Faculty Profiles - ARIMA, Hiroshi

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

Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors

Iwama, S; Kobayashi, T; Arima, H

NATURE REVIEWS ENDOCRINOLOGY Vol. 21 ( 5 ) page： 289 - 300 2025.5

Cushing徴候と女性化乳房を認め複数のホルモン産生が疑われた副腎皮質癌の一例

伊藤美穂, 半田朋子, 宮田崇, 杉山摩利子, 笹野公伸, 有馬寛

日本内分泌学会雑誌 Vol. 101 ( 1 ) page： 282 - 282 2025.5

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

Ryutaro Maeda, Takeshi Onoue, Keigo Mizutani, Koji Suzuki, Tomoko Handa, Tomoko Kobayashi, Shintaro Iwama, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Fumie Kinoshita, Hiroshi Arima

Diabetes research and clinical practice Vol. 222 page： 112074 - 112074 2025.4

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

AIMS: This study aimed to evaluate the effectiveness of continuous glucose monitoring (CGM) with low-glucose alerts for preventing hypoglycemia in insulin-treated drivers with diabetes. METHODS: This single-center, open-label, randomized crossover study involved 30 insulin-treated participants with diabetes who drove cars at least thrice weekly in Japan. Participants underwent two 4-week periods: an alert period using CGM with active low-glucose alerts and a no-alert period using blinded CGM without low-glucose alerts, separated by an eight-week washout period. The primary outcome was the percentage of time below range (TBR; <3.9 mmol/L). RESULTS: Twenty-seven of the 30 participants completed the CGM analysis. Although the TBR did not differ between the alert and no-alert periods among all participants, it significantly decreased during the alert period compared with the no-alert period among the participants with type 1 diabetes (-4.4 [95 % confidence interval - 8.7, -0.08]%, p = 0.047). The incidence of low-glucose when driving was significantly lower during the alert period than during the no-alert period (19 % vs. 33 %, p = 0.041). CONCLUSION: Low-glucose alerts improved the TBR in drivers with type 1 diabetes and reduced the incidence of low-glucose while driving among all insulin-treated drivers, suggesting that these alerts may ensure the safety of insulin-treated drivers.

DOI： 10.1016/j.diabres.2025.112074

Delphi panel consensus on recommendations for thromboprophylaxis of venous thromboembolism in endogenous Cushing's syndrome: a position statement Open Access

Isand, K; Arima, H; Bertherat, J; Dekkers, OM; Feelders, RA; Fleseriu, M; Gadelha, MR; Hinojosa-Amaya, JM; Karavitaki, N; Klok, FA; Mccormack, A; Newell-Price, J; Pavord, S; Reincke, M; Sinha, S; Valassi, E; Wass, J; Arias, AMP

EUROPEAN JOURNAL OF ENDOCRINOLOGY Vol. 192 ( 3 ) page： R17 - R27 2025.3

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

Compensatory mechanisms underlying arginine vasopressin regulation in transient polyuria during pregnancy. International journal Open Access

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

Peptides Vol. 184 page： 171352 - 171352 2025.2

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

Transient polyuria during pregnancy is reportedly caused by increased arginine vasopressin (AVP) degradation due to vasopressinase produced by the placenta. The mechanism underlying transient polyuria during pregnancy has not been established. In this study we measured urine volume, urine osmolality, and AVP transcriptional activity during pregnancy in wild-type and familial neurohypophysial diabetes insipidus (FNDI) mice. The FNDI mice were used as a partial AVP deficiency model. Vasopressinase was shown to be present in the placentas of pregnant mice. The Avp hnRNA level in the supraoptic nucleus, which is indicative of AVP transcriptional activity, was upregulated in wild-type and FNDI mice during late pregnancy. FNDI mice, but not wild-type mice, had a significant increase in urine volume and a decrease in urine osmolality during pregnancy. These data suggest that an increase in urine volume during pregnancy only occurs when the compensatory increase in AVP release is insufficient to counteract degradation by vasopressinase.

DOI： 10.1016/j.peptides.2025.171352

Guidance on Energy Intake Based on Resting Energy Expenditure and Physical Activity: Effective for Reducing Body Weight in Patients with Obesity. International journal Open Access

Tomoko Handa, Takeshi Onoue, Ryutaro Maeda, Keigo Mizutani, Koji Suzuki, Tomoko Kobayashi, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Nutrients Vol. 17 ( 2 ) 2025.1

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

OBJECTIVE: In treating obesity, energy intake control is essential to avoid exceeding energy expenditure. However, excessive restriction of energy intake often leads to resting energy expenditure (REE) reduction, increasing hunger and making weight loss difficult. This study aimed to investigate whether providing nutritional guidance that considers energy expenditure based on the regular evaluation of REE and physical activity could effectively reduce body weight (BW) in patients with obesity. METHODS: A single-arm, prospective interventional study was conducted on 20 patients with obesity (body mass index ≥ 25 kg/m2) at the Nagoya University Hospital for 24 weeks. REE and physical activity were regularly assessed, and the recommended energy intake was adjusted based on the values. The primary outcome was the change in BW, and the secondary outcomes included changes in REE and hunger ratings, which were assessed using a visual analog scale. RESULTS: Eighteen participants completed the study, demonstrating a significant reduction in BW after 24 weeks (-5.34 ± 6.76%, p < 0.0001). No significant changes were observed in REE or hunger ratings. No adverse events were reported throughout the study period. CONCLUSIONS: Guidance on energy intake based on REE and physical activity was effective for reducing BW in patients with obesity without decreasing REE or increasing hunger. This approach may reduce the burden on patients with obesity while losing BW.

DOI： 10.3390/nu17020202

A deep learning approach to predict differentiation outcomes in hypothalamic-pituitary organoids Open Access

Tomoyoshi Asano, Hidetaka Suga, Hirohiko Niioka, Hiroshi Yukawa, Mayu Sakakibara, Shiori Taga, Mika Soen, Tsutomu Miwata, Hiroo Sasaki, Tomomi Seki, Saki Hasegawa, Sou Murakami, Masatoshi Abe, Yoshinori Yasuda, Takashi Miyata, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Shintaro Iwama, Yoshinobu Baba, Hiroshi Arima

Communications Biology Vol. 7 ( 1 ) page： 1468 2024.12

Voluntary exercise suppresses inflammation and improves insulin resistance in the arcuate nucleus and ventral tegmental area in mice on a high-fat diet. International journal Open Access

Tomoyuki Sasaki, Mariko Sugiyama, Mitsuhiro Kuno, Takashi Miyata, Tomoko Kobayashi, Yoshinori Yasuda, Takeshi Onoue, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Ryoichi Banno, Hiroshi Arima

Physiology & behavior Vol. 287 page： 114703 - 114703 2024.12

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

A high-fat diet (HFD) causes inflammation with an increase in microglial activity in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA), resulting in insulin resistance in both regions. This leads to a deterioration in glucose and energy metabolism. The effect of voluntary exercise on HFD-induced inflammation in the central nervous system (CNS) remains unclear. To clarify the effects of voluntary exercise on the CNS, 8-week-old male C57BL6 mice were fed a chow diet (CHD) or HFD for 4 weeks; each group was further divided into running exercise (EX+) on a wheel and no exercise (EX-) groups. The expression of the inflammatory cytokine, tumor necrosis factor alpha (TNFα), in the ARC and VTA was significantly increased in the HFD/EX- group, with an increase of microglial activity noted, compared to the CHD/EX- group. The expression of TNFα was significantly suppressed, with a decrease of microglial activity, in the HFD/EX+ compared to HFD/EX- group. Insulin resistance in the ARC and VTA was improved with the suppression of TNFα expression. The HFD/EX- group showed significant weight gain and impaired glucose metabolism compared to the CHD/EX- group. The HFD/EX+ group showed an improvement in glucose and energy metabolism compared to the HFD/EX- group. In addition, voluntary wheel running suppressed HFD-induced inflammation in the ARC, with a decrease in microglial activity observed independently of weight changes. Our data suggest that voluntary exercise prevents obesity and improves glucose metabolism by suppressing inflammation in the ARC and VTA under HFD conditions.

DOI： 10.1016/j.physbeh.2024.114703

Development of pituitary dysfunction and destructive thyroiditis is associated with better survival in non-small cell lung cancer patients treated with programmed cell death-1 inhibitors: a prospective study with immortal time bias correction. International journal

Koji Suzuki, Tomoko Kobayashi, Tetsushi Izuchi, Koki Otake, Masahiko Ando, Tomoko Handa, Takashi Miyata, Mariko Sugiyama, Takeshi Onoue, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Megumi Inoue, Makoto Ishii, Hiroshi Arima, Shintaro Iwama

Frontiers in endocrinology Vol. 15 page： 1490042 - 1490042 2024.11

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

BACKGROUND: Immune-related adverse events (irAEs) are reported to be associated with better overall survival (OS) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. However, there may be a bias in that patients who develop irAEs must survive long enough to experience the irAEs, and no prospective studies adjusting for immortal time bias (ITB) have examined the relationship between OS and pituitary dysfunction or the two different types of thyroid dysfunction: destructive thyroiditis and hypothyroidism without prior thyrotoxicosis (isolated hypothyroidism). METHODS: Patients with NSCLC who received nivolumab or pembrolizumab at Nagoya University Hospital between November 2, 2015 and February 1, 2023 were enrolled. Endocrine irAEs were prospectively assessed during scheduled evaluations of hormone levels. The association between irAE development and survival when considering ITB was examined by time-dependent Cox regression analysis. RESULTS: Of the 194 patients included, 11 (5.7%), 10 (5.2%), and 5 (2.6%) developed pituitary dysfunction, destructive thyroiditis, and isolated hypothyroidism, respectively. The development of pituitary dysfunction (HR 0.36, 95% CI 0.13-0.98, p = 0.045) and destructive thyroiditis (HR 0.31, 95% CI 0.10-0.97, p = 0.044), but not isolated hypothyroidism (HR 1.15, 95% CI 0.42-3.20, p = 0.786), was significantly associated with longer OS. CONCLUSION: NSCLC patients developing pituitary dysfunction and destructive thyroiditis showed better OS even after adjusting for ITB, suggesting that these irAEs indicate a better prognosis.

DOI： 10.3389/fendo.2024.1490042

Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus

Arima, H; Cheetham, T; Christ-Crain, M; Cooper, D; Drummond, J; Gurnell, M; Levy, M; McCormack, A; Newell-Price, J; Verbalis, JG; Wass, J

CLINICAL ENDOCRINOLOGY Vol. 101 ( 5 ) page： 443 - 445 2024.11

質量分析によるAVP測定法は高張食塩水負荷試験を短縮できる

半田朋子, 萩原大輔, 有馬寛

日本内分泌学会雑誌 Vol. 100 ( 2 ) page： 608 - 608 2024.10

Internet of things-based approach for glycemic control in people with type 2 diabetes: A randomized controlled trial Invited Reviewed

Bouchi, R; Izumi, K; Ishizuka, N; Uemura, Y; Ohtsu, H; Miyo, K; Tanaka, S; Satoh-Asahara, N; Hara, K; Odawara, M; Kusunoki, Y; Koyama, H; Onoue, T; Arima, H; Tsushita, K; Watada, H; Kadowaki, T; Ueki, K

JOURNAL OF DIABETES INVESTIGATION Vol. 15 ( 9 ) page： 1287 - 1296 2024.9

Thyroid autoantibodies at baseline predict longer survival in non-small cell lung cancer patients treated with anti-programmed cell death-1 blockade: a prospective study. Reviewed

Takayuki Okuji, Shintaro Iwama, Tomoko Kobayashi, Yoshinori Yasuda, Masaaki Ito, Ayana Yamagami, Masahiko Ando, Tetsunari Hase, Hirofumi Shibata, Takahiro Hatta, Xin Zhou, Takeshi Onoue, Yohei Kawaguchi, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Yuichi Ando, Naozumi Hashimoto, Hiroshi Arima

Nagoya journal of medical science Vol. 86 ( 3 ) page： 452 - 463 2024.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The presence of anti-thyroid antibodies (ATAs) is a biomarker for the development of thyroid dysfunction induced by anti-programmed cell death-1 antibodies (PD-1-Abs). While patients with thyroid dysfunction reportedly showed better overall survival (OS), it remains unknown if ATAs at baseline can predict OS. Therefore, in this study, we examined the association of ATAs at baseline with OS in non-small cell lung cancer (NSCLC) patients with different levels of programmed cell death-1 ligand 1 (PD-L1) positivity associated with PD-1-Ab treatment efficacy. A total of 81 NSCLC patients treated with PD-1-Abs were evaluated for ATAs at baseline and prospectively for OS. Among the 81 patients, 49 and 32 patients had ≥50% (group A) and <50% (group B) PD-L1 positivity, respectively. Median OS did not differ significantly between patients with (n = 13) and without (n = 36) ATAs at baseline in group A. In contrast, median OS was significantly longer in patients with (n = 10) versus without (n = 22) ATAs at baseline in group B (not reached vs 378 days, respectively; 95% CI, 182 to 574 days, p = 0.049). These findings suggest that the presence of ATAs at baseline is a biomarker to predict better treatment efficacy of PD-1-Abs in NSCLC patients with low PD-L1 positivity, while the difference in OS in those with high PD-L1 positivity may be masked by increased tumor expression of PD-L1.

DOI： 10.18999/nagjms.86.3.452