Faculty Profiles - ARIMA, Hiroshi

Consensus on the Diagnosis of Cushing's Disease: A Collaborative Statement from the Korean Endocrine Society and Japan Endocrine Society Open Access

Lee, J; Fukuoka, H; Park, SS; Hong, AR; Kim, JH; Chin, SO; Baek, HS; Lim, DJ; Kageyama, K; Nishiyama, M; Tahara, S; Oyama, K; Sugawara, A; Yamashita, M; Inoshita, N; Arima, H; Kim, BJ; Chung, YS; Yoo, SJ; Otsuki, M; Kim, MK

ENDOCRINOLOGY AND METABOLISM Vol. 41 ( 1 ) page： 1 - 13 2026.2

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

Keigo Mizutani, Eita Uenishi, Takeshi Onoue, Ryutaro Maeda, Koji Suzuki, Tomoko Handa, Tomoko Kobayashi, Shintaro Iwama, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Masaki Okazaki, Atsushi Hashizume, Hiroshi Arima

Journal of diabetes investigation Vol. 17 ( 1 ) page： 34 - 41 2026.1

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

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

Consensus on the diagnosis of Cushing's disease: a collaborative statement from the Korean Endocrine Society and Japan Endocrine Society Open Access

Lee, J; Fukuoka, H; Park, SS; Hong, AR; Kim, JH; Chin, SO; Baek, HS; Lim, DJ; Kageyama, K; Nishiyama, M; Tahara, S; Oyama, KI; Sugawara, A; Yamashita, M; Inoshita, N; Arima, H; Kim, BJ; Chung, YS; Yoo, SJ; Otsuki, M; Kim, MK

ENDOCRINE JOURNAL Vol. 73 ( 2 ) page： 355 - 366 2026

Diagnostic criteria for acquired hypothalamic obesity-international expert guidance document Open Access

Müller, HL; Tanaka, T; Hasegawa, T; Isojima, T; Mori, J; Kurosaki, M; Nishioka, H; Choi, HJ; Hong, AR; Kim, JH; Arima, H

ENDOCRINE JOURNAL Vol. 73 ( 2 ) page： 341 - 353 2026

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. International journal Open Access

Koji Suzuki, Tomoko Kobayashi, Tetsushi Izuchi, Takanori Murase, Masahiko Ando, Tomoko Handa, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima, Shintaro Iwama

Frontiers in endocrinology Vol. 16 page： 1701500 - 1701500 2025.12

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

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

Efficacy of luseogliflozin for renal function preservation in patients with type 2 diabetes mellitus and impaired renal function: A randomized open-label clinical trial (RESOLUTION study) Open Access

Kitada, M; Toyoda, M; Sekine, O; Suzuki, D; Okada, Y; Morita, Y; Nishimura, H; Satoh, H; Kamiya, H; Takamura, T; Isono, M; Onoue, T; Arima, H; Tanaka, K; Miyamoto, M; Omura, Y; Yabe, D; Kato, T; Asano, A; Wakasa, Y; Miyamoto, S; Kume, S; Ito, T; Araki, S; Nakagawa, A; RESOLUTION Study Investigators

JOURNAL OF DIABETES INVESTIGATION Vol. 16 ( 12 ) page： 2160 - 2172 2025.12

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

Takashi Miyata, Daisuke Hagiwara, Ryosei Ashida, Satoshi Naito, Yohei Kawaguchi, Tomoko Handa, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Mami Matsumoto, Hidetoshi Urakubo, Nobuhiko Ohno, Hiroshi Arima

Cell and Tissue Research Vol. 402 ( 2 ) page： 139 - 144 2025.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

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

Xenotransplantation of ACTH-secreting human pluripotent stem cell (hPSC)-derived pituitary cells.

Other Link： https://link.springer.com/article/10.1007/s00441-025-04013-w/fulltext.html

Kondo, T; Suga, H; Tafa, S; Arima, H; Saito, R

TRANSPLANTATION Vol. 109 ( 10 ) page： S7 - S7 2025.10

Xenotransplantation of ACTH-secreting human pluripotent stem cell (hPSC)-derived pituitary cells

Kondo, T; Suga, H; Tafa, S; Arima, H; Saito, R

TRANSPLANTATION Vol. 109 ( 10 ) page： S7 - S7 2025.10

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

Yohei Kawaguchi, Yuichi Hodai, Satoshi Naito, Yuichi Kondo, Tetsuro Tsumura, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima, Daisuke Hagiwara

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

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

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. International journal Open Access

Shintaro Iwama, Tomoko Kobayashi, Tetsushi Izuchi, Koji Suzuki, Takanori Murase, Masahiko Ando, Tomoko Handa, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Shoichiro Mori, Tomoyasu Sano, Shusuke Akamatsu, Masashi Akiyama, Makoto Ishii, Hiroshi Arima

Endocrinology and metabolism (Seoul, Korea) Vol. 40 ( 3 ) page： 459 - 468 2025.6

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

BACKGRUOUND: 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

Safety and efficacy of retreatment with immune checkpoint inhibitors after severe immune-related adverse events

Mizuno, K; Ito, T; Sawada, T; Kobayashi, T; Iwama, S; Mori, S; Hase, T; Fukami, Y; Furusawa, K; Yura, Y; Morimoto, R; Sajiki, A; Ushida, H; Kato, N; Maruyama, S; Murohara, T; Katsuno, M; Ishii, M; Akiyama, M; Arima, H; Kawashima, H; Ando, Y

ONCOLOGIST Vol. 30 ( 6 ) 2025.6

【改訂3版糖尿病薬・インスリン治療基本と使い分け超Update 薬剤・デバイスの特徴を掴み、血糖管理に強くなる!】(第2章)インスリンの基本と使い方 CGMの進歩とBOTでの有効利用

半田朋子, 尾上剛史, 有馬寛

レジデントノート Vol. 27 ( 5 ) page： 984 - 992 2025.6

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

Linlin Fu, Mariko Sugiyama, Shahriar Kamal, Tsubasa Ide, Tadashi Takeda, Mitsuhiro Kuno, Hiroshi Takagi, Teruhiko Koike, Hiroshi Arima, Ryoichi Banno

International journal of molecular sciences Vol. 26 ( 10 ) 2025.5

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

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