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Aims: To investigate interstitial lung disease (ILD) in men with prostate cancer receiving hormone therapy. Methods: We gathered cases diagnosed with prostate cancer based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2004 to 2020. We divided the included cases into 3 groups based on the primary suspected drugs: a hormone therapy group, a positive control group (taxanes), and a negative control group. We employed reporting odds ratio, a disproportionality method, to detect the association between ILD events and target drugs. Results: We finally included a total of 85 403 cases, 69 894 cases (628 ILD event cases) in the hormone therapy group, 2302 cases (158 ILD event cases) in the positive control group and 13 207 cases (72 ILD event cases) in the negative control group. There were 394 ILD event cases (62.74%) in the hormone therapy group in Japan; 78.68% of the ILD events occurred within the first year after hormone treatment. Disproportionality analysis indicated that ILD events were significantly associated with nilutamide, flutamide, bicalutamide, goserelin, degarelix and apalutamide; the reporting odds ratios (95% confidence interval) were 32.14 (11.03–93.63), 9.93 (3.62–27.21), 8.19 (6.01–11.16), 3.74 (2.61–5.37), 2.41 (1.55–3.75) and 1.94 (1.01–3.75), respectively. Conclusion: Based on this FAERS pharmacovigilance analysis, the association between ILD events and hormone therapy drugs, including bicalutamide, flutamide, nilutamide, goserelin, degarelix and apalutamide, should not be ignored, especially in the Japanese population. Lung function of prostate cancer patients should be monitored when receiving the hormone therapy drugs mentioned above, especially for the first year post medication. [ABSTRACT FROM AUTHOR]

The present study investigated the associations of serum gamma-glutamyl transferase (GGT), a marker of fatty liver and oxidative stress, and ALT/AST, a marker of fatty liver, with percentage trunk fat and postload glucose, insulin resistance, and β-cell function in middle-aged Japanese individuals, whose BMI averaged < 23.0 kg/m 2 . Pancreatic β-cell function was assessed using the disposition index calculated by a product of the insulinogenic index (IGI) and Matsuda insulin sensitivity index, a biomarker of early-phase glucose-stimulated insulin secretion and whole-body insulin sensitivity, respectively. Multivariate linear regression analyses revealed that the disposition index was associated inversely with GGT independently of percentage trunk fat, homeostasis model assessment insulin resistance (HOMA-IR), a marker of insulin resistance, and Matsuda index. When IGI was included instead of the disposition index, IGI (inversely) and HOMA-IR were associated with GGT independently of percentage trunk fat and Matsuda index. When the area under the glucose concentration curve (AUCg) during an oral glucose tolerance test was included instead of the disposition index, AUCg and HOMA-IR emerged as independent determinants of GGT. ALT/AST was associated with HOMA-IR alone. Results suggest a different pathophysiologic basis between GGT and ALT/AST in predicting diabetic risk in non-obese Japanese., (© 2024. The Author(s).)

The relationship of adipose tissue insulin resistance (AT-IR, a product of fasting insulin and free fatty acids) and homeostasis-model assessment-insulin resistance (HOMA-IR) to β-cell function was studied cross-sectionally in the setting of subtle glucose dysregulation. Associations of AT-IR and HOMA-IR with fasting and post-glucose glycemia and β-cell function inferred from serum insulin kinetics during a 75 g oral glucose tolerance test were studied in 168 young female Japanese students. β-cell function was evaluated by disposition index calculated as a product of the insulinogenic index (IGI) and Matsuda index. AT-IR, not HOMA-IR, showed positive associations with post-glucose glycemia and area under the glucose response curve although both indices were associated with fasting glycemia. HOMA-IR, not AT-IR, was associated positively with log IGI whereas both indices were inversely associated with Matsuda index. AT-IR, not HOMA-IR, showed inverse associations with log disposition index. Associations of adipose tissue insulin resistance with β-cell function (inverse) and glucose excursion in young Japanese women may suggest that lipotoxicity to pancreatic β-cells for decades may be associated with β cell dysfunction found in Japanese patients with type 2 diabetes. Positive association of HOMA-IR with insulinogenic index may be associated with compensatory increased insulin secretion., (© 2024. The Author(s).)

Associations of adipose tissue insulin resistance index (AT-IR, a product of fasting insulin and free fatty acids) with body fat mass and distribution and appendicular skeletal muscle mass (ASM) were compared with results of homeostasis-model assessment-insulin resistance (HOMA-IR) in 284 Japanese female university students and 148 their biological mothers whose BMI averaged < 23 kg/m 2 . Although mothers compared with daughters had higher BMI, body fat percentage, trunk fat to body fat (TF/BF) ratio and lower leg fat to body fat (LF/BF), AT-IR and HOMA-IR did not differ. We had multivariable linear regression analyses which included TF/BF ratio, LF/BF ratio, weight-adjusted ASM (%ASM), height-adjusted ASM index (ASMI), fat mass index (FMI), and body fat percentage. In young women, AT-IR was independently associated with LF/BF ratio (Standardized β [Sβ]: - 0.139, p = 0.019) and ASMI (Sβ: - 0.167, p = 0.005). In middle-aged women, LF/BF ratio (Sβ: - 0.177, p = 0.049) and %ASM (Sβ: - 0.205, p = 0.02) emerged as independent determinants of AT-IR. HOMA-IR was associated with TF/BF ratio and FMI, a proxy of abdominal and general adiposity, respectively, in both young and middle-aged women. The inverse association of AT-IR with leg fat may support the notion that limited peripheral adipose storage capacity and small skeletal muscle size are important etiological components in insulin-resistant cardiometabolic disease in Japanese women., (© 2024. The Author(s).)

Objective: We assessed whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatic steatosis, may be associated with adipose tissue dysfunction more closely than hepatic and muscle insulin resistance (IR). Methods: Associations with adipose tissue IR index (AT-IR) calculated as a product of fasting insulin and free fatty acids, leptin/adiponectin ratio, a proxy of adipocyte dysfunction, homeostasis model assessment IR (HOMA-IR), hepatic and muscle IR inferred from plasma insulin kinetics during a 75 grams oral glucose tolerance test (OGTT) were studied in nondiabetic 307 young and 148 middle-aged Japanese women, whose body mass index averaged 20 and 22 kilograms/m 2 , respectively. Results: On multivariate linear regression analysis in young women, ALT/AST was associated with trunk/leg fat ratio (standardized β  = 0.202, P  = 0.007), a marker of abdominal fat accumulation, and AT-IR (standardized β  = 0.185, P  = 0.003) independently of HOMA-IR and Matsuda index ( R 2  = 0.07). In middle-aged women, leptin/adiponectin ratio (standardized β  = 0.446, P  < 0.001) and AT-IR (standardized β  = 0.292, P  = 0.009) emerged as determinants of ALT/AST independently of trunk/leg fat ratio, OGTT-derived hepatic IR, leptin, and adiponectin ( R 2  = 0.34). Conclusions: ALT/AST was associated with AT-IR and adipocyte dysfunction more closely than hepatic and muscle IR even in nondiabetic lean Japanese women.

Limited expandability of subcutaneous adipose tissue may be characteristics of first-degree relatives of type 2 diabetes. We tested the hypothesis that family history of type 2 diabetes (FHD) may be associated with reduced peripheral fat mass. Body composition and metabolic variables were compared between 18 and 111 Japanese female collegiate athletes, and between 55 and 148 nonathletes with positive (FHD +) and negative FHD (FHD-), respectively. We had multivariate logistic regression analyses for FHD + as dependent variable in a total population.BMI averaged < 21 kg/m 2 and did not differ between FHD + and FHD- nonathletes. Despite comparable BMI, body fat percentage and serum leptin were lower in FHD + nonathletes. This was due to lower arm and gluteofemoral fat percentage (both p = 0.02) whereas the difference in trunk fat percentage was not significant (p = 0.08). These differences were not found between two groups of athletes. FHD + women had lower HDL cholesterol despite lower BMI in a total population. Fasting insulin, serum adiponectin and high-sensitivity C-reactive protein did not differ between FHD + and FHD- athletes or nonathletes. Multivariate logistic regression analyses revealed independent associations of FHD + with BMI (odds ratio, 0.869; 95% confidential interval, 0.768-0.984; p = 0.02) and HDL cholesterol (odds ratio, 0.977; 95% confidential interval, 0.957-0.997, p = 0.02). In conclusion, FHD may be associated with reduced subcutaneous fat mass in young Japanese women, suggesting impaired adipose tissue expandability., (© 2022. The Author(s).)

Objective: We examined whether elevated blood pressure (BP) (≥120/80 mmHg) was associated with several anthropometric, metabolic, and clinical variables, including the family history of type 2 diabetes (FHD) and low birth weight, in young normal weight Japanese women. Methods: BP, body composition, and fasting glucose, insulin, lipids, lipoproteins, apolipoproteins, and adipokines were measured in 332 young Japanese women. They received a questionnaire on birth weight and FHD. Results: The prevalence of low birth weight was 2.4% and that of positive FHD was 22.9%. Homeostasis model assessment-insulin resistance averaged <1.5 and did not differ cross-sectionally between 32 women with elevated BP and 300 women with normal BP although mean body mass index was higher in the former than in the latter (21.7 ± 2.9 kg/m 2 vs. 20.8 ± 2.2 kg/m 2 , P  = 0.02). Women with elevated BP had higher fat mass index ( P  = 0.02) and trunk fat percentage ( P  = 0.04). They had lower high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 (both P  = 0.01) while fasting triglycerides and apolipoprotein B did not differ. In addition, they had higher plasminogen activator inhibitor-1 (PAI-1) ( P  = 0.001). Furthermore, the prevalence of low birth weight (9.4% vs. 1.7%, P  = 0.03) and positive FHD (40.6% vs. 20.0%, P  = 0.01) was higher in women with elevated BP. Multivariable logistic regression analyses revealed that elevated BP was independently associated with PAI-1 [odds ratio (OR); 1.05, 95% confidence interval (CI): 1.02-1.08, P  = 0.001], low birth weight (OR: 12.3, 95% CI: 2.3-67.3, P  = 0.04), and FHD (OR: 3.0, 95% CI: 1.3-7.9, P  = 0.01). Conclusion: Elevated BP was associated with positive FHD, low birth weight, and elevated serum PAI-1 in young normal weight Japanese women.

Introduction: Adipose tissue (AT) expandability may be facilitated by adiponectin and suppressed by orosomucoid, and reduced AT expandability may be associated with first-degree relatives of type 2 diabetes. We tested the hypothesis that orosomucoid may be associated not only with adiponectin and adipose tissue insulin resistance but also with a family history of type 2 diabetes (FHD). Research Design and Methods. Anthropometric and metabolic variables, adipokines, and measures of inflammatory and insulin resistance were cross-sectionally investigated in 153 young normal weight Japanese women. Stepwise multivariate linear regression analyses were used to identify the most important determinants of orosomucoid., Results: Orosomucoid was higher in women with positive ( n = 57) compared to women with negative FHD and was associated positively with FHD (both p = 0.01). Orosomucoid also showed positive associations with fasting glucose ( p < 0.001), free fatty acids ( p = 0.001), and HbA1c ( p = 0.007), whereas there was no association with fasting insulin and serum lipids. In addition, orosomucoid was associated inversely with adiponectin ( p = 0.02) and positively with adipose tissue-insulin resistance index (AT-IR, the product of fasting insulin and free fatty acids; p = 0.001) but not with homeostasis model assessment-insulin resistance, leptin, and high-sensitivity C-reactive protein. In multivariate analyses, AT-IR (standardized β , 0.22; p = 0.003), serum adiponectin (standardized β , -0.163; p = 0.032), FHD+ (standardized β , 0.178; p = 0.029), and HbA1c (standardized β , 0.213; p = 0.005) emerged as independent determinants of orosomucoid and explained 15.2% of its variability., Conclusions: These results are the first to demonstrate that orosomucoid is associated not only with adipose tissue-insulin resistance and adiponectin but also with FHD., Competing Interests: The authors declare that there is no duality of interest associated with this manuscript., (Copyright © 2022 Mari Honda et al.)

Introduction: We tested the hypothesis that family history of type 2 diabetes (FHD) is associated with reduced birth weight and reduced insulin secretion later in life., Materials and Methods: Birth weight, body composition by whole-body dual-energy X-ray absorptiometry, and homeostasis model assessment-insulin resistance were compared between Japanese women aged 20 years with positive ( n = 73) and negative ( n = 258) FHD. A subsample of 153 women (57 with positive FHD) underwent a 75 g oral glucose tolerance test. Multivariate logistic regression analyses were used to identify the most important determinants of FHD., Results: Women with positive as compared with negative FHD had lower birth weight (3132 ± 364 vs. 3238 ± 418 g, p = 0.04). However, the current fat mass index and trunk/leg fat ratio, sophisticated measures of general and abdominal fat accumulation, respectively, did not differ. Women with positive FHD had a lower insulinogenic index (2.4 ± 7.3 vs. 6.2 ± 16, p = 0.007) and higher area under the glucose curve (217 ± 47 vs. 198 ± 36 mg/dL/2 h, p = 0.006). However, fasting and postload insulinemia, homeostasis model assessment-insulin resistance, and Matsuda index did not differ. In multivariate logistic regression analysis, birth weight was marginally associated with FHD (odds ratio, 0.999; 95% confidential interval, 0.98-1.00000; p = 0.0509)., Conclusions: FHD was associated not only with reduced birth weight but also with decreased early-phase insulin secretion and increased postload glucose concentrations in Japanese women aged 20 years. These findings may be in keeping with the fetal insulin hypothesis and provide some evidence that FHD can alter size at birth, probably through genetic and shared environmental components, which consequently resulted in decreased early-phase insulin secretion and increased glucose excursion in the early twenties. FHD was not related to sophisticated measures of general and abdominal adiposity and insulin resistance/sensitivity., Competing Interests: The authors declare that there is no duality of interest associated with this manuscript., (Copyright © 2020 Mari Honda et al.)

Introduction: Circulating orosomucoid, an acute-phase protein, predicted type 2 diabetes mellitus risk in several Western countries. Here, we assessed serum orosomucoid (ORM) in relation to prediabetes in the Japanese., Research Design and Methods: Participants consisted of 83 middle-aged Japanese subjects with normal glucose tolerance (NGT), 37 with prediabetes and 4 with newly identified diabetes, whose homeostasis model assessment-insulin resistance (HOMA-IR) averaged 1.1±0.7, 1.4±0.9 and 1.7±0.8, respectively. Body composition, serum inflammatory markers, adiponectin, β-cell function and insulin resistance inferred from serum insulin kinetics during an oral glucose tolerance test were compared cross-sectionally between those with prediabetes and NGT., Results: Serum orosomucoid, but not high-sensitivity C reactive protein, was elevated in prediabetes (190±29 vs 141±31 mg/dL) with further elevation in diabetes (295±52 mg/dL) (all p<0.001). Prediabetes was associated with lower Oral Disposition Index (the product of the Insulinogenic Index and Matsuda Index) with further depression in diabetes. No association was found with skeletal muscle mass, HOMA-IR, serum triglyceride, high-density lipoprotein (HDL) cholesterol and adiponectin., Conclusions: Higher circulating ORM and reduced glucose induced insulin secretion were found in middle-aged Japanese people with prediabetes in the absence of insulin resistance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Determinants and correlates of a novel index of adipose tissue insulin resistance (AT-IR) (the product of fasting insulin and free fatty acid concentrations) were investigated in Japanese women without diabetes and obesity., Research Design and Methods: Cross-sectional associations of AT-IR with fat mass and distribution, and IR-related cardiometabolic variables were examined in 210 young and 148 middle-aged women whose average body mass index (BMI) was <23 kg/m 2 and waist was <80 cm. Multivariate linear regression analyses were used to identify most important determinants of AT-IR., Results: Young and middle-aged women did not differ in AT-IR (3.5±2.7 and 3.2±2.1, respectively). In both young and middle-aged women, AT-IR was positively associated with trunk/leg fat ratio, a sophisticated measure of abdominal fat accumulation, fasting plasma glucose (FPG), fasting triglycerides (FTG), serum alanine aminotransferase and γ-glutamyl-transpeptidase (all p<0.05). Furthermore, in middle-aged but not in young women, AT-IR showed positive associations with BMI, waist, fat mass index, low-density lipoprotein cholesterol, apolipoprotein B and systolic and diastolic blood pressure (BP) (all p<0.05). AT-IR showed no association with hemoglobin A1c, high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 in two groups of women. On multivariate analysis including waist, FPG, FTG, HDL cholesterol and systolic BP as independent variables, FPG, FTG and HDL cholesterol emerged as independent determinants of AT-IR in young women (cumulative R 2 =0.141) and waist in middle-aged women (cumulative R 2 =0.056). In a model which included trunk/leg fat ratio instead of waist, trunk/leg fat ratio and systolic BP were determinants of AT-IR in middle-aged women (cumulative R 2 =0.093). Results did not alter in young women., Conclusions: AT-IR may be a simple and useful surrogate index of adipose tissue insulin resistance even in populations without diabetes and obesity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To assess vascular function and characterize insulin secretion using a physiological approach in Japanese women with family history of type 2 diabetes (FHD)., Research Design and Methods: Standardized mixed-meal tests were performed with multiple postprandial glucose, insulin and free fatty acids (FFA) measurements over a 30-120 min period in 31 Japanese women aged 21-24 years. Arterial distensibility was assessed as well., Results: Fasting glucose, triglyceride and insulin averaged <90 mg/dL, <60 mg/dL and <5 μU/mL, respectively, and did not differ cross-sectionally between 10 with (FHD+) and 21 without FHD (FHD-). FHD+ showed higher insulin responses not only during the first 30 min (p=0.005) but also during the second hour (60-120 min, p<0,05) in spite of identical postprandial suppression of FFA and identical fasting and postprandial glucose and FFA concentrations, except for higher 60 min FFA in FHD+. Further, FHD+ had decreased arterial distensibility (p=0.003). On multivariate regression analysis, arterial distensibility emerged as the only significant independent predictor of FHD+. Endurance training in FHD+ did not alter decreased arterial distensibility whereas it abolished postprandial hyperinsulinemia., Conclusions: FHD was associated with decreased arterial distensibility and postprandial hyperinsulinemia despite nearly identical postprandial glycemia and postprandial FFA suppression, suggesting that impaired vascular insulin sensitivity may precede glucose and lipid dysmetabolism in normal weight Japanese women aged 22 years., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine whether serum adiponectin and orosomucoid were associated with postload glucose ≤70 mg/dL during an oral glucose tolerance test (OGTT), termed as postload low glycemia, a possible inverse marker for dysglycemia., Research Design and Methods: 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period in 168 normal-weight Japanese women (18-24 years). Insulin resistance (IR) and β-cell function inferred from serum insulin kinetics during OGTT, fat mass and distribution by dual-energy X-ray absorptiometry (DXA), serum adiponectin and inflammatory markers were compared cross-sectionally between 39 women with and 129 women without postload low glycemia., Results: Of 168 women, 161 had normal glucose tolerance. Women with as compared with those without postload low glycemia had lower fasting and postload glycemia despite similar fasting and postload insulinemia. They had higher insulinogenic index (p=0.03) and lower adipose IR (a product of fasting free fatty acid and insulin, p=0.01), although DXA-derived general and central adiposity, the Matsuda Index and homeostasis model assessment-IR did not differ. In addition, they had higher adiponectin and lower orosomucoid (both p<0.001). Multivariate logistic regression analyses revealed that adiponectin (OR: 1.14, 95% CI 1.03 to 1.26, p=0.009) and orosomucoid (0.96, 0.93 to 0.97, p=0.008) were associated with postload low glycemia independently of adipose IR and insulinogenic index., Conclusions: Higher adiponectin and lower orosomucoid were associated with 70 or lower mg/dL of postload glucose, a possible inverse marker for dysglycemia, in young women independently of DXA-derived fat mass and distribution, insulin secretion and IR., Competing Interests: Competing interests: None declared.

Aim: Although the mean body mass index (BMI) of Japanese patients with type 2 diabetes was within the normal range, we have previously shown that approximately half of all patients classified as normal weight had been formerly obese. The present study examined the clinical features of Japanese type 2 diabetic patients who are currently of normal weight but had formerly been obese (NWFO)., Methods: Body weight history with selfreported body weight was obtainable for 108 of 114 type 2 diabetic outpatients who had been regularly attending our department. Common carotid artery intimamedia thickness (IMT) was also measured., Results: At the time of the examinations, 5 (5%) and 36 (33%) of 108 type 2 diabetic patients were lean (BMI <18.5 kg/m(2)) and obese (BMI ≥25 kg/m(2)), respectively, whereas normal weight (BMI ≥18.5-<25 kg/m(2)) was found in 67 (62%) patients. Among 108 patients, 67 (62%) were normal weight, of which 32 (48%) were formerly obese (NWFO). NWFO patients with a mean age of 65 years old at the clinic visit had reached their lifetime maximum body weight at age 45 and became diabetic at age 51 years. Obese patients aged 62 years at the clinic visit became diabetic at age 50 and had reached their maximum weight at age 51 years. Diabetes duration was 11 years in patients who had never been obese. Thus, NWFO patients had been exposed to obesity-related metabolic abnormalities and/or hyperglycemia for 20 years on average whereas obese and never obese patients had been exposed for 11-12 years. Although obese patients had higher fasting TG and greater BMI than NWFO, both obese and NWFO patients had similarly lower HDL cholesterol levels than those who had never been obese; however, there was no difference among the 3 groups in diabetic treatment, diabetes duration, HbA1c levels, and prevalence of atherosclerotic risk factors, including smokers, users of statins and antihypertensive drugs. Carotid max IMT was thicker in NWFO type 2 diabetic patients (0.86±0.04 mm) than either obese patients (0.78±0.03 mm, p=0.041) or those who had never been obese (0.78±0.02 mm, p=0.046)., Conclusion: This report confirms that approximately half of 108 Japanese type 2 diabetic patients who are currently normal weight were formerly obese and shows that these patients had a thicker carotid IMT than either obese patients or those who had never been obese. Formerly obese diabetic patients who have lost weight and are currently normal weight might have been exposed to long-term obesity-related cardiometabolic abnormalities and/or hyperglycemia, resulting in increased common carotid IMT. We therefore suggest that an improved clinical screening tool would include the assessment of body weight history for all Japanese type 2 diabetic patients at their first clinic visit.

The aim of this study was to examine the characteristics of gastroesophageal reflux disease in Japan. We evaluated the correlation between clinical symptoms and endoscopic findings in an age- and sex-specific manner. This study included 6010 Japanese subjects who had not received medication or undergone laparotomy for gastrointestinal disease. All subjects were questioned in regard to clinical symptoms by paramedical personnel before endoscopic examination. Esophageal mucosal breaks were evaluated according to the Los Angeles Classification of Esophagitis. The ratio of subjects with each complaint to all subjects is as follows: heartburn, 27.0%; dysphagia, 16.9%; odynophagia, 19.2%; acid regurgitation, 7.1%. The proportion of each grade was grade A, 9.6%; grade B, 4.6%; and grade C + D, 2.0%. The most common related symptom for endoscopic esophagitis among these four symptoms was heartburn (odds ration, 2.5), although about 40% of subjects with severe esophagitis of grade C or D did not complain of heartburn. Regarding odynophagia, acid regurgitation, and dysphagia, odds ratios were about 1.0. The age-related ratio of esophagitis and severe disease with grades C and D increased in women over 60 years of age. An age-related slouched position was related to the increased esophagitis in these elderly women. Male subjects whose body mass index was more than 25 tended to show a greater prevalence in the age group 30-50 years. The prevalence of hiatal herniation increased in an age-related manner. These data indicate the characteristics of esophagitis in Japan are as follows: (1) the prevalence of reflux esophagitis is about 15% and most of these cases are grade A or B; and (2) the prevalence of severe esophagitis increases in older women, who do not always complain of clinical symptoms.