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1. Effects of glucokinase haploinsufficiency on the pancreatic β‐cell mass and function of long‐term high‐fat, high‐sucrose diet‐fed mice

Author: Ikumi Shigesawa, Akinobu Nakamura, Yuki Yamauchi, Shinichiro Kawata, Asuka Miyazaki, Hiroshi Nomoto, Hiraku Kameda, Yasuo Terauchi, and Tatsuya Atsumi
Subjects: β‐cell mass, Glucokinase, Glucose‐stimulated insulin secretion, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ABSTRACT Aims/Introduction We previously showed that glucokinase haploinsufficiency improves the glucose tolerance of db/db mice by preserving pancreatic β‐cell mass and function. In the present study, we aimed to determine the effects of glucokinase haploinsufficiency on the β‐cell mass and function of long‐term high‐fat, high‐sucrose (HFHS) diet‐fed mice. Materials and Methods Four‐week‐old male glucokinase haploinsufficient (Gck+/−) mice and 4‐week‐old male wild‐type (Gck+/+) mice (controls) were each divided into two groups: an HFHS diet‐fed group and a normal chow‐fed group, and the four groups were followed until 16, 40 or 60 weeks‐of‐age. Their glucose tolerance, glucose‐stimulated insulin secretion and β‐cell mass were evaluated. In addition, islets were isolated from 40‐week‐old mice, and the expression of key genes was compared. Results Gck+/−HFHS mice had smaller compensatory increases in β‐cell mass and glucose‐stimulated insulin secretion than Gck+/+HFHS mice, and their glucose tolerance deteriorated from 16 to 40 weeks‐of‐age. However, their β‐cell mass and glucose‐stimulated insulin secretion did not decrease between 40 and 60 weeks‐of‐age, but rather, tended to increase, and there was no progressive deterioration in glucose tolerance. The expression of Aldh1a3 in pancreatic islets, which is high in several models of diabetes and is associated with an impairment in β‐cell function, was high in Gck+/+HFHS mice, but not in Gck+/−HFHS mice. Conclusions Glucokinase haploinsufficiency prevents the progressive deterioration of pancreatic β‐cell mass/function and glucose tolerance in long‐term HFHS diet‐fed mice.
Published: 2024
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2. Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study)

Author: Yuki Oe, Hiroshi Nomoto, Kyu Yong Cho, Kei Yokozeki, Tsubasa Ono, Aika Miya, Hiraku Kameda, Akinobu Nakamura, Yoshiaki Arimura, and Tatsuya Atsumi
Subjects: Glucagon-like peptide 1 receptor, Aged, Type 2 diabetes, Cognitive test, Oral medicine, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Background Oral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world. Methods We retrospectively studied subjects > 65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65–74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity. Results We studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (− 13.1 ± 7.5 mmol/mol and − 3.0 ± 2.4 kg, respectively; P
Published: 2024
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3. Real-world clinical evidence of oral semaglutide on metabolic abnormalities in subjects with type 2 diabetes: a multicenter retrospective observational study (the Sapporo-Oral SEMA study)

Author: Sho Furusawa, Hiroshi Nomoto, Chiho Oba-Yamamoto, Jun Takeuchi, Miki Ito, Hiroyoshi Kurihara, Shin Aoki, Aika Miya, Hiraku Kameda, Akinobu Nakamura, and Tatsuya Atsumi
Subjects: clinical trial, glucagon-like peptide-1 receptor agonist, glycemic control, type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Oral semaglutide has potent anti-hyperglycemic efficacy in phase III trials. However, the complicated dosing instructions hamper to use this drug; therefore, we evaluated the efficacy and safety of oral semaglutide in subjects with type 2 diabetes in a real-world clinical setting. In this multi-center retrospective observational study, we analyzed subjects with type 2 diabetes newly treated with an oral semaglutide for >6 months at four medical centers located in Sapporo, Japan. The changes in glycated hemoglobin, body weight, and other metabolic parameters were evaluated and any adverse event leading to semaglutide discontinuation were recorded from February 2021 to December 2022. This study was registered with the University Hospital Medical Information Network Center (UMIN000050583). Of 543 subjects who met the inclusion criteria, data for 434 subjects (age 55.5 ± 12.6 years; body mass index 29.6 ± 6.0 kg/m2) were analyzed. After a 6 months of observation period, semaglutide 3 mg, 7 mg, or 14 mg was used by 55 (12.7%), 241 (55.5%), and 138 (31.8%) of subjects, respectively. Both glycated hemoglobin and body weight significantly improved: 7.65 ± 1.11% to 6.88 ± 0.91% (p < 0.001) and 80.2 ± 19.2 kg to 77.6 ± 19.2 kg (p < 0.001), respectively. Efficacy was also confirmed in the subgroup switched from other anti-hyperglycemic agents, including dipeptidyl peptidase-4 inhibitors. In total, 154 subjects had symptomatic gastrointestinal symptoms and 39 (7.2%) were discontinued semaglutide due to the adverse events. None of the participants experienced severe hypoglycemic events. Oral semaglutide in subjects with type 2 diabetes improved glycemic control and body weight in a real-world clinical setting.
Published: 2024
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4. Switching from Conventional Fibrates to Pemafibrate Has Beneficial Effects on the Renal Function of Diabetic Subjects with Chronic Kidney Disease

Author: Rimi Izumihara, Hiroshi Nomoto, Kenichi Kito, Yuki Yamauchi, Kazuno Omori, Yui Shibayama, Shingo Yanagiya, Aika Miya, Hiraku Kameda, Kyu Yong Cho, So Nagai, Ichiro Sakuma, Akinobu Nakamura, and Tatsuya Atsumi
Subjects: diabetes mellitus, type 2, fibric acids, renal insufficiency, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Background Fibrates have renal toxicity limiting their use in subjects with chronic kidney disease (CKD). However, pemafibrate has fewer toxic effects on renal function. In the present analysis, we evaluated the effects of pemafibrate on the renal function of diabetic subjects with or without CKD in a real-world clinical setting. Methods We performed a sub-analysis of data collected during a multi-center, prospective, observational study of the effects of pemafibrate on lipid metabolism in subjects with type 2 diabetes mellitus complicated by hypertriglyceridemia (the PARM-T2D study). The participants were allocated to add pemafibrate to their existing regimen (ADD-ON), switch from their existing fibrate to pemafibrate (SWITCH), or continue conventional therapy (CTRL). The changes in estimated glomerular filtration rate (eGFR) over 52 weeks were compared among these groups as well as among subgroups created according to CKD status. Results Data for 520 participants (ADD-ON, n=166; SWITCH, n=96; CTRL, n=258) were analyzed. Of them, 56.7% had CKD. The eGFR increased only in the SWITCH group, and this trend was also present in the CKD subgroup (P
Published: 2024
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5. Positive association between the proinsulin-to-C-peptide ratio and prolonged hyperglycemic time in type 2 diabetes

Author: Aika Miya, Akinobu Nakamura, Hiroshi Nomoto, Hiraku Kameda, and Tatsuya Atsumi
Subjects: proinsulin, type 2 diabetes, continuous glucose monitoring, β-cell dysfunction, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: The proinsulin-to-C-peptide (PI:C) ratio is an index applied during the early stage of pancreatic β-cell dysfunction. The aim of this study was to identify the characteristics associated with the PI:C ratio to discuss pancreatic β-cell dysfunction progression during the natural course of type 2 diabetes and its relationship with glycemic management. This multicenter, prospective observational study included 272 outpatients with type 2 diabetes. Continuous glucose monitoring was performed and fasting blood samples were collected and analyzed. We identified the clinical factors associated with the PI:C ratio by multiple regression analysis. The mean age of the cohort was 68.0 years, mean hemoglobin A1c 7.1% (54 mmol/mol), and mean body mass index 24.9 kg/m2. Multiple regression analysis showed that a prolonged time above the target glucose range (>180 mg/dL) and high body mass index contributed to a high PI:C ratio. However, no associations were found between the PI:C ratio and glucose variability indices. These findings suggested that the PI:C ratio is positively associated with a prolonged hyperglycemic time in type 2 diabetes, whereas its relationship with glucose variability remains unclear.
Published: 2024
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6. Positive association between proinsulin and fatty liver index in people with type 2 diabetes

Author: Akinobu Nakamura, Aika Miya, Yuka Suzuki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, and Tatsuya Atsumi
Subjects: fatty liver index, hepatic steatosis, proinsulin, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: The post-hoc study, derived from our previous prospective observational study, investigated the association between fasting serum proinsulin levels and hepatic steatosis in people with type 2 diabetes. The severity of hepatic steatosis was assessed using the fatty liver index. A total of 268 participants were divided into three groups: low (n = 110), moderate (n = 75), and high fatty liver index (n = 83). In both the crude and age/sex-adjusted analysis, logarithm-transformed proinsulin was significantly higher in the high fatty liver index group than in the low or moderate groups (all p < 0.01). The moderate fatty liver index group showed higher logarithm-transformed proinsulin than the low group (both p < 0.01). Positive associations between proinsulin and fatty liver index shown in this study would support an involvement of hepato-pancreatic crosstalk in the pathophysiology of type 2 diabetes.
Published: 2024
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7. Preferable effects of pemafibrate on liver function and fibrosis in subjects with type 2 diabetes complicated with liver damage

Author: Hiroshi Nomoto, Kenichi Kito, Hiroshi Iesaka, Takahisa Handa, Shingo Yanagiya, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Jun Takeuchi, So Nagai, Ichiro Sakuma, Akinobu Nakamura, and Tatsuya Atsumi
Subjects: Pemafibrate, Liver function, Type 2 Diabetes, Nutritional diseases. Deficiency diseases, RC620-627
Abstract: Abstract Background Pemafibrate has been reported to ameliorate lipid profiles and liver dysfunction. However, which patients derive benefit from the hepatoprotective effects of pemafibrate is unclear. Methods We conducted a sub-analysis of the PARM-T2D study where subjects with type 2 diabetes complicated by hypertriglyceridemia were prospectively treated with pemafibrate or conventional therapies for 52 weeks. From the original cohort, subjects who had metabolic-associated fatty liver disease without changing their treatment regimens for comorbidities were analyzed. Eligible subjects (n = 293) (average age 61.2 ± 11.7 years, 37.5% female) treated with pemafibrate (pemafibrate, n = 152) or controls who did not change their treatment regimens (controls, n = 141) were divided into three groups based on their alanine aminotransferase (ALT) levels: ALT ≤ upper normal limit (UNL) (pemafibrate, n = 65; controls, n = 50), UNL
Published: 2023
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8. Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function

Author: Yuki Yamauchi, Akinobu Nakamura, Takashi Yokota, Kiyohiko Takahashi, Shinichiro Kawata, Kazuhisa Tsuchida, Kazuno Omori, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Toshihisa Anzai, Shinya Tanaka, Yasuo Terauchi, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Medicine, Science
Abstract: Abstract We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.
Published: 2022
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9. Add-on imeglimin versus metformin dose escalation regarding glycemic control in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin: study protocol for a multicenter, prospective, randomized, open-label, parallel-group comparison study (MEGMI study)

Author: Kyu Yong Cho, Tatsuya Atsumi, Hiroshi Nomoto, Jun Takeuchi, So Nagai, Akinobu Nakamura, Hideaki Miyoshi, Shinji Taneda, Aika Miya, Hiraku Kameda, Akihiro Takahashi, and Hiroyoshi Kurihara
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Introduction Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin.Research design and methods This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500–1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52–85 mmol/mol (7.0%–9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects.Results This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy.Conclusions This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D.Trial registration number jRCT1011220005.
Published: 2022
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10. Dipeptidyl peptidase‐4 inhibitor might exacerbate Graves’ disease: A multicenter observational case–control study

Author: Tomonori Sekizaki, Hiraku Kameda, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Kiyohiko Takahashi, Arina Miyoshi, Norio Wada, Jun Takeuchi, So Nagai, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Dipeptidyl peptidase‐4, Graves' disease, Case‐control study, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Dipeptidyl peptidase‐4 (DPP‐4), namely CD26, is expressed on the surface of immune cells, suggesting that inhibition of DPP‐4 might affect the immune system. The current multicenter observational case–control study was carried out to investigate the effects of DPP‐4 inhibitor (DPP‐4i) administration on Graves' disease (GD) activity. This study comprised patients with GD and type 2 diabetes, who were administered an oral hypoglycemic agent including DPP‐4i. Exacerbation of GD was defined as an increase of antithyroid drug dose by 6 months after oral hypoglycemic agent administration. A total of 80 patients were enrolled and divided into an exacerbation group or a non‐exacerbation group. The frequency of DPP‐4i administration was significantly higher in the exacerbation group (88%) than that in the non‐exacerbation group (31%). In multivariate logistic regression analysis, there was a significant association between DPP‐4i administration and GD exacerbation (odds ratio 7.39). The current study suggests that DPP‐4i administration is associated with GD exacerbation.
Published: 2021
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11. Glucokinase is required for high‐starch diet‐induced β‐cell mass expansion in mice

Author: Kazuhisa Tsuchida, Akinobu Nakamura, Hideaki Miyoshi, Kelaier Yang, Yuki Yamauchi, Shinichiro Kawata, Kazuno Omori, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yusuke Seino, Yasuo Terauchi, and Tatsuya Atsumi
Subjects: β‐Cell mass, Glucokinase, High‐starch diet, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction We aimed to determine whether glucokinase is required for β‐cell mass expansion induced by high‐starch diet (HSTD)‐feeding, as has been shown in its high‐fat diet‐induced expansion. Materials and Methods Eight‐week‐old male wild‐type (Gck+/+) or glucokinase haploinsufficient (Gck+/−) mice were fed either a normal chow (NC) or an HSTD for 15 weeks. The bodyweight, glucose tolerance, insulin sensitivity, insulin secretion and β‐cell mass were assessed. Results Both HSTD‐fed Gck+/+ and Gck+/− mice had significantly higher bodyweight than NC‐fed mice. Insulin and oral glucose tolerance tests revealed that HSTD feeding did not affect insulin sensitivity nor glucose tolerance in either the Gck+/+ or Gck+/− mice. However, during the oral glucose tolerance test, the 15‐min plasma insulin concentration after glucose loading was significantly higher in the HSTD group than that in the NC group for Gck+/+, but not for Gck+/− mice. β‐Cell mass was significantly larger in HSTD‐fed Gck+/+ mice than that in NC‐fed Gck+/+ mice. In contrast, the β‐cell mass of the HSTD‐fed Gck+/− mice was not different from that of the NC‐fed Gck+/− mice. Conclusions The results showed that HSTD feeding would increase pancreatic β‐cell mass and insulin secretion in Gck+/+, but not Gck+/− mice. This observation implies that glucokinase in β‐cells would be required for the increase in β‐cell mass induced by HSTD feeding.
Published: 2021
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12. Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study

Author: Kyu Yong Cho, Hiroshi Nomoto, Akinobu Nakamura, Shinichiro Kawata, Hajime Sugawara, Jun Takeuchi, So Nagai, Kazuno Omori, Kazuhisa Tsuchida, Aika Miya, Ikumi Shigesawa, Kenichi Tsuchida, Shingo Yanagiya, Hiraku Kameda, Hiroki Yokoyama, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Naoki Nishimoto, Tatsuya Atsumi, and Hideaki Miyoshi
Subjects: Post‐prandial blood glucose, Sodium–glucose cotransporter 2inhibitor, Time in range, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction We recently reported the beneficial effect of the combination of sodium–glucose cotransporter 2 inhibitor and dipeptidyl peptidase‐4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. Materials and Methods The CALMER study was a multicenter, open‐label, prospective, randomized, parallel‐group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. Results All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2–82.7%, P
Published: 2021
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13. Favorable effect of sodium–glucose cotransporter 2 inhibitor, dapagliflozin, on non‐alcoholic fatty liver disease compared with pioglitazone

Author: Kyu Yong Cho, Akinobu Nakamura, Kazuno Omori, Takahiro Takase, Aika Miya, Kohei Yamamoto, Hiroshi Nomoto, Hiraku Kameda, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, and Hideaki Miyoshi
Subjects: Fatty liver, Sodium–glucose cotransporter 2 inhibitor, Type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Sodium–glucose cotransporter 2 inhibitors, as well as thiazolidines, suppress nonalcoholic fatty liver disease (NAFLD); however, few comparative studies have been reported. Dapagliflozin has shown non‐inferiority compared with pioglitazone for glycemic control, and superiority regarding weight reduction in patients with type 2 diabetes. We carried out a secondary analysis for the favorable effects of sodium–glucose cotransporter inhibitors for NAFLD. Materials and Methods In this multicenter, open‐label, prospective, randomized, parallel‐group comparison trial, patients taking pioglitazone for ≥12 weeks were randomly switched to dapagliflozin or continued pioglitazone for a further 24 weeks. The fatty liver index (FLI), consisting of body mass index, triglycerides, waist circumference and γ‐glutamyl transpeptidase, was used for the evaluation of NAFLD. Results A total of 53 participants with NAFLD (27 dapagliflozin; 26 pioglitazone) were included in this analysis. FLI decreased significantly in the dapagliflozin group (48.7 ± 23.4 to 42.1 ± 23.9) compared with the pioglitazone group (49.0 ± 26.1 to 51.1 ± 25.8; P
Published: 2021
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14. Beneficial effects of switching to denosumab from bisphosphonates or selective estrogen receptor modulators in postmenopausal women with type 2 diabetes and osteopenia/osteoporosis

Author: Arina Miyoshi, Hiraku Kameda, So Nagai, Akinobu Nakamura, Aika Miya, Takahiro Takase, Tatsuya Atsumi, and Hideaki Miyoshi
Subjects: Denosumab, Osteoporosis, Type 2 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Patients with type 2 diabetes mellitus have a higher bone fracture risk than patients without diabetes. Although denosumab (Dmab) is a potent bone resorption inhibitor, its efficacy in patients with type 2 diabetes mellitus has not been elucidated. In this study, we investigated the effects of switching to Dmab from bisphosphonates (BP) or a selective estrogen receptor modulator (SERM) in postmenopausal type 2 diabetes mellitus patients. Materials and Methods This was a three medical institutions, prospective, observational study for postmenopausal patients with type 2 diabetes mellitus whose T‐score of femoral neck or lumbar spine bone mineral density was under −1.0 standard deviation, even after >6 months of BP or SERM administration. After obtaining consent, participants were treated for osteopenia/osteoporosis by either continuing BP (BP‐BP group)/SERM (SERM‐SERM group), or by switching to Dmab (BP‐Dmab or SERM‐Dmab groups). Changes in bone mineral density and bone metabolism marker levels were evaluated after 6 months. Results A total of 48 patients were included in this study, and each group comprised 12 patients. No significant difference existed in baseline characteristics among the groups. The average age and glycated hemoglobin were 71 ± 8 years and 7.2 ± 0.9%, respectively. In the SERM‐Dmab group, lumbar spine bone mineral density was significantly increased by 5.0% compared with the SERM‐SERM group (P
Published: 2021
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15. Effect of Switching to Once-Weekly Semaglutide on Non-Alcoholic Fatty Liver Disease: The SWITCH-SEMA 1 Subanalysis

Author: Hiroshi Nomoto, Yuka Takahashi, Yoshinari Takano, Hiroki Yokoyama, Kazuhisa Tsuchida, So Nagai, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, and Tatsuya Atsumi
Subjects: fatty liver, glucagon-like receptor agonists, once-weekly semaglutide, type 2 diabetes, Pharmacy and materia medica, RS1-441
Abstract: Non-alcoholic fatty liver disease (NAFLD) is an important common comorbidity in individuals with type 2 diabetes (T2DM). Although some glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on NAFLD, the efficacy of once-weekly semaglutide has not been established. This was a subanalysis of the SWITCH-SEMA 1 study, a multicenter, prospective, randomized, parallel-group trial comparing switching from liraglutide or dulaglutide to once-weekly semaglutide in subjects with T2DM (SWITCH) versus continuing current GLP-1RAs (Continue) for 24 weeks. This subanalysis consisted of participants who were suspected to have NAFLD [fatty liver index (FLI) ≥ 30]. In total, 58 participants met the criteria of this subanalysis. There were no statistical differences in baseline characteristics between the SWITCH (n = 31) and Continue groups (n = 27). FLI significantly improved during treatment in the SWITCH group (68.6 to 62.7) but not in the Continue group (71.1 to 72.3) (p < 0.01). The improvement of FLI in the SWITCH group was greater in switching from dulaglutide to semaglutide and significantly correlated with older age (p = 0.016) and lower baseline FLI (p < 0.01). The multiple linear regression analysis revealed that the switch from dulaglutide was associated with an improvement in FLI (p = 0.041). Switching from conventional GLP-1RAs to once-weekly semaglutide might be beneficial for individuals with NAFLD complicated with T2DM.
Published: 2023
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16. Favorable Effect of Pemafibrate on Insulin Resistance and β-Cell Function in Subjects with Type 2 Diabetes and Hypertriglyceridemia: A Subanalysis of the PARM-T2D Study

Author: Hiroshi Nomoto, Kenichi Kito, Hiroshi Iesaka, Yuki Oe, Shinichiro Kawata, Kazuhisa Tsuchida, Shingo Yanagiya, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Ichiro Sakuma, Naoki Manda, Akinobu Nakamura, and Tatsuya Atsumi
Subjects: insulin resistance, pemafibrate, type 2 diabetes, Pharmacy and materia medica, RS1-441
Abstract: Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has beneficial effects on lipid metabolism. However, its effects on glucose metabolism in individuals with type 2 diabetes (T2DM) remain to be fully clarified. This was a subanalysis of the PARM-T2D study, a multicenter prospective observational study on the use of pemafibrate versus conventional therapy for 52 weeks in subjects with T2DM complicated with hypertriglyceridemia. The subanalysis included participants who did not change their treatment for diabetes and did not receive insulin or insulin secretagogues during the study period. Changes in glucose metabolism markers, including homeostatic model assessment (HOMA2) scores and disposition index, were assessed. A total of 279 participants (141 in the pemafibrate group; 138 in the control group) met the criteria for the subanalysis. There were no significant changes in HbA1c during the 52-week study period in both groups. However, the pemafibrate group showed significant improvements versus the control group for insulin resistance assessed by HOMA2-R (−0.15 versus 0.08; estimated treatment difference −0.23 (95% confidence interval −0.44, −0.02); p = 0.03) and maintenance of β-cell function assessed by disposition index (0.015 versus −0.023; estimated treatment difference 0.037 (95% confidence interval 0.005, 0.069); p = 0.02). Correlation analyses showed that improvements in HOMA2-R and disposition index were significantly associated with improvements in lipid abnormalities and γ-glutamyl transpeptidase. In conclusion, pemafibrate reduced insulin resistance and maintained β-cell function in subjects with T2DM and hypertriglyceridemia, presumably by improving lipid profiles and lipid-related hepatocyte stress.
Published: 2023
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17. Impaired insulin secretion predicting unstable glycemic variability and time below range in type 2 diabetes patients regardless of glycated hemoglobin or diabetes treatment

Author: Aika Miya, Akinobu Nakamura, Takahisa Handa, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Glucose variability, Hypoglycemia, Insulin secretion, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction To identify the coefficient of variation (CV) threshold for unstable glucose variability (GV) and hypoglycemia, and to characterize a patient population with unstable GV and hypoglycemia. Materials and Methods This was an observational study that enrolled 284 Japanese outpatients with type 2 diabetes who underwent continuous glucose monitoring. The C‐peptide index (CPI = [(fasting serum C‐peptide) / (plasma glucose)] × 100) was used as a marker of endogenous insulin secretion. The CV threshold between stable and unstable GV was defined as the upper limit of the CV distribution in the subgroup of patients who did not receive insulin nor insulin secretagogues (relatively stable GV subgroup, n = 104). The optimal CV range corresponding to time below target range ≥4% was determined for all patients using receiver operating characteristic curve analysis. Various characteristics of patients with unstable GV and hypoglycemia were extracted using multivariate logistic regression analysis. Results The upper limit of the CV in the relatively stable GV subgroup was 40. The optimal CV range corresponding to time below target range ≥4% was also defined as CV ≥40 (area under the curve 0.85) for all patients. The CPI was an independent risk for CV ≥40 (odds ratio 0.17, 95% confidence interval 0.04–0.50, P
Published: 2021
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18. The association between hypoglycemia and glycemic variability in elderly patients with type 2 diabetes: a prospective observational study

Author: Takahisa Handa, Akinobu Nakamura, Aika Miya, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Narihito Yoshioka, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Coefficient of variation, Continuous glucose monitoring, Hypoglycemia, Nutritional diseases. Deficiency diseases, RC620-627
Abstract: Abstract Background This study aimed to explore predictive factors of time below target glucose range (TBR) ≥ 1% among patients’ characteristics and glycemic variability (GV) indices using continuous glucose monitoring data in elderly patients with type 2 diabetes. Methods We conducted a prospective observational study on 179 (71 female) Japanese outpatients with type 2 diabetes aged ≥ 65 years. The characteristics of the participants with TBR ≥ 1% were evaluated by multivariate logistic regression analysis. Receiver-operating characteristic (ROC) curve analyses of GV indices, comprising coefficient of variation (CV), standard deviation, and mean amplitude of glycemic excursions, were performed to identify the optimal index for the identification of patients with TBR ≥ 1%. Results In the multivariate logistic regression analysis, none of the clinical characteristics, including HbA1c and C-peptide index, were independent markers for TBR ≥ 1%, while all three GV indices showed significant associations with TBR ≥ 1%. Among the three GV indices, CV showed the best performance based on the area under the curve in the ROC curve analyses. Conclusions Among elderly patients with type 2 diabetes, CV reflected TBR ≥ 1% most appropriately among the GV indices examined. Trial registration UMIN-CTR: UMIN000029993. Registered 16 November 2017
Published: 2021
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19. Log-linear relationship between endogenous insulin secretion and glycemic variability in patients with type 2 diabetes on continuous glucose monitoring

Author: Aika Miya, Akinobu Nakamura, Takahisa Handa, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Yoichi M. Ito, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Medicine, Science
Abstract: Abstract The contribution of endogenous insulin secretion to glycemic variability (GV) may differ between patients with impaired insulin secretion and those with preserved secretion. Our objective was to determine the linearity of the relationship between fasting C-peptide (CPR) as a marker of endogenous insulin secretion and GV in type 2 diabetes (T2DM), regardless of the type of antidiabetic treatment. We conducted a prospective observational study using continuous glucose monitoring obtained from 284 Japanese outpatients with T2DM with various HbA1c values and antidiabetic treatment. We constructed a prediction curve of base-line CPR versus coefficient of variation (CV) and identified the clinical factors associated with CV using multiple regression analysis. Fasting CPR showed a significant negative log-linear relationship with CV (P
Published: 2021
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20. Combination of alcohol and glucose consumption as a risk to induce reactive hypoglycemia

Author: Chiho Oba‐Yamamoto, Jun Takeuchi, Akinobu Nakamura, Ryoko Takikawa, Ayano Ozaki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, and Hideaki Miyoshi
Subjects: Alcohol, Hypoglycemia, Oral glucose tolerance test, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Alcohol consumption has been reported to cause hypoglycemia. However, the mechanism involved has not been unequivocally established. This study comprised healthy volunteers. We carried out a prospective trial to compare the effects of glucose and alcohol consumption, alone or in combination, on glucose and lipid metabolism. Materials and Methods A 75‐g oral glucose tolerance test (OGTT), a combined 75‐g glucose plus 20‐g alcohol tolerance test (OGATT) and a 20‐g alcohol tolerance test (OATT) were carried out in the participants. Plasma glucose, insulin, triglyceride and ethanol concentrations during each test were compared. Results We studied 10 participants. Their plasma glucose concentrations 15 and 30 min after the intake of 75 g of glucose were significantly higher during the OGATT than the OGTT. Hypoglycemia occurred in five participants after the OGATT, which was significantly more frequently than after the OGTT (P = 0.046). Hypoglycemia did not occur after the OATT, and the ethanol concentration was significantly lower after the OGATT than the OATT. The changes in triglyceride concentration from 30 min after the consumption of 75 g of glucose were significantly greater during the OGATT than the OGTT. The plasma insulin concentrations peaked after 60 min during both the OGTT and OGATT, and were significantly higher during the OGATT (P = 0.047). There were no differences between the two interventions in the Matsuda or disposition indexes. Conclusions Hypoglycemia occurred more frequently after the simultaneous consumption of alcohol plus glucose than after the consumption of glucose alone, suggesting that alcohol in the combination of glucose induces reactive hypoglycemia.
Published: 2021
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21. Severe infection including disseminated herpes zoster triggered by subclinical Cushing’s disease: a case report

Author: Yuki Yamauchi, Hiraku Kameda, Kazuno Omori, Michio Tani, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Shinya Tanaka, and Tatsuya Atsumi
Subjects: Subclinical Cushing’s disease, Disseminated herpes zoster, Infection, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Background Subclinical Cushing’s disease (SCD) is defined by corticotroph adenoma-induced mild hypercortisolism without typical physical features of Cushing’s disease. Infection is an important complication associated with mortality in Cushing’s disease, while no reports on infection in SCD are available. To make clinicians aware of the risk of infection in SCD, we report a case of SCD with disseminated herpes zoster (DHZ) with the mortal outcome. Case presentation An 83-year-old Japanese woman was diagnosed with SCD, treated with cabergoline in the outpatient. She was hospitalized for acute pyelonephritis, and her fever gradually resolved with antibiotics. However, herpes zoster appeared on her chest, and the eruptions rapidly spread over the body. She suddenly went into cardiopulmonary arrest and died. Autopsy demonstrated adrenocorticotropic hormone-positive pituitary adenoma, renal abscess, and DHZ. Conclusions As immunosuppression caused by SCD may be one of the triggers of severe infection, the patients with SCD should be assessed not only for the metabolic but also for the immunodeficient status.
Published: 2021
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22. Sodium–glucose cotransporter 2 inhibitors reduce day‐to‐day glucose variability in patients with type 1 diabetes

Author: Koki Chiba, Hiroshi Nomoto, Akinobu Nakamura, Kyu Yong Cho, Kumiko Yamashita, Yui Shibayama, Aika Miya, Hiraku Kameda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, and Hideaki Miyoshi
Subjects: Glucose variability, Sodium–glucose cotransporter 2 inhibitor, Type 1 diabetes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes. Materials and Methods Patients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day‐to‐day glucose variability, as the primary end‐point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring. Results A total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6–38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P
Published: 2021
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23. Effects of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide on glucose metabolism in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, parallel-group comparison study (the SWITCH-SEMA 2 study)

Author: Kyu Yong Cho, Hiroki Yokoyama, Tatsuya Atsumi, Hiroshi Nomoto, Jun Takeuchi, So Nagai, Yoshio Kurihara, Shin Aoki, Akinobu Nakamura, Hideaki Miyoshi, Shinji Taneda, Ichiro Sakuma, Sho Furusawa, Aika Miya, and Hiraku Kameda
Subjects: Medicine
Abstract: Introduction Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor.Methods and analysis This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%–9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters.Ethics and dissemination This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020–013).Trial registration number UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.
Published: 2022
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24. Switching from Insulin Degludec plus Dipeptidyl Peptidase-4 Inhibitor to Insulin Degludec/Liraglutide Improves Glycemic Variability in Patients with Type 2 Diabetes: A Preliminary Prospective Observation Study

Author: Yuki Oe, Hiroshi Nomoto, Akinobu Nakamura, Saki Kuwabara, Yuka Takahashi, Ayano Yasui, Rimi Izumihara, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, and Hideaki Miyoshi
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Incretins reduce glycemic variability (GV) in patients with type 2 diabetes, but it is unknown whether switching from a combination of basal insulin and a DPP-4 inhibitor to insulin degludec/liraglutide (IDegLira) improves GV. We performed an exploratory prospective observational study to compare the effect of IDegLira and the combination on GV. We recruited hospitalized patients with type 2 diabetes who had stable glycemic control with insulin degludec (≤16 units/day) and taking a DPP-4 inhibitor. GV was analyzed using continuous glucose monitoring (CGM) before and after switching the medication to IDegLira. The principal endpoint was the change in mean amplitude of glycemic excursions (MAGE). Other indices of GV and CGM parameters were analyzed as the secondary endpoints. Fifteen participants were enrolled and 12 completed the study. In these participants, the DPP-4 inhibitor and insulin degludec were discontinued, and the equivalent dose of IDegLira was commenced. Switching to IDegLira significantly improved MAGE from 74.9 (60.3, 97.7) mg/dL to 64.8 (52.0, 78.2) mg/dL (P
Published: 2022
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25. Impact of sodium–glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria

Author: Akinobu Nakamura, Hideaki Miyoshi, Hiraku Kameda, Kumiko Yamashita, and Yoshio Kurihara
Subjects: Chronic kidney disease, Diabetic kidney disease, Estimated glomerular filtration rate, sodium–glucose cotransporter 2 inhibitor, Nutritional diseases. Deficiency diseases, RC620-627
Abstract: Abstract Background We compared the effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR)
Published: 2020
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26. Protective effect of sodium–glucose cotransporter 2 inhibitors in patients with rapid renal function decline, stage G3 or G4 chronic kidney disease and type 2 diabetes

Author: Hideaki Miyoshi, Hiraku Kameda, Kumiko Yamashita, Akinobu Nakamura, and Yoshio Kurihara
Subjects: Estimated glomerular filtration rate, Kidney disease, Sodium–glucose cotransporter 2 inhibitors inhibitor, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract Aims/Introduction The risk of end‐stage kidney disease increases in proportion to the decline in the estimated glomerular filtration rate (eGFR). Although protective effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on the eGFR decline were shown in several large‐scale clinical trials, there are no studies investigating patients with a high risk of end‐stage kidney disease. We investigated the efficacy and safety of SGLT2i in advanced renal dysfunction patients (stage G3 or G4 of chronic kidney disease) with a rapid decline in eGFR. Materials and Methods This retrospective, longitudinal study enrolled patients with type 2 diabetes who were treated with SGLT2i, and whose eGFR was 20% over 2 years (%ΔeGFR−2y) before initiating SGLT2i. The primary end‐point was the change in eGFR 2 years after initiation (%ΔeGFR+2y) compared with %ΔeGFR−2y. Results A total of 17 patients among 553 patients treated with SGLT2i for ≥2 years were included in the study. The average age, glycated hemoglobin and eGFR at SGLT2i initiation were 68.5 years, 7.3% and 38.3 mL/min/1.73 m2, respectively. %ΔeGFR+2y in patients who were treated with SGLT2i was significantly increased compared with the patients not treated with SGLT2i (2.3 and −21.7%, respectively; P
Published: 2019
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27. Case of fulminant type 1 diabetes induced by the anti‐programmed death‐ligand 1 antibody, avelumab

Author: Yui Shibayama, Hiraku Kameda, Shoichiro Ota, Kazuhisa Tsuchida, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Anti‐programmed death‐ligand 1 antibody, Fulminant type 1 diabetes, Immune‐related adverse events, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Abstract With the expansive use of immune checkpoint inhibitors, the frequency of immune‐related adverse events, including autoimmune type 1 diabetes, has been exponentially increased. The anti‐programmed death‐ligand 1 antibody, avelumab, has recently been approved for metastatic Merkel cell carcinoma therapy. Here, we report a patient that developed fulminant type 1 diabetes during avelumab treatment. An 81‐year‐old woman with no history of diabetes received avelumab for metastatic Merkel cell carcinoma. Elevated plasma glucose level (483 mg/dL), hemoglobin A1c level (7.5%) and ketosis were observed after 10 courses of avelumab without any symptoms related to hyperglycemia. As the laboratory tests showed insulin depletion, we diagnosed her with fulminant type 1 diabetes induced by avelumab. This is the first reported case of avelumab‐induced type 1 diabetes, illustrating the necessity for close monitoring of glycemic control during avelumab therapy, as well as other immune checkpoint inhibitors.
Published: 2019
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28. Breakdown of Autonomously Functioning Thyroid Nodule Accompanied by Acromegaly After Octreotide Treatment

Author: Hiroshi Nomoto, Hiraku Kameda, Akinobu Nakamura, Kazuhisa Tsuchida, So Nagai, Tatsuya Atsumi, and Hideaki Miyoshi
Subjects: autonomously functioning thyroid nodule, acromegaly, somatostatin analog, pituitary adenoma, thyrotoxicosis, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Patients with acromegaly are at increased risk of developing certain tumors, including goiter and thyroid nodules, and occasionally autonomous thyroid nodules. A 53-year-old woman presented at our hospital with untreated acromegaly. She had typical physical features of acromegaly with pituitary adenoma, and thyrotoxicosis with thyroid-stimulating hormone suppression was also confirmed. Thyroid ultrasonography and scintigraphy showed an autonomously functioning thyroid nodule on her right lobe. Because her thyrotoxicosis was mild, she was initially treated with octreotide for acromegaly. However, 1 month after octreotide administration, she developed neck pain and fever with transient thyrotoxicosis. The blood flow around the nodule then decreased and the excess trapping of isotope detected by scintigraphy was reduced, followed by normalization of insulin-like growth factor-1 levels and thyroid function. This case suggests that octreotide may have unexpected effects on autonomous thyroid nodules. However, further studies are needed to determine the clinical course of autonomously functioning thyroid nodules, including thyroid function and tumor manifestations, during octreotide therapy.
Published: 2019
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29. Type 1 diabetes mellitus in a melanoma patient treated with adjuvant nivolumab therapy

Author: Takuya Maeda, Shinya Kitamura, Teruki Yanagi, Atsushi Narahira, Kodai Miyamoto, Hiroo Hata, kyu Yong Cho, Hiraku Kameda, Akinobu Nakamura, and Hiroshi Shimizu
Subjects: Dermatology, RL1-803, Immunologic diseases. Allergy, RC581-607
Published: 2019
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30. Lymphocytic panhypophysitis and anti-rabphilin-3A antibody with pulmonary sarcoidosis

Author: Yuka Takahashi, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Hiroki Nishimura, Hirokazu Kimura, Masaru Suzuki, Satoshi Konno, Ai Shimizu, Yoshihiro Matsuno, Michinari Okamoto, Hiroaki Motegi, Naoko Iwata, Haruki Fujisawa, Atsushi Suzuki, Yoshihisa Sugimura, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Male, Anti-rabphilin-3a antibody, Sarcoidosis, Endocrinology, Diabetes and Metabolism, Middle Aged, Hypopituitarism, Diabetes Insipidus, Neurogenic, Endocrinology, Sarcoidosis, Pulmonary, Pituitary Gland, Lymphocytic panhypophysitis, Humans, Autoimmune Hypophysitis, Panhypopituitarism
Abstract: Purpose To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis. Methods and results A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis. Conclusion To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies.
Published: 2023

31. The agreement between measured <scp>HbA1c</scp> and optimized target <scp>HbA1c</scp> based on the Dementia Assessment Sheet for Community‐based Integrated Care System 8‐items ( <scp>DASC</scp> ‐8): A cross‐sectional study of elderly patients with diabetes

Author: Aika Miya, Akinobu Nakamura, Isao Yokota, Kyu Yong Cho, Hiraku Kameda, Hiroshi Nomoto, Takahiro Takase, Kazuno Omori, Mayuko Ono, So Nagai, Shinji Taneda, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: General Medicine
Published: 2022
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32. Inverse association between glucose variability and body fat in type 2 diabetes with impaired endogenous insulin secretion assessed using continuous glucose monitoring: A prospective observational study

Author: Aika Miya, Akinobu Nakamura, Yuka Suzuki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yoichi M. Ito, So Nagai, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Internal Medicine
Published: 2023
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33. Author response for 'Inverse association between glucose variability and body fat in type 2 diabetes with impaired endogenous insulin secretion using continuous glucose monitoring: a prospective observational study'

Author: null Aika Miya, null Akinobu Nakamura, null Yuka Suzuki, null Hiroshi Nomoto, null Hiraku Kameda, null Kyu Yong Cho, null Yoichi M. Ito, null So Nagai, null Hideaki Miyoshi, and null Tatsuya Atsumi
Published: 2023
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34. Author response for 'Improvement of glycemic control and treatment satisfaction by switching from liraglutide or dulaglutide to subcutaneous semaglutide in patients with type 2 diabetes: A multicenter, prospective, randomized, open‐label, parallel‐group comparison study ( <scp>SWITCH‐SEMA</scp> 1 study)'

Author: null Yuka Takahashi, null Hiroshi Nomoto, null Hiroki Yokoyama, null Yoshinari Takano, null So Nagai, null Atsushi Tsuzuki, null Kyu Yong Cho, null Aika Miya, null Hiraku Kameda, null Jun Takeuchi, null Shinji Taneda, null Yoshio Kurihara, null Tatsuya Atsumi, null Akinobu Nakamura, null Hideaki Miyoshi, null Yuka Hamaya, null Asuka Miyazaki, null Kento Nakata, null Rimi Izumihara, null Risa Kamigaki, null Kazuhisa Tsuchida, null Kyu‐Yong Cho, null Hiromichi Kijima, and null SWITCH‐SEMA 1 study group
Published: 2023
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35. Glucokinase activation leads to an unsustained hypoglycaemic effect with hepatic triglyceride accumulation in <scp> db/db </scp> mice

Author: Kelaier Yang, Hiraku Kameda, Kazuhisa Tsuchida, Ikumi Shigesawa, Shinichiro Kawata, Hideaki Miyoshi, Kyu Yong Cho, Yuki Yamauchi, Tatsuya Atsumi, Hiroshi Nomoto, Yasuo Terauchi, Kazuno Omori, Akinobu Nakamura, and Kiyohiko Takahashi
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Mice, chemistry.chemical_compound, Endocrinology, Internal medicine, Glucokinase, Internal Medicine, medicine, Animals, Humans, Hypoglycemic Agents, Carbohydrate-responsive element-binding protein, Triglycerides, Triglyceride, biology, business.industry, Pancreatic islets, Gluconeogenesis, Fatty acid synthase, medicine.anatomical_structure, Liver, chemistry, Lipogenesis, biology.protein, Phosphoenolpyruvate carboxykinase, business
Abstract: Aims Glucokinase activators (GKAs) show a hypoglycaemic effect through augmentation of insulin secretion in pancreatic beta-cells and glucose utilization in the liver. The results from some clinical studies of GKAs suggested they show an unsustained hypoglycaemic effect. We investigated how sub-chronic administration of a GKA results in attenuation in the hypoglycaemic effect in a diabetic condition. Materials and methods Six-week-old db/db mice were fed standard chow containing a GKA or the sodium-glucose cotransporter 2 inhibitor, ipragliflozin for 1, 6, 14, or 28 days. We performed histological evaluation and gene expression analysis of the pancreatic islets and liver after each treatment and compared the results to untreated mice. Results The unsustained hypoglycaemic effect of GKAs was reproduced in db/db mice in conjunction with significant hepatic fat accumulation. The initial reactions to treatment with the GKA in the liver were the upregulation of the gene expression of carbohydrate response element-binding protein beta (Chrebp-b) and the downregulation of phosphoenolpyruvate carboxykinase (Pepck) on day 1. Subsequently, the initial changes in Chrebp-b and Pepck disappeared and increases in the expression of genes involved in lipogenesis, including acetyl-CoA carboxylase and fatty acid synthase, were observed. There were no significant changes in the pancreatic beta-cells nor hepatic insulin signalling. Conclusions The GKA showed an unsustained hypoglycaemic effect and promoted hepatic fat accumulation in db/db mice. Dynamic changes in the expression of hepatic genes involved in lipogenesis and gluconeogenesis could affect the unsustained hypoglycaemic effect of the GKA despite no changes in pancreatic beta-cell function and mass. This article is protected by copyright. All rights reserved.
Published: 2021
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36. Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study

Author: Ikumi Shigesawa, Naoki Nishimoto, Kazuno Omori, Shin Aoki, Kenichi Tsuchida, Tatsuya Atsumi, So Nagai, Shinji Taneda, Shinichiro Kawata, Hiraku Kameda, Aika Miya, Shingo Yanagiya, Akinobu Nakamura, Hiroshi Nomoto, Hideaki Miyoshi, Kyu Yong Cho, Hajime Sugawara, Kazuhisa Tsuchida, Hiroki Yokoyama, Jun Takeuchi, and Yoshio Kurihara
Subjects: Blood Glucose, Male, Endocrinology, Diabetes and Metabolism, 030204 cardiovascular system & hematology, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Prospective Studies, Canagliflozin, Area under the curve, SGLT2 inhibitor, General Medicine, Articles, Postprandial, Clinical Science and Care, Post-Prandial Blood Glucose, Thiazolidines, Original Article, Drug Therapy, Combination, Female, medicine.drug, Adult, medicine.medical_specialty, Combination therapy, 030209 endocrinology & metabolism, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, DPP-4 inhibitor, Humans, Hypoglycemic Agents, Sodium–glucose cotransporter 2inhibitor, Teneligliptin, Sodium-Glucose Transporter 2 Inhibitors, Glycemic, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Glucose Tolerance Test, medicine.disease, RC648-665, Post‐prandial blood glucose, chemistry, Diabetes Mellitus, Type 2, Hyperglycemia, Time in range, Pyrazoles, Glycated hemoglobin, business
Abstract: Aims/Introduction We recently reported the beneficial effect of the combination of sodium–glucose cotransporter 2 inhibitor and dipeptidyl peptidase‐4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. Materials and Methods The CALMER study was a multicenter, open‐label, prospective, randomized, parallel‐group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. Results All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2–82.7%, P
Published: 2021

37. Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor

Author: Hideaki Miyoshi, Kyu Yong Cho, Yukihiro Fujita, Tomonori Sekizaki, So Nagai, Akinobu Nakamura, Hiroshi Nomoto, Hiraku Kameda, Tsuyoshi Yanagimachi, Tatsuya Atsumi, Takahiro Takase, and Chiho Oba-Yamamoto
Subjects: medicine.medical_specialty, Adenoma, endocrine system diseases, Dipeptidyl peptidase-4 inhibitor, Growth hormone, Internal medicine, Acromegaly, Internal Medicine, medicine, Humans, Prospective Studies, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Human Growth Hormone, nutritional and metabolic diseases, General Medicine, medicine.disease, Growth hormone secretion, glucose-dependent insulinotropic polypeptide, Real-time polymerase chain reaction, Endocrinology, Cross-Sectional Studies, Glucose, Growth Hormone, Immunohistochemistry, Original Article, business, Immunostaining, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract: Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.
Published: 2021

38. Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease

Author: Shlomo Melmed, Hiraku Kameda, Anat Ben-Shlomo, Shozo Yamada, Masaaki Yamamoto, Yasuhiko Kawakami, Akira Takeshita, Masahide Tone, Masato Yamamoto, Yukiko Tone, and Takako Araki
Subjects: Male, 0301 basic medicine, Pro-Opiomelanocortin, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Pituitary-Adrenal System, pituitary adenoma, Biochemistry, 0302 clinical medicine, Endocrinology, Cyclic AMP Response Element-Binding Protein, Promoter Regions, Genetic, biology, Cushing disease, POMC, Exons, ACTH-Secreting Pituitary Adenoma, Treatment Outcome, Female, AcademicSubjects/MED00250, hormones, hormone substitutes, and hormone antagonists, Adenoma, Adult, Hypothalamo-Hypophyseal System, endocrine system, medicine.medical_specialty, Adolescent, CREB, Young Adult, 03 medical and health sciences, Adrenocorticotropic Hormone, Proopiomelanocortin, Internal medicine, medicine, Humans, Pituitary Neoplasms, Online Only Articles, Pituitary ACTH Hypersecretion, Enhancer, Clinical Research Articles, Aged, Biochemistry (medical), Pituitary tumors, Promoter, Cushing's disease, medicine.disease, ACTH, 030104 developmental biology, Gene Expression Regulation, biology.protein, Cancer research, Corticotropic cell, 030217 neurology & neurosurgery
Abstract: Context Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. Objective We characterized the 5′ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. Methods We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. Results We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. Conclusion We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.
Published: 2021
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39. Combination of alcohol and glucose consumption as a risk to induce reactive hypoglycemia

Author: Ayano Ozaki, Hiroshi Nomoto, Chiho Oba-Yamamoto, Akinobu Nakamura, Ryoko Takikawa, Hideaki Miyoshi, Kyu Yong Cho, Jun Takeuchi, Tatsuya Atsumi, and Hiraku Kameda
Subjects: Blood Glucose, Male, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Alcohol, 01 natural sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin, Medicine, Prospective Studies, Alcohol tolerance, Reactive hypoglycemia, Articles, General Medicine, Healthy Volunteers, Clinical Science and Care, Female, Original Article, Adult, 010407 polymers, medicine.medical_specialty, Alcohol Drinking, Oral glucose tolerance test, Hypoglycemia, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Internal Medicine, Humans, Ethanol, Triglyceride, business.industry, Central Nervous System Depressants, nutritional and metabolic diseases, Glucose Tolerance Test, RC648-665, medicine.disease, 0104 chemical sciences, Oral glucosetolerance test, Glucose, Endocrinology, chemistry, business, 030217 neurology & neurosurgery
Abstract: Aims/Introduction Alcohol consumption has been reported to cause hypoglycemia. However, the mechanism involved has not been unequivocally established. This study comprised healthy volunteers. We carried out a prospective trial to compare the effects of glucose and alcohol consumption, alone or in combination, on glucose and lipid metabolism. Materials and Methods A 75‐g oral glucose tolerance test (OGTT), a combined 75‐g glucose plus 20‐g alcohol tolerance test (OGATT) and a 20‐g alcohol tolerance test (OATT) were carried out in the participants. Plasma glucose, insulin, triglyceride and ethanol concentrations during each test were compared. Results We studied 10 participants. Their plasma glucose concentrations 15 and 30 min after the intake of 75 g of glucose were significantly higher during the OGATT than the OGTT. Hypoglycemia occurred in five participants after the OGATT, which was significantly more frequently than after the OGTT (P = 0.046). Hypoglycemia did not occur after the OATT, and the ethanol concentration was significantly lower after the OGATT than the OATT. The changes in triglyceride concentration from 30 min after the consumption of 75 g of glucose were significantly greater during the OGATT than the OGTT. The plasma insulin concentrations peaked after 60 min during both the OGTT and OGATT, and were significantly higher during the OGATT (P = 0.047). There were no differences between the two interventions in the Matsuda or disposition indexes. Conclusions Hypoglycemia occurred more frequently after the simultaneous consumption of alcohol plus glucose than after the consumption of glucose alone, suggesting that alcohol in the combination of glucose induces reactive hypoglycemia., Hypoglycemia occurred more frequently following the simultaneous ingestion of alcohol plus glucose than following the ingestion of glucose alone, suggesting that alcohol in the combination of glucose induces reactive hypoglycemia.
Published: 2021

40. Letter to the Editor Regarding Efficacy of IDegLira Versus IDegAsp Therapy in Patients with Type 2 Diabetes: A Randomized Crossover Study by isCGM

Author: Yuki Oe, Hiroshi Nomoto, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, and Tatsuya Atsumi
Subjects: Pharmacology (medical), General Medicine
Published: 2022

41. 116-OR: Changes in Glucose Tolerance and Related Factors after Renal Transplantation in Recipients with Impaired Glucose Tolerance

Author: MAIKO KUSUMI, AKINOBU NAKAMURA, AIKA MIYA, HIROSHI NOMOTO, HIRAKU KAMEDA, KYUYONG CHO, KIYOHIKO HOTTA, NOBUO SHINOHARA, HIDEAKI MIYOSHI, and TATSUYA ATSUMI
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: Background and Aims: Our previous study revealed that more than half of patients with impaired glucose tolerance (IGT) before renal transplantation improved to normal glucose tolerance after transplantation. However, the mechanism was not clear. This study aimed to investigate whether changes in glucose tolerance were associated with insulin secretion and resistance in Japanese renal transplant recipients diagnosed with IGT before transplantation. Materials and Methods: We analyzed data for 179 patients ≥20 years of age who received their first renal transplantation in our hospital from April 2005-October 20 and had no history of diabetes before transplantation. A total of 54 recipients who received the oral glucose tolerance test (OGTT) before and 1 year after transplantation and were diagnosed with IGT before transplantation. Patients were divided into two groups according to negative or positive changes in area under the blood glucose curves from 0-120 min after ingestion: improved group and non-improved group, respectively. Insulin secretion was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and insulin sensitivity was estimated by the Matsuda index (MI) and homeostasis model assessment of insulin resistance (HOMA-IR) . Results: Thirty and 24 patients were in the improved and non-improved groups, respectively. ISSI-2 significantly increased from 1.67±0.44 to 2.00±0.60 (P Conclusion: Improvement of glucose tolerance after renal transplantation in patients diagnosed with IGT before transplantation is related to improvement of insulin secretion. Disclosure M. Kusumi: None. A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H. Nomoto: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.
Published: 2022
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42. 1462-P: Effect of Energy Restriction on the Intracellular Metabolism of Rodent Pancreatic ß-Cells In Vitro and Obese Mice

Author: KOKI CHIBA, HIROSHI NOMOTO, RIMI IZUMIHARA, HIRAKU KAMEDA, KYUYONG CHO, HIDEAKI MIYOSHI, and TATSUYA ATSUMI
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: Background: In pancreatic β-cells under diabetic conditions, metabolic stressors cause mitochondrial dysfunction and reduce oxidative phosphorylation, resulting in impaired intracellular metabolism. It has been suggested that aberrant activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a role in this impairment. However, it is not clear whether the defect in activation of PFKFB3 is reversible. We investigated the effects of energy restriction on PFKFB3 and other metabolic enzymes in pancreatic β-cells. Methods: INS-1 832/13 cells and islets from C57BL/6J mice were cultured in medium containing a low (5.5 mM; low-G) or a high (22 mM: high-G) glucose concentration for 48 hours, or high-G for 24 hours followed by low-G for another 24 hours. The protein expression of glycolysis-related enzymes was measured using western blotting (WB) . Next, 6-week-old ob/+ and ob/ob mice were fed a standard chow diet ad lib or the same diet restricted to 2 g/day for 4 weeks. The body mass, blood glucose concentration, glucose tolerance, and insulin resistance of the mice were compared. The expression of glycolytic enzymes in the pancreatic islets was evaluated using WB and immunohistochemical staining. Results: In both INS-1 832/13 cells and isolated islets, higher expression of PKFFB3 was observed in the high-G group than in the low-G group. However, this was normalized by changing from a high-G to a low-G environment. Ad lib-fed ob/ob mice showed hyperglycemia and greater weight gain than ob/+ mice. The expression of PFKFB3, isocitrate dehydrogenase, and hexokinase was higher in ad lib-fed ob/ob mice. Restricted feeding suppressed weight gain and improved glucose tolerance versus ad lib-fed ob/ob mice. The high expression of PFKFB3 was ameliorated by restricted feeding. Conclusion: The intracellular metabolic changes in pancreatic β cells that are associated with obesity and diabetes are flexible. Disclosure K. Chiba: Research Support; Grant for Young Researcher from Japan Association for Diabetes Education and Care, Japan Diabetes Society Junior Scientist Development Grant, Japan Society for the Promotion of Science, MSD Life Science Foundation, Promotion for Young Research Talent and Network, The Akiyama Life Science Foundation, The Uehara Memorial Foundation. H. Nomoto: None. R. Izumihara: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.
Published: 2022
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43. 120-OR: Hepatic Steatosis Is Inversely Associated with Improvement of Pancreatic Beta-Cell Function after Vertical Sleeve Gastrectomy in Patients with Type 2 Diabetes

Author: AKINOBU NAKAMURA, YUKI OE, MAIKO KUSUMI, AIKA MIYA, HIROSHI NOMOTO, HIRAKU KAMEDA, KYUYONG CHO, KOJI OGAWA, YUMA EBIHARA, TATSUYA ATSUMI, and HIDEAKI MIYOSHI
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: Background: Improvement of beta-cell function is reportedly involved in the improvement of glucose tolerance and remission of diabetes after bariatric and metabolic surgery. However, the impact of this surgery on beta-cell function in Japanese patients is not clear. The objective of this study was to investigate the effect of this surgery on beta-cell function and the characteristics and factors related to changes in beta-cell function. Methods: We conducted a prospective study of patients with type 2 diabetes who underwent vertical sleeve gastrectomy. A 75-g OGTT was performed before and 1 year after this surgery. Glucose tolerance was evaluated using the area under the blood glucose curve (AUCglu) during the OGTT. Insulin secretion was evaluated by the insulin secretion-sensitivity index-2 (ISSI-2) and disposition index (DI) , and insulin sensitivity was estimated using the Matsuda index (MI) and HOMA-IR. Visceral fat and subcutaneous fat area were quantified by abdominal CT examination, and hepatic fat content was quantified using the MRI proton density fat fraction. Results: The mean age of 15 patients (6 females) was 41.9 ± 8.8 years. After 1 year of the surgery, BMI (Before 42.0±8.2 kg/m2, After 32.7±7.2 kg/m2; P < 0.01) , HbA1c, and AUCglu were significantly reduced. ISSI-2 and DI were significantly increased, with no significant changes in the MI or HOMA-IR. Changes in ISSI-2 and DI were inversely associated with hepatic fat content before the surgery (ISSI-2: r = -0.63, P < 0.05; DI: r = -0.59, P < 0.05) , but not with age, BMI, visceral fat area, AUCglu, ISSI-2, DI, MI or HOMA-IR before the surgery. Conclusion: Our results showed that beta-cell function was improved by vertical sleeve gastrectomy even in Japanese obese patients with type 2 diabetes. The degree of improvement in beta-cell function was associated with the degree of preoperative hepatic steatosis, suggesting that a hepatic-pancreatic association may exist. Disclosure A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. Y. Oe: None. M. Kusumi: None. H. Nomoto: None. H. Kameda: None. K. Cho: None. K. Ogawa: None. Y. Ebihara: None. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd.
Published: 2022
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44. 1465-P: Metabolic Remodeling in Pancreatic Beta Cells in Japanese Patients with Type 2 Diabetes

Author: RIMI IZUMIHARA, HIROSHI NOMOTO, KOKI CHIBA, HIRAKU KAMEDA, KYUYONG CHO, AKINOBU NAKAMURA, HIDEAKI MIYOSHI, HIROKI MIZUKAMI, and TATSUYA ATSUMI
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: Background and Aims: It has been shown that metabolic remodeling from oxidative phosphorylation to glycolysis via activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) occurs in pancreatic beta cells in non-Asians with diabetes, resulting in impaired beta cell function. We used multiple autopsy pancreatic sections to investigate whether such changes occur in Japanese patients with type 2 diabetes (T2D) , and if so, which clinical and pathological features of islets relate to this remodeling. Methods: Autopsy pancreatic sections from patients with T2D and non-diabetic donors (ND) were stained with antibodies against PFKFB3, insulin, and glucagon. The PFKFB3-positive ratio of pancreatic beta cells and alpha cells between T2D and ND were compared. Next, the relationships between PFKFB3-postive beta cell ratio, patient background factors and pathological features of the islets were explored. Results: In total, 36 cases (18 cases each for T2D and ND) were enrolled and 50-100 islets/case were evaluated. Mean age was 70.6 ± 7.7 vs. 64.3 ± 12.8 years and body mass index (BMI) 22.4 ± 4.2 vs. 23.3 ± 4.5 kg/m2, respectively. T2D duration was 9.8 ± 9.9 years. The PFKFB3-positive beta cell ratio was significantly higher in T2D (29.7 ± 18.6% vs. 11.1 ± 8.7%, p Conclusion: Our results indicate that intracellular metabolic remodeling mediated by upregulation of PFKFB3 occurs in pancreatic beta cells of Japanese patients with T2D. Low BMI and amyloid deposition may affect PFKFB3 expression in beta cells from patients with T2D. Disclosure R.Izumihara: None. H.Nomoto: None. K.Chiba: Research Support; Grant for Young Researcher from Japan Association for Diabetes Education and Care, Japan Diabetes Society Junior Scientist Development Grant, Japan Society for the Promotion of Science , MSD Life Science Foundation, Promotion for Young Research Talent and Network, The Akiyama Life Science Foundation, The Uehara Memorial Foundation. H.Kameda: None. K.Cho: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. H.Mizukami: None. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. Funding JSPS KAKENHI Grant Number JP20281167.Japan Diabetes Society Junior Scientist Development Grant.MSD Life Science Foundation, Public Interest Incorporated Foundation.
Published: 2022
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45. 1424-P: Impact of Laparoscopic Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease in Obese Patients with Type 2 Diabetes: Prospective Observational Study

Author: YUKI OE, TAKAHIRO TAKASE, KYUYONG CHO, KOJI OGAWA, YUMA EBIHARA, AIKA MIYA, HIROSHI NOMOTO, HIRAKU KAMEDA, AKINOBU NAKAMURA, TATSUYA ATSUMI, and HIDEAKI MIYOSHI
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: Background: Bariatric/metabolic surgery is a valid treatment option for patients with obesity, type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD) . Although magnetic resonance imaging (MRI) is more accurate, the evaluation of NAFLD is generally limited to ultrasonography and various scoring systems. Here, we show a therapeutic effect of laparoscopic sleeve gastrectomy (LSG) on NAFLD in Japanese patients with T2DM using MRI. Methods: We conducted a prospective observational study of Japanese patients with obesity, T2DM, and NAFLD over 1 year (UMIN000034667) . The participants were 20 surgically (LSG group) and 20 medically (control group) treated patients. We compared various parameters at baseline and 1 year later in the two groups. The primary outcome was the change in the MRI proton density fat fraction and elasticity of the liver. The secondary outcomes were changes in metabolic parameters, including body mass index (BMI) , HbA1c, and diabetic remission rate. Results: To date, 28 patients (LSG 15, control 13) have completed the study. Their baseline BMIs were LSG 39.5 [35.5, 45.1] kg/m2 and control 35.9 [32.6, 43.6] kg/m2 (P=0.12) . One year after surgery, the index of hepatic steatosis, MRI proton density fat fraction (LSG −13.3±8.4%, control −0.8±5.5%, P Conclusion: We have shown that LSG causes marked weight loss and diabetic remission in many patients. NAFLD was also markedly ameliorated, especially hepatic steatosis, although a longer study may be required to detect an improvement in fibrosis. Disclosure Y.Oe: None. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T.Takase: None. K.Cho: None. K.Ogawa: None. Y.Ebihara: None. A.Miya: None. H.Nomoto: None. H.Kameda: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd.
Published: 2022
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46. 686-P: Unstable Glucose Variability in Type 2 Diabetes Patients with Small Abdominal Visceral Fat Area and Impaired Endogenous Insulin Secretion

Author: AIKA MIYA, AKINOBU NAKAMURA, HIROSHI NOMOTO, HIRAKU KAMEDA, KYUYONG CHO, SO NAGAI, YOICHI M. ITO, HIDEAKI MIYOSHI, and TATSUYA ATSUMI
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: Background: Impaired endogenous insulin secretion was related to instability of glucose variability (GV) in patients with type 2 diabetes (T2DM) in our previous studies. However, some patients, including those with fasting serum C-peptide (CPR) ≤2 ng/mL, did not show this relationship. Given these findings, the present study aimed to identify other factors that affect GV in T2DM patients with impaired endogenous insulin secretion. Methods: Data were obtained from our prospective observational study, comprising 2Japanese outpatients with T2DM who underwent continuous glucose monitoring (CGM) , fasting blood sample collection, and a computed tomography scan of their abdominal visceral and subcutaneous fat. Fasting CPR was used as a marker of endogenous insulin secretion and the coefficient of variation (CV) for the CGM data was used as a measure of GV. Background characteristics related to unstable GV were identified by multivariate logistic regression analysis after we extracted the data for patients with T2DM and CPR ≤2 ng/mL. All tests were two-sided. P Results: In the total cohort, mean age was 67.0 (IQR 58.0, 74.8) years, mean HbA1c 7.1% (IQR 6.6%, 7.7%) , and mean body mass index (BMI) 25.0 (IQR 23.0, 28.4) kg/m2. In patients with low CPR (≤2 ng/mL; n=119) , small visceral fat area (VFA) was an independent risk factor for CV above the median CV (OR 0.98, 95% CI 0.97-0.99, P=0.0443) , while subcutaneous fat area (SFA) and BMI were equally distributed. In patients with high CPR (>2 ng/mL; n=85) , VFA, SFA, and BMI were equally distributed between patients with CV above or below the median CV. Conclusions: GV is unstable in T2DM patients with impaired endogenous insulin secretion, particularly in patients with small VFA. The present findings suggest that visceral fat is related to the stability of GV. Disclosure A.Miya: None. A.Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H.Nomoto: None. H.Kameda: None. K.Cho: None. S.Nagai: Other Relationship; Eli Lilly and Company. Y.M.Ito: None. H.Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Speaker’s Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T.Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Speaker’s Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.
Published: 2022
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47. Use of magnetic resonance venography for inferior petrosal sinus sampling

Author: Taku Sugiyama, Toshiya Osanai, Yukitomo Ishi, Kikutaro Tokairin, Kinya Ishizaka, Hiraku Kameda, Noriyuki Fujima, Ken Kazumata, Naoki Nakayama, and Hiroaki Motegi
Subjects: medicine.medical_specialty, Magnetic Resonance Spectroscopy, magnetic resonance venography, venography, Venography, Petrosal Sinus Sampling, urologic and male genital diseases, 030218 nuclear medicine & medical imaging, magnetic resonance, 03 medical and health sciences, 0302 clinical medicine, Adrenocorticotropic Hormone, Magnetic resonance venography, medicine, Humans, Sampling (medicine), Retrospective Studies, medicine.diagnostic_test, business.industry, Inferior petrosal sinus, Magnetic resonance imaging, Phlebography, inferior petrosal sinus sampling, Inferior petrosal sinus sampling, Nephrology, Surgery, Radiology, business, 030217 neurology & neurosurgery
Abstract: Background: Inferior petrosal sinus (IPS) sampling (IPSS) is a transvenous interventional procedure performed to diagnose Cushing’s disease. The reported IPSS failure rate is approximately 10% because IPS catheter delivery is conducted blindly and is challenging because of IPS anatomical variations. This study aimed to evaluate the usefulness of preprocedural magnetic resonance venography (MRV) for assessing IPS access routes before IPSS. Methods: Nineteen consecutive patients who underwent IPSS at a single university hospital in Japan were retrospectively studied. A preprocedural MRV protocol optimized to visualize the IPS before IPSS was established and utilized in the eight most recent cases. An IPSS procedure was considered successful when bilateral IPS catheterization was accomplished. Patient demographics, IPSS success rate, and radiation dose required during IPSS were compared between two groups: MRV group ( N = 8) and no-MRV group ( N = 11) before IPSS. Results: There were no significant differences in age, sex, and IPSS success rates between the groups. The average radiation dose was 663.6 ± 246.8 (SD) mGy and 981.7 ± 389.5 (SD) mGy in the MRV group and no-MRV group, respectively. Thus, there was a significant reduction in radiation exposure in the MRV group ( p = 0.044). Catheterization of the left IPS was unsuccessful in only one patient in the MRV group owing to IPS hypoplasty, as found on the MRV. Conclusions: Hypoplastic IPSs occur in patients and can complicate IPSS. Preprocedural MRV assessment is useful for understanding venous anatomy and preventing unnecessary intravenous catheter manipulation during IPSS, which involves blind manipulation around the IPS.
Published: 2021
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48. Successful management of a patient with active Cushing‍’‍s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia

Author: Sho Nakakubo, Hideaki Miyoshi, Hirokazu Sugino, Naoko Inoshita, Yoshiyuki Kenmotsu, Tatsuya Atsumi, Kyu Yong Cho, Masaru Suzuki, Junichi Nakamura, Hiroshi Nomoto, Yu Yamashita, Yutaka Sawamura, Akiko Yuno, Akinobu Nakamura, Yuka Takahashi, Satoshi Konno, Hiraku Kameda, Akira Shimatsu, and Keisuke Kamada
Subjects: Adenoma, Adult, Pediatrics, medicine.medical_specialty, Health Personnel, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Disease, Guanidines, Neurosurgical Procedures, Block and replace regimen, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Japan, Pregnenediones, Trimethoprim, Sulfamethoxazole Drug Combination, medicine, Humans, Combined Modality Therapy, Medical management, Pituitary ACTH Hypersecretion, Hydrocortisone, Coronavirus disease 2019, Heparin, SARS-CoV-2, business.industry, COVID-19, Dihydrotestosterone, Cushing's disease, Metyrapone, Cushing’s disease, medicine.disease, Amides, Benzamidines, Regimen, Pneumonia, ACTH-Secreting Pituitary Adenoma, Treatment Outcome, Basal (medicine), Pyrazines, 030220 oncology & carcinogenesis, Disease Progression, Female, business, medicine.drug
Abstract: We provide the details of the successful management of a patient with active Cushing’s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing’s disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient’s dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the ‘block and replace’ regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient’s basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing’s disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.
Published: 2021

49. Sodium–glucose cotransporter 2 inhibitors reduce day‐to‐day glucose variability in patients with type 1 diabetes

Author: Hiroshi Nomoto, Kumiko Yamashita, Koki Chiba, Aika Miya, Shin Aoki, Hiraku Kameda, Hideaki Miyoshi, Yui Shibayama, Kyu Yong Cho, Tatsuya Atsumi, Akinobu Nakamura, and Yoshio Kurihara
Subjects: Blood Glucose, Male, Sodium–glucose cotransporter 2 inhibitor, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Hypoglycemia, Gastroenterology, Sodium-glucose cotransporter 2 inhibitor, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Type 1 diabetes, 030212 general & internal medicine, Sodium-Glucose Transporter 2 Inhibitors, Retrospective Studies, Glycated Hemoglobin, business.industry, SGLT2 inhibitor, General Medicine, Articles, Glucose variability, Middle Aged, medicine.disease, Prognosis, RC648-665, Ketoacidosis, Diabetes Mellitus, Type 1, Clinical Science and Care, chemistry, Sodium/Glucose Cotransporter 2, Ketone bodies, Female, Original Article, Glycated hemoglobin, SGLT2 Inhibitor, business, Biomarkers, Follow-Up Studies
Abstract: Aims/Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes. Materials and Methods Patients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day‐to‐day glucose variability, as the primary end‐point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring. Results A total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6–38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P, The purpose of this study was to determine the efficacy and safety of sodium–glucose cotransporter 2 inhibitors in patients with type 1 diabetes. The changes in day‐to‐day glucose variability, as the primary end‐point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring. Sodium–glucose cotransporter 2 inhibitors improved day‐to‐day glucose variability and time in the target glucose range, without increasing frequency of hypoglycemia, in patients with type 1 diabetes, and reduced glycated hemoglobin, body mass and the required insulin dose.
Published: 2021

50. Effects of Switching from Liraglutide or Dulaglutide to Subcutaneous Semaglutide on Glucose Metabolism and Treatment Satisfaction in Patients with Type 2 Diabetes: Protocol for a Multicenter, Prospective, Randomized, Open-Label, Blinded-Endpoint, Parallel-Group Comparison Study (The SWITCH-SEMA 1 Study)

Author: Tatsuya Atsumi, Chiho Oba-Yamamoto, Shin Aoki, Shinji Taneda, Hiraku Kameda, Hideaki Miyoshi, Hiroshi Nomoto, Kyu Yong Cho, Yoshio Kurihara, Jun Takeuchi, Hiroki Yokoyama, Akinobu Nakamura, So Nagai, and Yuka Takahashi
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Study Protocol, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Type 2 diabetes mellitus, Internal Medicine, Clinical endpoint, Medicine, Glucagon-like peptide 1 receptor, Glycemic, Treatment satisfaction, business.industry, Liraglutide, Semaglutide, Clinical trial, chemistry, Glucagon-like peptide-1 receptor agonist, Dulaglutide, Glycated hemoglobin, business, medicine.drug
Abstract: Introduction Glucagon-like peptide (GLP)-1 receptor agonists exert potent hypoglycemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent manner. Once-weekly subcutaneous administration of the GLP-1 receptor agonist semaglutide has beneficial effects on glycemic and body weight control, but it is currently unclear if semaglutide provides superior glycemic control compared to conventional GLP-1 receptor agonists in the Japanese population. We aim to compare the effects of once-weekly subcutaneous semaglutide with those of liraglutide or dulaglutide administration in Japanese patients with T2D. Methods This study is a multicenter, prospective, randomized, open-label, blinded-endpoint, parallel-group trial. In total, 100 participants with T2D who have been treated with liraglutide (0.9–1.8 mg/day in plan A) or dulaglutide (0.75 mg/week in plan B) for more than 12 weeks and have a glycated hemoglobin (HbA1c) level of 6.0–9.9% and a body mass index (BMI) of ≥ 22 kg/m2 will be randomized to either continue using their existing GLP-1 receptor agonist or switch to subcutaneous semaglutide once weekly for 24 weeks. Biochemical analysis, physical assessment, and a quality-of-life questionnaire (DTSQ) will be completed at baseline and at the end of the study. The primary endpoint is the effect of semaglutide on the change in HbA1c. The secondary endpoints are the mean changes in total DTSQ score, body mass, abdominal circumference, systolic and diastolic blood pressure, pulse rate, factors associated with improvement in HbA1c and secondary endpoints, side effects, and other laboratory parameters. Planned Outcomes The results of the study will provide useful information regarding the effects of switching to semaglutide from other GLP-1 receptor agonists on glycemic control in patients with T2D. Ethics and Dissemination The Hokkaido University Certified Review Board (CRB no. 1180001) has approved the protocol (no. 018-005). The results will be disseminated in peer-reviewed journals and at scientific conferences. Trial Registration UMIN000042369 in the University Hospital Medical Information Network (UMIN); jRCT1011200008 in the Japan Registry of Clinical Trials (jRCT); pre-results.
Published: 2021
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