Research activity information

• Transient adrenocorticotropic hormone elevation with a disproportionate cortisol response prior to the onset of immune checkpoint inhibitor-related hypophysitis.

  Hina Inui-Yasuda, Hironori Bando, Miki Watanabe, Hiroki Numata, Ayaka Iwase, Maki Kanzawa, Yuriko Sasaki, Tomoko Yamada, Kaori Hozumi, Kai Yoshimura, Yasunori Fujita, Yushi Hirota, Hidenori Fukuoka

  OBJECTIVE: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy. However, they are associated with immune-related adverse events (irAEs), including ICI-related hypophysitis (ICI-RH). Secondary adrenal insufficiency, the most common endocrine manifestation, is often life-threatening if left untreated. Transient elevations in adrenocorticotropic hormone (ACTH) levels before the onset of ICI-RH have been reported; however, their clinical significance remains unclear. CASE PRESENTATION: We describe the case of a 76-year-old woman with renal cell carcinoma who underwent nephrectomy followed by pembrolizumab therapy. Initially, the patient had normal baseline adrenal function. However, 12 weeks after the initiation of pembrolizumab, she exhibited transient ACTH elevation without a proportionate increase in cortisol. Fifteen weeks after treatment initiation, the patient developed fatigue and nausea. Laboratory tests revealed hyponatremia with low ACTH and cortisol levels. Hydrocortisone replacement rapidly improved the patient’s symptoms. Stimulation testing confirmed an isolated ACTH deficiency, whereas the other pituitary axes remained intact. Magnetic resonance imaging revealed no pituitary enlargement and tumor pathology revealed weak ACTH expression. DISCUSSION: This case illustrates ICI-related hypophysitis presenting as isolated ACTH deficiency, preceded by a transient ACTH elevation without a corresponding increase in serum cortisol. A literature review indicated a heterogeneous pattern of ACTH and cortisol dynamics, likely reflecting differences in ACTH bioactivity and adrenal responsiveness. Transient ACTH elevation may represent early pituitary damage, which is analogous to transient thyrotoxicosis in thyroid irAEs. Recognition of this phenomenon may enable early ICI-RH detection. CONCLUSION: Transient ACTH elevation, even without a concurrent cortisol increase, may serve as an early marker of ICI-RH.

  Mar. 2026, Hormones (Athens, Greece), English, International magazine

  Scientific journal


• Similarities and differences in the intestinal actions of metformin and imeglimin.

  Kenji Sugawara, Kaori Hozumi, Hiroshi Mizuma, Daisuke Sasaki, Masakazu Shinohara, Akihiko Kondo, Yasuyoshi Watanabe, Wataru Ogawa

  AIMS: Imeglimin is a novel antidiabetic drug that shares structural similarity with metformin. While the intestinal effects of metformin have attracted widespread attention, those of imeglimin remain underexplored. MATERIALS AND METHODS: C57BL/6J mice were treated with metformin or imeglimin for RNA sequencing of intestinal tissue. Gut microbiota composition was evaluated in KK-Ay mice by 16S rRNA sequencing of faecal samples. To assess direct effects on the human microbiome, a gut simulator was used with faecal samples from healthy and diabetic individuals. Intestinal glucose dynamics were assessed in C57BL/6J mice following administration of [18F]fluorodeoxyglucose, with subsequent analysis of tissue distribution. RESULTS: Bulk RNA-sequencing of colonic tissue revealed that both drugs induced similar patterns of gene expression changes, including a prominent upregulation of Gdf15. However, single-cell RNA-sequencing uncovered distinct effects of the two drugs, with metformin having a pronounced impact on the functional properties of enterocytes and imeglimin increasing the proportion of IgA-producing plasma cells. Metformin reduced gut microbial diversity and induced substantial changes in microbial composition, whereas imeglimin exerted less pronounced effects. Gut simulator analysis with human faecal samples showed that both drugs directly altered gut microbial populations but in different ways. Finally, metformin promoted glucose excretion into the intestinal lumen, whereas imeglimin had a minimal effect on this process. CONCLUSIONS: In conclusion, although metformin and imeglimin exerted similar effects on gene expression in the colon at the whole-tissue level, they showed distinct cell type-specific actions, and they differed in their influence on gut microbiota and intestinal glucose dynamics.

  Nov. 2025, Diabetes, obesity & metabolism, 27(11) (11), 6654 - 6667, English, International magazine

  Scientific journal


• Observational Study of the Impact of Infusion Set Replacement in Insulin Pump Users on Glycemic Management.

  Kai Yoshimura, Shin Urai, Kaori Hozumi, Mei Nakatsuji, Shuichiro Saito, Seiji Nishikage, Akane Yamamoto, Tomofumi Takayoshi, Wataru Ogawa, Yushi Hirota

  BACKGROUND: Although several studies have evaluated the impact of prolonged infusion set use in insulin pump users on glycemic management with the use of continuous glucose monitoring (CGM), real-world assessments without intervention have been unavailable. METHODS: This retrospective observational study recruited individuals with type 1 diabetes who received insulin pump therapy with real-time CGM. Insulin pump and CGM logs were extracted from the Medtronic CareLink system, and a dataset was constructed programmatically, counting tracking days from infusion set replacement every 24 hours up to day 4. The primary outcome was mean sensor glucose (SG) level, and the impact of infusion set usage duration on glycemic management was assessed. RESULTS: The study enrolled 45 individuals with a median age of 40 (interquartile range = 32-51) years and median body mass index of 22.5 (21.2-23.8) kg/m². Mean SG was significantly higher on day 4 (median of 151.9 [136.5-173.7] mg/dL) than on day 2 (144.4 [124.0-162.9] mg/dL, P = .024). Similarly, time above range (TAR), time in range (TIR), and time in tight range (TITR) had worsened on day 4 compared with day 2. The TAR increased from a median of 22.0% (7.3%-35.8%) on day 2 to 27.6% (17.7%-44.9%) on day 4, whereas TIR decreased from 74.2% (59.9%-87.1%) to 66.5% (52.0%-79.8%) and TITR decreased from 47.6% (37.1%-67.5%) to 42.2% (34.6%-54.1%). CONCLUSIONS: Our evaluation of the real-world impact of prolonged infusion set use revealed an association between longer use and worsening of glycemic management.

  Jun. 2025, Journal of diabetes science and technology, 19322968251345837 - 19322968251345837, English, International magazine

  Scientific journal


• Survey of glucocorticoid dose escalation in patients with adrenal insufficiency during the peri-COVID-19 vaccination period.

  Hironori Bando, Masaaki Yamamoto, Michiko Takahashi, Keitaro Kanie, Yuriko Sasaki, Yuka Oi, Seiji Tomofuji, Kaori Hozumi, Seiji Nishikage, Shin Urai, Naoki Yamamoto, Masaki Suzuki, Hiroki Shichi, Genzo Iguchi, Hidenori Fukuoka, Wataru Ogawa

  There is uncertainty regarding the need for COVID-19 peri-vaccination glucocorticoid coverage in patients with adrenal insufficiency. In this survey conducted in a single tertiary medical institution, 167 consecutive outpatients taking physiological glucocorticoids because of adrenal insufficiency were included. The patients declared if they developed an adrenal crisis after vaccination, and the amount and duration of an increase in their glucocorticoid dosage, if any. None of the patients without preventive glucocorticoid increase suffered an adrenal crisis after COVID-19 vaccination. Only 8.3% (14 cases) and 27.5% (46 cases) of the patients needed to escalate the dose of glucocorticoids when systemic symptoms appeared after the first and second injections, respectively. Glucocorticoids were increased in patients <60 years of age more than in patients ≥60 years of age at the time of both the first (p = 0.026) and second injections (p = 0.005). Sex and the causes of adrenal insufficiency were not associated with the frequency of the patients who needed glucocorticoid dose escalation. In the cases with increased glucocorticoids, the median dosage for escalation was 10 mg (hydrocortisone equivalent). In conclusion, even without prophylactic glucocorticoid administration, adrenal crisis did not occur during the peri-COVID-19 vaccination period. The dose escalation of steroid was more frequent in younger patients following the second vaccination. Careful monitoring of adverse effects and the appropriate management of glucocorticoids when necessary are essential following COVID-19 vaccinations.

  Jan. 2023, Endocrine journal, 70(1) (1), 89 - 95, English, Domestic magazine

  Scientific journal


• Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes.

  Kaori Hozumi, Kenji Sugawara, Takaya Ishihara, Naotada Ishihara, Wataru Ogawa

  Imeglimin is a recently launched antidiabetic drug structurally related to metformin. To provide insight into the pharmacological properties of imeglimin, we investigated its effects on hepatocytes and compared them with those of metformin. The effects of imeglimin on mitochondrial function in HepG2 cells or mouse primary hepatocytes were examined with an extracellular flux analyzer and on gene expression in HepG2 cells by comprehensive RNA-sequencing analysis. The effects of the drug on AMPK activity in HepG2 cells, mouse primary hepatocytes, and mouse liver were also examined. Treatment of HepG2 cells or mouse primary hepatocytes with imeglimin reduced the oxygen consumption rate coupled to ATP production. Imeglimin activated AMPK in these cells whereas the potency was smaller than metformin. Bolus administration of imeglimin in mice also activated AMPK in the liver. Whereas the effects of imeglimin and metformin on gene expression in HepG2 cells were similar overall, the expression of genes encoding proteins of mitochondrial respiratory complex III and complex I was upregulated by imeglimin but not by metformin. Our results suggest that imeglimin and metformin exert similar pharmacological effects on mitochondrial respiration, AMPK activity, and gene expression in cultured hepatocytes, whereas the two drugs differ in their effects on the expression of certain genes related to mitochondrial function.

  Jan. 2023, Scientific reports, 13(1) (1), 746 - 746, English, International magazine

  Scientific journal


• 成人期診断22q11.2欠失症候群における内分泌異常の検討

  横井 愛紗, 福岡 秀規, 山本 雅昭, 穂積 かおり, 廣田 勇士, 小川 渉

  (一社)日本内分泌学会, Apr. 2021, 日本内分泌学会雑誌, 97(1) (1), 336 - 336, Japanese


• 心肺停止に偽性アルドステロン症の関与が疑われた副腎腫瘍の一例

  齋藤 修一郎, 穂積 かおり, 稲葉 惟子, 山本 雅昭, 廣田 勇士, 福岡 秀規, 小川 渉

  (一社)日本内分泌学会, Oct. 2020, 日本内分泌学会雑誌, 96(2) (2), 561 - 561, Japanese


• 心肺停止に偽性アルドステロン症の関与が疑われた副腎腫瘍の一例

  齋藤 修一郎, 穂積 かおり, 稲葉 惟子, 山本 雅昭, 廣田 勇士, 福岡 秀規, 小川 渉

  (一社)日本内分泌学会, Oct. 2020, 日本内分泌学会雑誌, 96(2) (2), 561 - 561, Japanese


• Acromegaly caused by a somatotroph adenoma in patient with neurofibromatosis type 1.

  Kaori Hozumi, Hidenori Fukuoka, Yukiko Odake, Takehito Takeuchi, Tomoko Uehara, Takeshi Sato, Naoko Inoshita, Kenichi Yoshida, Ryusaku Matsumoto, Hironori Bando, Yushi Hirota, Genzo Iguchi, Masaaki Taniguchi, Naoki Otsuki, Chikako Nishigori, Kenjiro Kosaki, Tomonobu Hasegawa, Wataru Ogawa, Yutaka Takahashi

  Although acromegaly has been reported in patients with Neurofibromatosis type 1 (NF1), these cases have not been associated with growth hormone (GH)-producing somatotroph adenoma, but with optic pathway glioma. A 68 year-old Japanese woman, who had been clinically diagnosed with NF1, was referred to our hospital due to a thyroid tumor and hypercalcemia. Acromegaly was suspected due to her facial features, and subsequent examinations revealed the presence of GH excess with a pituitary tumor, leading to the diagnosis of acromegaly. Histological and immunohistochemical analysis demonstrated an eosinophilic pituitary adenoma with diffuse positivity for GH, indicating typical somatotroph adenoma. In addition, her thyroid tumor was diagnosed histologically as follicular thyroid carcinoma (FTC) with primary hyperparathyroidism (PHPT). To investigate the pathogenesis of this untypical multiple endocrine tumor case of NF1, genetic analysis was performed using peripheral leukocytes and tissue of resected tumors. A heterozygous novel germline nonsense mutation (p.Arg1534*) in exon 35 of the NF1 gene was detected from peripheral leukocytes, which results in a truncated protein lacking the critical domain for GTPase activity, strongly suggesting its causal role in NF1. The loss of heterozygosity (LOH) in exon 35 of the NF1 gene was not detected in the somatotroph adenoma, parathyroid adenoma, and FTC. Although any mutations of the following genes; MEN1, CDKN1B, and PAX8-PPARγ were not detected, a heterozygous GNAS R201C mutation was detected in the somatotroph adenoma. To our knowledge, this is the first rare MEN1-like case of genetically diagnosed NF1 complicated with acromegaly caused by a somatotroph adenoma.

  Oct. 2019, Endocrine journal, 66(10) (10), 853 - 857, English, Domestic magazine

  Scientific journal

• 急性期にAutomated Insulin Delivery(AID)療法を併用して治療した1型糖尿病の3症例

  大江 晃央, 山田 倫子, 乾 妃那, 松田 琢磨, 宮崎 裕也, 澤部 史一, 芳村 魁, 穂積 かおり, 坂東 弘教, 福岡 秀規, 小川 渉, 廣田 勇士

  日本先進糖尿病治療・1型糖尿病研究会, Oct. 2025, 日本先進糖尿病治療・1型糖尿病研究会雑誌, 19(2) (2), 100 - 100, Japanese


• TSHの周期性分泌が示唆されたGH・TSH産生下垂体腺腫の1例

  大井佑夏, 山本雅昭, 稲葉惟子, 穂積かおり, 志智大城, 志智大城, 福岡秀規, 小川渉

  2020, 日本内分泌学会雑誌, 96(2) (2)


• 造血幹細胞移植10年後に部分性脂肪萎縮症を発症したと考えられた1例

  淺原俊一郎, 穂積かおり, 廣田勇士, 山本雅昭, 福岡秀規, 小川渉

  2019, 日本肥満学会・日本肥満症治療学会合同学術集会プログラム・抄録集, 40th-37th


• 重症ニューモシスチス肺炎を呈した異所性ACTH症候群の一例

  穂積かおり, 福岡秀規, 山本雅昭, 杉澤良介, 江木盛時, 大路剛, 梅澤佳乃子, 廣田勇士, 小川渉, 高橋裕

  2019, 日本内分泌学会雑誌, 95(2) (2)


• 成人期診断22q11.2欠失症候群における内分泌異常の特徴

  横井愛紗, 福岡秀規, 穂積かおり, 山本雅昭, 廣田勇士, 小川渉, 高橋裕

  2019, 日本内分泌学会雑誌, 95(2) (2)


• 神経線維腫症I型に多彩な内分泌腫瘍を合併した先端巨大症の1例

  小武由紀子, 福岡秀規, 穂積かおり, 佐藤武志, 吉田健一, 松本隆作, 坂東弘教, 隅田健太郎, 西沢衡, 高橋路子, 井口元三, 長谷川奉延, 小川渉, 高橋裕

  2017, Progress in Medicine, 37(2) (2)


• NF1に先端巨大症を含む多発性内分泌腫瘍を合併した一例

  小武由紀子, 福岡秀規, 穂積かおり, 竹内健人, 佐藤武志, 吉田健一, 松本隆作, 坂東弘教, 隅田健太郎, 西沢衡, 高橋路子, 井口元三, 長谷川奉延, 小川渉, 高橋裕

  2016, 日本内分泌学会雑誌, 92(2) (2)

• メトホルミン及びイメグリミンによる筋量制御機構の包括的解析

  穂積 かおり

  日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 01 Apr. 2025 - 31 Mar. 2027


• メトホルミンとイメグリミンによる筋量制御メカニズムの解明

  穂積 かおり

  日本学術振興会, 科学研究費助成事業, 研究活動スタート支援, 神戸大学, 31 Jul. 2024 - 31 Mar. 2026