax) expression is characteristic of tanycytes in contrast to its transient expression of whole hypothalamic precursors. In this study, we found that Rax+ residual cells in the maturation phase of hypothalamic differentiation in mouse embryonic stem cell (mESC) cultures had similar characteristics to ventral tanycytes. They expressed typical neural stem/progenitor cell markers, including Sox2, vimentin, and nestin, and differentiated into mature neurons and glial cells. Quantitative RT-PCR analysis showed that Rax+ residual cells expressed Fgf-10, Fgf-18, and Lhx2, which are expressed by ventral tanycytes. They highly expressed tanycyte-specific genes Dio2 and Gpr50 compared with Rax+ early hypothalamic progenitor cells. Therefore, Rax+ residual cells in the maturation phase of hypothalamic differentiation were considered to be more differentiated and similar to late progenitor cells and tanycytes. They self-renewed and formed neurospheres when cultured with exogenous FGF-2. Additionally, these Rax+ neurospheres differentiated into three neuronal lineages (neurons, astrocytes, and oligodendrocytes), including neuropeptide Y+ neuron, that are reported to be differentiated from ventral tanycytes toward the arcuate nuclei. Thus, Rax+ residual cells were multipotent neural stem/progenitor cells. Rax+ neurospheres were stably passaged and retained high Sox2 expression even after multiple passages. These results suggest the successful induction of Rax+ tanycyte-like cells from mESCs [induced tanycyte-like (iTan) cells]. These hypothalamic neural stem/progenitor cells may have potential in regenerative medicine and as a research tool.

DOI： 10.1210/en.2019-00105

Sequestosome 1 (SQSTM1/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture. International journal

Takashi Tominaga, Motomitsu Goto, Takeshi Onoue, Akira Mizoguchi, Mariko Sugiyama, Taku Tsunekawa, Daisuke Hagiwara, Yoshiaki Morishita, Yoshihiro Ito, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Neuroscience letters Vol. 656 page： 103 - 107 2017.8

Language：English Publishing type：Research paper (scientific journal)

Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild-type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-eIF2α protein expression in both WT and p62KO cultures, but all peak values were greater in p62KO cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity.

DOI： 10.1016/j.neulet.2017.06.014

Concurrent Pituitary and Thyroid Immune-Related Adverse Events after Immune Checkpoint Inhibitors Associated with HLA-DR15-related Haplotypes.

Kobayashi T, Iwama S, Sugiyama E, Koyama S, Izuchi T, Suzuki K, Murase T, Ando M, Inaba H, Izumi H, Goto K, Handa T, Onoue T, Miyata T, Sugiyama M, Hagiwara D, Suga H, Banno R, Akatsuka Y, Nishikawa H, Arima H, Hospitals Group NUR

Cancer immunology research 2026.2

Defining a serum cortisol cutoff level post-CRH stimulation for diagnosing ACTH deficiency: A retrospective study validated by a nationwide registry Open Access

Izuchi, T; Iwama, S; Yamagami, A; Kobayashi, T; Suzuki, K; Murase, T; Ando, M; Murasawa, S; Mukai, K; Takagi, H; Fukuoka, H; Handa, T; Onoue, T; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Banno, R; Tahara, S; Nishiyama, M; Kageyama, K; Otsuki, M; Arima, H

FRONTIERS IN ENDOCRINOLOGY Vol. 17 page： 1741709 2026.2

Language：English Publisher：Frontiers in Endocrinology

Background: The corticotropin-releasing hormone (CRH) stimulation test is used to diagnose adrenocorticotropic hormone (ACTH) deficiency; however, the serum cortisol cutoff value indicating impaired response on this test (18 µg/dL [approximately 500 nmol/L]) was established from the insulin tolerance test. We aimed to define a serum cortisol cutoff after CRH stimulation to diagnose ACTH deficiency. Methods: Patients who underwent CRH stimulation at Nagoya University Hospital from 2016 to 2022 were divided retrospectively into two groups based on the need for hydrocortisone replacement at final follow-up (discovery cohort). Plasma ACTH and serum cortisol levels were measured at baseline and 30, 60, 90, and 120 minutes post-CRH administration using a current monoclonal antibody-based cortisol assay. The optimal cortisol cutoffs at each time point were determined by receiver operating characteristic (ROC) analysis. These cutoffs were validated using a nationwide disease registry in Japan (validation cohort). Results: In the discovery cohort (n = 227), cortisol levels were significantly higher in patients who did not receive hydrocortisone therapy (n = 136) than in those who did (n = 91) at all time points (p < 0.001). ROC analysis revealed that a 30-minute post-CRH cortisol level of 12.6 µg/dL (347.6 nmol/L) provided the best diagnostic performance to identify patients not requiring hydrocortisone therapy (sensitivity: 88.2%; specificity: 92.3%; AUC: 0.969). In the validation cohort (n = 52), this cutoff was confirmed as optimal (sensitivity: 81.0%; specificity: 86.4%; accuracy: 83.7%). Conclusion: A 30-minute post-CRH serum cortisol level of 12.6 µg/dL is a useful cutoff for diagnosing ACTH deficiency.

DOI： 10.3389/fendo.2026.1741709

The Time of the Hypertonic Saline Infusion Test for the Diagnosis of AVP Deficiency Can Be Shortened With LC-MS/MS Open Access

Handa, T; Hagiwara, D; Maeda, R; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Iwama, S; Suga, H; Banno, R; Kuwatsuka, Y; Arima, H

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Vol. 111 ( 2 ) page： e382 - e389 2026.2

Language：English Publisher：Journal of Clinical Endocrinology and Metabolism

Context In clinical practice, plasma arginine vasopressin (AVP) concentrations have been measured with a radioimmunoassay (RIA). However, RIAs have limitations, such as long turnaround time, use of radioisotopes, and restricted antibody availability. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) offers a promising alternative, eliminating the need for radioisotopes and antibodies while providing faster results. Objective This study aimed to assess the usefulness of LC-MS/MS for measuring plasma AVP concentrations in diagnosing AVP deficiency (AVP-D). Methods We included 16 patients with AVP-D and 28 controls. All participants underwent a hypertonic saline infusion test (HST), during which plasma AVP concentrations were measured using RIA and LC-MS/MS. Regression coefficients (gradients) for serum sodium vs plasma AVP concentrations were evaluated at 90 and 120 minutes, and receiver-operating characteristic analyses were performed based on these regression coefficients. Results The area under the receiver-operating characteristic curve at 90 minutes was 0.97 (95% CI, 0.83-1.00) and 0.93 (95% CI, 0.80-0.98) for LC-MS/MS and RIA, respectively. A regression gradient cutoff with optimal values distinguished AVP-D from controls with a sensitivity of 100% in LC-MS/MS and RIA, whereas the specificity was 96% and 81% with LC-MS/MS and RIA, respectively. Sensitivity or specificity did not differ in 120 minutes between the 2 methods. Conclusion LC-MS/MS demonstrated superior diagnostic accuracy for AVP-D at 90 minutes of HST, indicating that the HST time can be shortened from 120 to 90 minutes by measuring AVP with LC-MS/MS. Clinical trial registration The study was registered with the University Hospital Medical Information Network (UMIN) registry (UMIN000043023).

DOI： 10.1210/clinem/dgaf432

Increased HbA1c relative to actual glycemic control in patients treated with sodium-glucose cotransporter 2 inhibitors Open Access

Mizutani, K; Uenishi, E; Onoue, T; Maeda, R; Suzuki, K; Handa, T; Kobayashi, T; Iwama, S; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Okazaki, M; Hashizume, A; Arima, H

JOURNAL OF DIABETES INVESTIGATION Vol. 17 ( 1 ) page： 34 - 41 2026.1

Language：English Publisher：Journal of Diabetes Investigation

Aims/Introduction: Among patients with diabetes receiving sodium–glucose cotransporter 2 (SGLT2) inhibitors, HbA1c levels are higher than glycated albumin levels. This study therefore aimed to evaluate the discrepancy between HbA1c and glucose management indicator (GMI), an index of glucose management derived from continuous glucose monitoring, in this population. Materials and Methods: This multicenter retrospective cohort study included patients with diabetes in whom HbA1c and GMI were simultaneously measured at two Japanese institutions. Data were collected when HbA1c levels had stabilized for at least 6 months after the administration of an oral hypoglycemic agent. The primary outcome was the discrepancy between HbA1c and GMI among patients receiving SGLT2 inhibitors and those receiving other oral hypoglycemic agents. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding factors. Results: In total, 136 patients were included; of these, 109 and 27 were included in the SGLT2 inhibitor group and control group, respectively. After IPTW adjustment, the discrepancy between HbA1c and GMI (HbA1c–GMI) was significantly higher in the SGLT2 inhibitor group than in the control group (β = 0.42; 95% confidence interval 0.14–0.70; P = 0.003). Conclusions: Patients receiving SGLT2 inhibitors may have increased HbA1c relative to their actual glycemic control.

DOI： 10.1111/jdi.70191

Increased risk of hyperthyroidism induced by immune checkpoint inhibitors in patients with existing or prior Graves' disease: a nested prospective cohort study with propensity score matching Open Access

Suzuki, K; Kobayashi, T; Izuchi, T; Murase, T; Ando, M; Handa, T; Onoue, T; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Banno, R; Arima, H; Iwama, S

FRONTIERS IN ENDOCRINOLOGY Vol. 16 page： 1701500 2025.12

Language：English Publisher：Frontiers in Endocrinology

Background: Thyroid dysfunction induced by immune checkpoint inhibitors (ICIs) commonly manifests as destructive thyroiditis and hypothyroidism, while hyperthyroidism (Graves’ disease) is rare. However, the clinical characteristics of thyroid dysfunction in patients with existing or prior Graves’ disease treated with ICIs remain unclear. Methods: A case-control study was performed using a prospective cohort of patients treated with ICIs between November 2015 and January 2024. At baseline, cases had Graves’ disease without overt thyroid dysfunction or prior Graves’ disease and were matched 1:5 with controls by age, gender, antithyroid antibody status at baseline, and ICI type. The incidence of thyroid dysfunction induced by ICIs was compared between cases and controls. The incidence of hyperthyroidism was compared with the exacerbation rate in ICI-untreated outpatients with Graves’ disease who were in remission or had no overt thyroid dysfunction for ≥1 year without changes in low-dose antithyroid medication. Results: Nineteen patients (13 in remission and 6 receiving thiamazole at baseline) were included and matched with 95 controls. During follow-up, 5 cases negative for thyroid-stimulating hormone receptor antibody (TRAb) at baseline developed thyrotoxicosis: 3 were TRAb-positive (2 with increased uptake on thyroid scintigraphy) suggesting hyperthyroidism, and 2 had destructive thyroiditis (TRAb-negative). The incidence of hyperthyroidism was significantly higher in cases than in controls (3/19 [15.8%] vs 0/95 [0%], p < 0.05), whereas the incidence of destructive thyroiditis (2/19 [10.5%] vs. 15/95 [15.8%], p = 0.734) or isolated hypothyroidism (0/19 [0%] vs. 13/95 [13.7%], p = 0.121) did not differ between groups. The incidence of hyperthyroidism was also higher in cases than in outpatients with ICI-unrelated Graves’ disease (3/19 [15.8%] vs 10/269 [3.7%], respectively; p < 0.05). Conclusion: Patients with existing or prior Graves’ disease have an increased risk of hyperthyroidism following ICI treatment, highlighting their need for careful differential diagnosis of thyrotoxicosis.

DOI： 10.3389/fendo.2025.1701500

Phagophores originate from endoplasmic reticulum membranes in vasopressin neurons in a mouse model of familial neurohypophysial diabetes insipidus Open Access

Miyata, T; Hagiwara, D; Ashida, R; Naito, S; Kawaguchi, Y; Handa, T; Kobayashi, T; Sugiyama, M; Onoue, T; Iwama, S; Suga, H; Banno, R; Matsumoto, M; Urakubo, H; Ohno, N; Arima, H

CELL AND TISSUE RESEARCH Vol. 402 ( 2 ) page： 139 - 144 2025.11

Language：English Publisher：Cell and Tissue Research

Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) gene. In AVP neurons in a mouse model of FNDI, aggregates of mutant AVP precursors accumulate within a specific compartment of the endoplasmic reticulum (ER). However, as FNDI mice aged, or were exposed to repeated water deprivation, the ER lumen dilated and mutant aggregates dispersed throughout the ER. Meanwhile, autophagic isolation membranes, known as phagophores, emerged to envelop ER containing these aggregates, indicating induction of ER-phagy. Previous in vitro studies showed that phagophores originate from ER membranes, but the structural relationship between phagophores and the ER membrane in vivo remains unknown. In this study, we used serial block-face scanning electron microscopy to investigate the structural relationship between phagophores, ER membranes, and protein aggregates within dilated ER of AVP neurons from FNDI mice subjected to intermittent water deprivation for 4 weeks. Three-dimensional analysis revealed that phagophores enveloped aggregates located within the dilated ER. Serial imaging further demonstrated a physical connection between these phagophores and intact ER membranes. This study provides the first in vivo evidence of the structural continuity between phagophores and the ER membrane in AVP neurons in a mouse model of FNDI.

DOI： 10.1007/s00441-025-04013-w

Reticulon 4 reflects endoplasmic reticulum stress in arginine vasopressin neurons Open Access

Kawaguchi, Y; Hodai, Y; Naito, S; Kondo, Y; Tsumura, T; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Iwama, S; Suga, H; Banno, R; Arima, H; Hagiwara, D

NEUROREPORT Vol. 36 ( 10 ) page： 540 - 546 2025.7

Language：English Publisher：Neuroreport

Objectives Arginine vasopressin (AVP) is synthesized in the magnocellular supraoptic nucleus and paraventricular nuclei of the hypothalamus, where AVP neurons function under a consistently high demand for AVP production. AVP neurons are subject to endoplasmic reticulum (ER) stress even under basal conditions, and this ER stress is further exacerbated when AVP production increases due to dehydration. Reticulon (RTN) is essential for ER formation and stabilization and plays a critical role in membrane morphogenesis within the ER. This study aimed to investigate the expression of RTN family members in hypothalamic AVP neurons. Methods Fluorescence immunohistochemistry and in-situ hybridization were employed to examine the expression of RTN family members in hypothalamic AVP neurons of adult male mice. Water deprivation and treatment with a chemical chaperone 4-phenylbutyric acid were used to increase and decrease the ER stress of AVP neurons, respectively. Results Among the RTN family members, only RTN4 was found to be expressed in hypothalamic AVP neurons. RTN4 was colocalized with ER organelle markers, including immunoglobulin heavy chain binding protein and calnexin. Furthermore, RTN4 expression increased during ER stress induced by water deprivation. On the other hand, increased RTN4 expression by water deprivation was attenuated by 4-phenylbutyric acid treatment. Conclusions Our results suggest that RTN4 expression in AVP neurons is closely associated with ER stress caused by increased protein production in neuroendocrine cells.

DOI： 10.1097/WNR.0000000000002174

Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study Open Access

Iwama, S; Kobayashi, T; Izuchi, T; Suzuki, K; Murase, T; Ando, M; Handa, T; Onoue, T; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Banno, R; Hase, T; Mori, S; Sano, T; Akamatsu, S; Akiyama, M; Ishii, M; Arima, H

ENDOCRINOLOGY AND METABOLISM Vol. 40 ( 3 ) page： 459 - 468 2025.6

Language：English Publisher：Endocrinology and Metabolism

Background: Anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) monotherapy induces two types of pituitary immunerelated adverse events (irAEs): multiple pituitary hormone deficiency (Multi-D; impairment of ≥2 anterior pituitary hormones) and isolated adrenocorticotropic hormone (ACTH) deficiency (IAD). Combination therapy with CTLA-4-Ab and anti-programmed cell death-1 antibody (PD-1/CTLA-4-Abs), which is increasingly replacing CTLA-4-Ab monotherapy, frequently causes pituitary irAEs; however, whether it increases Multi-D/IAD incidence is unknown. Methods: In total, 74 and 748 patients with malignancies treated with PD-1/CTLA-4-Abs and PD-1-Ab, respectively, were prospectively evaluated for ACTH and cortisol levels at baseline and every 6 weeks after treatment initiation, and then observed until the last clinical visit. The characteristics of pituitary irAEs were evaluated by pituitary stimulation tests and compared with those induced by PD-1-Ab monotherapy. Results: PD-1/CTLA-4-Abs therapy showed higher incidence rates of pituitary irAEs (16/74 [21.6%] vs. 25/748 [3.3%], P<0.001), Multi-D (9/74 [12.2%] vs. 2/748 [0.3%], P<0.001), and IAD (7/74 [9.5%] vs. 23/748 [3.1%], P=0.014) than PD-1-Ab monotherapy. ACTH deficiency was observed in all cases, whereas the prevalence rates of luteinizing hormone deficiency (8/16 [50.0%] vs. 1/25 [4.0%]), follicle-stimulating hormone deficiency (6/16 [37.5%] vs. 1/25 [4.0%]), and thyrotropin deficiency (4/16 [25.0%] vs. 0/25 [0%]) were significantly higher after PD-1/CTLA-4-Abs than after PD-1-Ab treatment. Pituitary enlargement, which was observed only in the Multi-D cases, was significantly more frequent after PD-1/CTLA-4-Abs than after PD-1-Ab treatment (6/16 [37.5%] vs. 0/25 [0%], P=0.002). Conclusion: This prospective study revealed high risks of both Multi-D and IAD under PD-1/CTLA-4-Abs treatment, emphasizing the need for careful evaluation of pituitary function.

DOI： 10.3803/EnM.2024.2180

Effects of Combination Treatment with Leptin and Liraglutide on Glucose Metabolism in Insulin-Dependent Diabetic Mice Open Access

Fu, LL; Sugiyama, M; Kamal, S; Ide, T; Takeda, T; Kuno, M; Takagi, H; Koike, T; Arima, H; Banno, R

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol. 26 ( 10 ) 2025.5

Language：English Publisher：International Journal of Molecular Sciences

We investigated whether the peripheral co-administration of leptin and liraglutide (a glucagon-like peptide-1 receptor agonist) improved glucose metabolism in a mouse model of insulin-dependent diabetes mellitus (IDDM). Twelve-week-old male C57BL/6J mice were injected intraperitoneally with a high dose of streptozotocin to induce IDDM or vehicle-treated. Mice with IDDM were divided into four groups: leptin treatment alone (LEP), liraglutide treatment alone (LIRA), co-administration of leptin and liraglutide treatment (LEP+LIRA), untreated mice (UNT). Vehicle-treated mice were the healthy controls (HC). The blood glucose (BG) levels were measured, and a glucose tolerance test (GTT) was performed to compare the five groups. Leptin was administered peripherally at 20 μg/day using an osmotic pump, while liraglutide was administered subcutaneously at 1000 μg/kg/day. Monotherapy with leptin or liraglutide significantly improved glucose metabolism, as assessed by comparing BG levels and GTTs with those of the UNT group. Mice in the LEP+LIRA group showed even greater improvements in glucose metabolism than the monotherapy groups. Notably, glucose metabolism in the LEP+LIRA group improved comparably with the HC group. Thus, the peripheral co-administration of leptin and liraglutide effectively improved glucose metabolism in mice with IDDM without the use of insulin.

DOI： 10.3390/ijms26104595

Continuous glucose monitoring with low-glucose alerts in insulin-treated drivers with diabetes: A randomized crossover study.

Maeda R, Onoue T, Mizutani K, Suzuki K, Handa T, Kobayashi T, Iwama S, Miyata T, Sugiyama M, Hagiwara D, Suga H, Kinoshita F, Arima H

Diabetes research and clinical practice page： 112074 2025.2

Dapagliflozin increased pancreatic beta cell proliferation and insulinogenic index in mice fed a high-fat and high-sodium chloride diet. International journal Open Access

Tomonori Hirose, Hiroshi Takagi, Mitsuhiro Kuno, Tomoyuki Sasaki, Keigo Taki, Yoshihiro Ito, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Biochemical and biophysical research communications Vol. 749 page： 151364 - 151364 2025.2

Language：English Publishing type：Research paper (scientific journal)

People in Eastern Asia, including Japan, traditionally consume higher amounts of sodium chloride than in the United States and Western Europe, and it is common knowledge that impaired insulin secretion-rather than insulin resistance-is highly prevalent in Asian people who have diabetes mellitus. We previously reported that mice fed a high-fat and high-sodium chloride (HFHS) diet had a relatively lower degree of obesity than mice fed a high-fat diet, but had a comparatively impaired insulin secretion. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to dampen down the sympathetic nervous system, which reportedly is activated by a high-sodium chloride diet. In this study, we examined the effects of dapagliflozin, a SGLT2 inhibitor, on glucose metabolism and insulin secretion in mice fed a HFHS diet. C57BL6/J mice were fed a HFHS diet for 6 weeks and subsequently divided into two treatment groups fed: (1) a HFHS diet mixed with dapagliflozin for up to 3 weeks (HFHS + Da) and (2) a HFHS diet without dapagliflozin (HFHS). Dapagliflozin improved glucose tolerance and the insulinogenic index accompanied by increased pancreatic beta cell proliferation. Furthermore, dapagliflozin decreased both the tyrosine hydroxylase-positive area in pancreatic islets and catecholamine excretion in urine. Our results suggest that dapagliflozin improved insulin secretion by suppressing sympathetic nerve activation in mice fed a HFHS diet.

DOI： 10.1016/j.bbrc.2025.151364

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